The effects of sertraline administration from adolescence to adulthood on physiological and emotional development in prenatally stressed rats of both sexes

Sertraline (SERT) is a clinically effective Selective Serotonin Reuptake Inhibitor (SSRI) known to increase and stabilize serotonin levels. This neurotransmitter plays an important role in adolescent brain development in both rodents and humans, and its dysregulation has been correlated with deficits in behavior and emotional regulation. Since prenatal stress may disturb serotoninergic homeostasis, the aim of this study was to examine the long-lasting effects of exposure to SERT throughout adolescence on behavioral and physiological developmental parameters in prenatally stressed Wistar rats. SERT was administered (5 mg/kg/day p.o.) from the age of 1–3 months to half of the progeny, of both sexes, of gestating dams stressed by use of a restraint (PS) or not stressed. Our data reveal that long-term SERT treatment slightly reduced weight gain in both sexes, but reversed the developmental disturbed “catch-up” growth found in PS females. Neither prenatal stress nor SERT treatment induced remarkable alterations in behavior and had no effects on mean startle reflex values. However, a sex-dependent effects of PS was found: in males the PS paradigm slightly increased anxiety-like behavior in the open field, while in females, it impaired startle habituation. In both cases, SERT treatment reversed the phenomena. Additionally, the PS animals exhibited a disturbed leukocyte profile in both sexes, which was reversed by SERT. The present findings are evidence that continuous SERT administration from adolescence through adulthood is safe in rodents and lessens the impact of prenatal stress in rats.

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title: Chronic administration of sertraline, a selective serotonin uptake inhibitor, decreased the density of β-adrenergic receptors in rat frontoparietal cortex
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title: Sertraline: a new antidepressant.
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title: Sertraline treatment of children and adolescents with obsessive-compulsive disorder or depression: pharmacokinetics, tolerability, and efficacy.
abstract: To evaluate the pharmacokinetics, safety, and efficacy of sertraline in children (6 to 12 years old) and adolescents (13 to 17 years old).



Children (n = 29) and adolescents (n = 32) with major depression, obsessive-compulsive disorder (OCD), or both received a single dose of 50 mg of sertraline followed, 1 week later, by 35 days of sertraline treatment as follows: (1) either a starting dose of 25 mg/day titrated to 200 mg/day in 25-mg increments or (2) a starting dose of 50 mg/day titrated to 200 mg/day in 50-mg increments. Sertraline and desmethylsertraline pharmacokinetics were determined approximately weekly, and efficacy measures were assessed before drug administration and at the end of treatment.



Mean area under the plasma concentration-time curve (AUC), peak plasma concentration (Cmax), and elimination half-life (t1/2) for sertraline and desmethylsertraline were similar to previously reported adult values. No titration-dependent pharmacokinetic or safety differences were seen. While Cmax and AUC0-24 were greater for children versus adolescents, these differences disappeared after parameters were normalized for body weight. Sertraline was well tolerated in both children and adolescents, with adverse experiences similar to those previously reported by adult patients. Efficacy measurements indicated improvement (p < .001) in depression and OCD symptomatology.



Sertraline can be safely administered to pediatric patients using the currently recommended adult titration schedule.

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title: Long-term sertraline treatment of children and adolescents with obsessive-compulsive disorder.
abstract: To evaluate the safety and effectiveness of sertraline in the long-term treatment of pediatric obsessive-compulsive disorder (OCD).



Children (6-12 years; n= 72) and adolescents (13-18 years; n = 65) with DSM-III-R-defined OCD who had completed a 12-week, double-blind, placebo-controlled sertraline study were given open-label sertraline 50 to 200 mg/day in this 52-week extension study. Concomitant psychotherapy was allowed during the extension study Outcome was evaluated by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), National Institute of Mental Health Global Obsessive-Compulsive Scale, and Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I) scores.



Significant improvement (p < .0001) was demonstrated on all four outcome parameters on an intent-to-treat analysis for the overall study population (n = 132), as well as the child and the adolescent samples. At endpoint, 72% of children and 61% of adolescents met response criteria (>25% decrease in CY-BOCS and a CGI-I score of 1 or 2). Significant (p < .05) improvements were also demonstrated from the extension study baseline to endpoint on all outcome parameters in those patients who received sertraline during the 12-week, double-blind acute study. Long-term sertraline treatment was well tolerated, and there were no discontinuations due to changes in vital signs, laboratory values, or electrocardiograms.



Sertraline (50-200 mg/day) was effective and generally well tolerated in the treatment of childhood and adolescent OCD for up to 52 weeks. Improvement was seen with continued treatment.

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title: Early deprivation leads to long-term reductions in motivation for reward and 5-HT1A binding and both effects are reversed by fluoxetine
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title: Prenatal stress in rats predicts immobility behavior in the forced swim test Effects of a chronic treatment with tianeptine
abstract: Prenatally-stressed (PS) rats are characterized by a general impairment of the hypothalamo-pituitary-adrenal (HPA) axis and sleep disturbances indicating that this model has face validity with some clinical features observed in a subpopulation of depressed patients. The prolonged corticosterone secretion shown by PS rats in response to stress was positively correlated with an increased immobility behavior in the forced swim test. To investigate the predictive validity of this model, a separate group of animals was chronically treated with the antidepressant tianeptine (10 mg/kg i.p. for 21 days). Such chronic treatment reduced in PS rats immobility time in the forced swim test. These findings suggest that the PS rat is an interesting animal model for the evaluation of antidepressant treatment.

title: Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?
abstract: The hypothesis explored in this review is that the high levels of serotonin in the blood seen in some autistic children (the so‐called hyperserotonemia of autism) may lead to some of the behavioral and cellular changes also observed in the disorder. At early stages of development, when the blood–brain Barrier is not yet fully formed, the high levels of serotonin in the blood can enter the brain of a developing fetus and cause loss of serotonin terminals through a known negative feedback function of serotonin during development. The loss of serotonin innervation persists throughout subsequent development and the symptoms of autism appear. A review of the basic scientific literature on prenatal treatments affecting serotonin is given, in support of this hypothesis, with an emphasis on studies using the serotonin agonist, 5‐methoxytryptamine (5‐MT).

title: Inhibition of Serotonin But Not Norepinephrine Transport during Development Produces Delayed, Persistent Perturbations of Emotional Behaviors in Mice
abstract: Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whether in utero exposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life.

title: Prenatal stress: Effect on development of rat brain serotonergic neurons
abstract: Maternal low-level stress was found to produce persistent changes in serotonin (5-HT) receptor binding in several brain regions of the offspring. [3H]5-HT binding was increased in cerebral cortex, decreased in hippocampus and unchanged in pons medulla while [3H]spiperone binding was increased in all three regions at 60 days of age. The binding changes appeared to be due to altered numbers of binding sites with no change in dissociation constants. Regional differences were also found when the ability of nerve terminals to synthesize [14C]5-HT from L-[14C]tryptophan was studied. Prenatal stress reduced the rate of [14C]5-HT synthesis in hippocampus but not in cortex or pons medulla. When younger offspring were studied, binding of [3H]5-HT to cerebrocortical membranes was found to be reduced at 16 days of age and increased at 40 days while [3H]spiperone showed only an increased binding at 40 days. In contrast, prenatal stress resulted in increased nighttime locomotor activity whether measured at 23, 40 or 60 days of age. The present study provides additional evidence that prenatal stress affects the development of serotonergic neurons and it is possible that such changes may underlie the reported behavioural deficits in offspring of stressed female rats.

title: Maternal stress induces synaptic loss and developmental disabilities of offspring
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title: Prenatal stress induces long term stress vulnerability, compromising stress response systems in the brain and impairing extinction of conditioned fear after adult stress
abstract: Stress is a risk factor for the development of affective disorders, including depression, post-traumatic stress disorder, and other anxiety disorders. However, not all individuals who experience either chronic stress or traumatic acute stress develop such disorders. Thus, other factors must confer a vulnerability to stress, and exposure to early-life stress may be one such factor. In this study we examined prenatal stress (PNS) as a potential vulnerability factor that may produce stable changes in central stress response systems and susceptibility to develop fear- and anxiety-like behaviors after adult stress exposure. Pregnant Sprague-Dawley rats were immobilized for 1 h daily during the last week of pregnancy. Controls were unstressed. The male offspring were then studied as adults. As adults, PNS or control rats were first tested for shock-probe defensive burying behavior, then half from each group were exposed to a combined chronic plus acute prolonged stress (CAPS) treatment, consisting of chronic intermittent cold stress (4 °C, 6 h/d, 14 days) followed on day 15 by a single session of sequential acute stressors (social defeat, immobilization, cold swim). After CAPS or control treatment, different groups were tested for open field exploration, social interaction, or cued fear conditioning and extinction. Rats were sacrificed at least 5 days after behavioral testing for measurement of tyrosine hydroxylase (TH) and glucocorticoid receptor (GR) expression in specific brain regions, and plasma adrenocorticotropic hormone (ACTH) and corticosterone. Shock-probe burying, open field exploration and social interaction were unaffected by any treatment. However, PNS elevated basal corticosterone, decreased GR protein levels in hippocampus and prefrontal cortex, and decreased TH mRNA expression in noradrenergic neurons in the dorsal pons. Further, rats exposed to PNS plus CAPS showed attenuated extinction of cue-conditioned fear. These results suggest that PNS induces vulnerability to subsequent adult stress, resulting in an enhanced fear-like behavioral profile, and dysregulation of brain noradrenergic and hypothalamic-pituitary-adrenal axis (HPA) activity.

title: Preclinical pharmacology of sertraline: a potent and specific inhibitor of serotonin reuptake.
abstract: Specific serotonin reuptake inhibitors constitute a new class of psychotherapeutic agents that promote enhanced central serotonergic neurotransmission in animal studies. Sertraline, a member of this class, exhibits considerable potency and specificity in inhibiting serotonin neuronal reuptake in preclinical studies. Thus, it is likely to exert antidepressant activity without significant anticholinergic, cardiovascular, and sedative side effects. Other animal studies demonstrating decreases in food intake and body weight and reduction in voluntary alcohol consumption after sertraline administration suggest a potential for wider clinical application.

title: Serotonin, the periaqueductal gray and panic
abstract: This article reviews experimental evidence and theoretical constructs that implicate serotonin (5-HT) modulation of defensive behavior within the midbrain periaqueductal gray in panic disorder (PD). Evidence with conflict tests in experimental animals indicates that 5-HT enhances anxiety, whereas results with aversive stimulation of the dorsal periaqueductal gray point to an anxiolytic role of 5-HT. To solve this contradiction, it has been suggested that the emotional states determined by the two types of animal model are different. Conflict tests would generate conditioned anxiety, whereas periaqueductal gray stimulation would produce unconditioned fear, as evoked by proximal threat. Clinically, the former would be related to generalized anxiety while the latter to PD. Thus, 5-HT is supposed to facilitate anxiety, but to inhibit panic. This hypothesis has been tested in the animal model of anxiety and panic named the elevated T-maze, in two procedures of human experimental anxiety applied to healthy volunteers or panic patients, and in CO2-induced panic attacks. Overall, the obtained results have shown that drugs that enhance 5-HT function increase different indexes of anxiety, but decrease indexes of panic. Drugs that impair 5-HT function have the opposite effects. Thus, so far the predictions derived from the above hypothesis have been fulfilled.

title: Prenatal Stress Depresses Immune Function in Rats
abstract: The aim of the present study was to determine the effect of prenatal stress on immune function in rats. Pregnant rats were stressed by noise and light, three times weekly throughout pregnancy. Experiments were performed on male and female offspring aged 2 months. Cellular immune responses of splenic lymphocytes to B-cell (pokeweed mitogen (PWM) and T-cell (phytohemagglutinin (PHA)) mitogens were measured by [3H]thymidine uptake, and natural killer (NK) cell cytotoxicity in blood and splenic lymphocytes was measured against the murine T-cell lymphoma, YAC-1, by a 4-h [51Cr] release assay. Prenatal stress suppressed immune function as shown by a) decreased NK cytotoxicity in splenic and blood lymphocytes, indicating that the effect was not confined to a particular immune compartment, and b) decreased rate of proliferation of splenic lymphocytes to PWM and a smaller depressant effect on their response to PHA. The suppression of B-cell proliferation was more marked in the female and that of NK cell cytoxicity, in the male. Prenatal stress did not alter the distribution of subsets of lymphocytes, in either the spleen or blood, indicating that the reduction in proliferative and cytotoxic activity resulted from functional modifications of effector mechanisms in the cells rather from alterations in their migration between immune compartments. The mechanisms underlying this effect of prenatal stress are not clear but could result from an action of maternal stress hormones on the developing fetal neuroendocrine system.

title: Prenatal origins of individual variation in behavior and immunity
abstract: The in utero environment plays a critical role in initiating the normal ontogeny of many physiological systems. As a consequence, disturbances during prenatal life can affect the baby's maturational trajectory and sometimes cause chronic alterations that influence health postpartum. Our review summarizes a series of studies in rhesus monkeys supporting these conclusions. Psychological disturbance or pharmacological stimulation of the gravid female's pituitary-adrenal axis affected the infant's neurological development: monkeys evinced immature neuromotor reflexes at birth, greater emotionality during the first year of life, and a smaller hippocampus as juveniles. Immune responses of the infants were also affected: lymphocyte proliferation, natural killer activity and cytokine production were reduced. Several mediating pathways were implicated, including the placental transfer of hormones and nutrients, and a differential response of the infant monkey to the rearing environment. For example, the establishment of beneficial types of microflora in the gastrointestinal tract was significantly reduced, which was associated with a greater risk for enteric infection. These findings indicate that events during fetal life can persistently influence physiology after birth and tilt the balance away from health and toward illness.

title: Psychosocial maternal stress during pregnancy affects serum corticosterone, blood immune parameters and anxiety behaviour in adult male rat offspring
abstract: Exposure to prenatal stress can impair the behavioural and hormonal development in mammals. However, the consequences for the immune system are rarely investigated and there is only limited evidence that naturalistic prenatal stressors do also have the potential to affect the offspring. Thus, by using a social conflict model in female Long-Evans rats, we investigated the effects of prenatal social stress on several behavioural, hormonal and immunological parameters. Offspring from stressed and non-stressed pregnant females were housed in pairs after weaning, and tested at an age of 4-6 months. Prenatally stressed (PS) males were more active in the elevated plus-maze test as indicated by significantly more frequent entries into the open arms compared to prenatal control males (PC). In addition, PS males had significantly lower serum corticosterone concentrations under basal conditions as well as after ACTH-challenge. The basal number of total leukocytes was significantly lower in the PS group due to significantly lower lymphocyte counts. In particular, the CD4+ T-helper cell subset was affected. The lymphocyte proliferation to pokeweed mitogen was lower in PS males. Because some of the present findings do not correspond to previous studies using conventional stressors, we assume that the nature of the stressor plays an important role for pregnancy outcome and behaviour and physiology of the offspring in later life.

title: Early life programming of obesity and metabolic disease
abstract: It is becoming increasingly apparent that conditions experienced in early life play an important role in the long-term health of individuals. Alterations in development due to impaired, excessive or imbalanced growth, both in utero and during critical periods of relative plasticity beyond birth, can lead to the permanent programming of physiological systems. The regulation of energy balance is one area that is receiving particular attention, as rates of obesity and associated metabolic and cardiovascular disease continue to rise. Over recent decades, much progress has been made toward understanding the way in which metabolic tissues and physiological systems develop, and the impact of early life events and nutrition on these processes. It is apparent within human populations that some individuals are better able to maintain an appropriate body weight in the face of an obesogenic environment. Animal models have been widely used for the investigation of differential susceptibility to diet-induced obesity (DIO) and impaired energy balance regulation, and are shedding light on key pathways that may be involved. Alterations in pathways mediating energy homeostasis, outlined below, are likely candidates for programming effects following disturbed growth in early life.

title: Prenatal maternal anxiety predicts reduced adaptive immunity in infants
abstract: Prenatal anxiety has been linked with altered immune function in offspring in animal studies, but the relevance for human health is unknown. We examined prenatal maternal anxiety as a predictor of adaptive immunity in infants at 2 and 6 months of age as part of a prospective longitudinal study. The humoral immune response to hepatitis B vaccine was assessed at 2 months (n=80) and 6 months (n=76) of age. Prenatal anxiety predicted lower hepatitis B antibody titers at 6 months of age independent of obstetric and socio-demographic covariates; the effects were limited to those infants who had not completed the 3-dose vaccine series (for transformed titer values, r=-.36, p<.05). Cell-mediated immune responses at 2 (n=56) and 6 (n=54) months of age were examined by ELISpot assays for interferon(IFN)-γ, interleukin(IL)-2, and IL-4 responder cell frequencies to three antigens: hepatitis B surface antigen, tetanus toxoid, and phytohaemagglutinin (PHA). Prenatal maternal anxiety was associated with reduced IFN-γ and increased IL-4 responder cell frequencies at 6 months of age, independent of obstetric and socio-demographic covariates. No effect of prenatal anxiety was found on adaptive immunity at 2 months of age. The findings provide the first demonstration in humans that prenatal anxiety alters adaptive immunity in the infant.

title: Astrocyte–neuron vulnerability to prenatal stress in the adult rat brain
abstract: Chronic activation of the stress response during pregnancy has been shown to be injurious to the development of the offspring. We have previously demonstrated that restraint prenatal stress inflicted during the last week of pregnancy in rats increased dopamine and glutamate receptors in forebrain areas of the adult offsprings. In this study, the same prenatal insult was employed to assess morphological changes in astrocytes and in the dendritic arborization in frontal cortex, striatum, and hippocampus of the adult rat brain. On postnatal day 90, brains were processed for immunocytochemistry using primary antibodies to glial fibrillary acidic protein (GFAP; the main cytoskeletal astroglial protein), S100B protein (an astroglial‐derived neurotrophic factor), MAP‐2 (a microtubule‐associated protein present almost exclusively in dendrites), and synaptophysin (Syn; one major integral protein of the synaptic vesicles membrane). The results show a significant increase in the cell area of GFAP‐immunoreactive (‐IR) astrocytes, with high levels of S100B protein and a significant decrease in the relative area of MAP‐2‐IR neuronal processes in prenatally stressed adult rats. The expression of synaptophysin decreased in all areas studied. These results demonstrate that prenatal stress induces a long‐lasting astroglial reaction and a reduced dendritic arborization, with synaptic loss in the brain of adult offspring. In addition to the neurochemical alterations previously reported, these morphological changes might be underlying the behavioral and learning impairment previously observed in prenatally stressed rats.

title: Involvement of pGluR1, EAAT2 and EAAT3 in offspring depression induced by prenatal stress
abstract: It is widely known that prenatal stress (PS) exposure causes depression-like behaviour to offspring, as well as maladaptive responses including neurobiological and physiological changes. However, the underlying mechanism of PS induced juvenile-onset depression remains largely unravelled. The inadequacies of monoamine deficiency hypothesis, the emerging evidence of altered glutamate neurotransmission in mood disorders, as well as our previous studies inspired us to assess the potential role of glutamatergic system in the pathogenesis of juvenile depression. In this research, we examined the expression of phosphorylated GluR1 subunit of ionotropic receptor alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the Na+-dependent glutamate transporters excitatory amino acid transporter 2 (EAAT2) and EAAT3 in the hippocampus, striatum and frontal cortex of 1-month-old rat offspring after mid and late PS exposure. Prenatally stressed offspring rats showed significantly prolonged duration of immobility and shortened immobility latency in tail suspension test. We also detected that PS significantly altered the expression of glutamate receptor and glutamate transporters of these depressed rats. In brief, the changes of phosphorylated GluR1 subunit of AMPAR protein level in the hippocampus and frontal cortex, as well as markedly decreased EAAT2 mRNA expression in the hippocampus, striatum and frontal cortex and EAAT3 mRNA expression in the hippocampus of stressed rats were both observed. These results underpinned that glutamate receptors and glutamate transporters might be involved in the progress of depression-like behaviour in juvenile rat offspring induced by PS.

title: The Effect of Early Poststressor Intervention with Sertraline on Behavioral Responses in an Animal Model of Post-Traumatic Stress Disorder
abstract: Whereas several well-controlled studies have established the selective serotonin reuptake inhibitors (SSRIs) as the recommended first-line pharmacotherapeutic agents for acute and chronic post-traumatic stress disorder (PTSD), drug interventions in the acute postexposure phase have not been studied to the same extent and tend to be largely speculative. This study employed an animal model which assesses prevalence of individual stress–response behavior patterns in order to assess the short-term effects of a brief treatment regimen with an SSRI (sertraline) administered immediately after stress–exposure, with those of an identical delayed regimen and of saline. Prevalence rates of rats displaying extreme anxiety-like behavioral responses to predator stress, compared to partial and minimal responses, were assessed in the elevated plus maze and startle response paradigms, with and without intraperitoneal administration of sertraline for 7 days immediately postexposure, or 7 days after exposure. Immediate postexposure administration of sertraline reduced anxiety-like and avoidant behavior, decreased hyperarousal responses and diminished the overall incidence of extreme (PTSD-like) behavioral responses, compared to the delayed treatment regimen and to saline controls. Brief immediate poststress exposure treatment with sertraline reduced prevalence rates of extreme behavioral disruption in the short-term. SSRI drugs are thus worthy of further investigation as agents of secondary prevention in the acute aftermath of stress–exposure.

title: Prenatal Restraint Stress and Long-Term Affective Consequences
abstract: Chronic or repeated stress during critical periods of human fetal brain development has been associated with various learning, behavioral and/or mood disorders in later life. In this investigation, pregnant Fischer 344 rats was individually restrained three times a day for 45 min during the last week of gestation in transparent plastic cylinders while at the same time being exposed to bright light. Control pregnant females were left undisturbed in their home cages. Anxiety and depressive-like behavior was measured in the offspring at an age of 6 months using the open field test, the home cage emergence test and the forced swim test. Prenatally stressed rats spent more time in the corners and less time along the walls of an open field, while no difference in total distance moved was observed. In addition, prenatally stressed rats took more time to leave their home cage in the home cage emergence test. On the other hand, no differences in immobility were observed in the forced swim test. Moreover, prenatally stressed rats showed lower stress-induced plasma corticosterone levels compared with control rats. Prenatal stress (PS) had no effect on the number of 5-bromo-2-deoxyuridine-positive cells – used as a measure for cell proliferation – in the dentate gyrus of these rats. These data further support the idea that PS may perturb normal anxiety-related development. However, the present data also suggest that an adaptive or protective effect of PS should not be ignored. Genetic factors are likely to play a role in this respect.

title: Neurochemical modulation of sensory-motor reactivity: Acoustic and tactile startle reflexes
abstract: The present review argues that the startle reflex is particularly well suited as a model system to analyze how drugs alter stimulus reactivity and reflex excitability. It then reviews all the literature to date on how drugs or lesions that are thought to alter neurochemical transmitter systems affect acoustic and/or tactile startle. Hypotheses are presented to account for how serotonin, dopamine, norepinephrine, acetylcholine, and opiates modulate startle. Effects on startle plasticity such as habituation, sensitization, and potentiation resulting from prior associative learning are also included.

title: Effects of strain and serotonergic agents on prepulse inhibition and habituation in mice
abstract: Neural sensorimotor gating mechanisms prevent the interruption of ongoing information processing routines by ensuing stimuli to permit mental integration and adaptive behavior. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is now being investigated using murine models to exploit transgenic and "knockout" technology. The present studies were undertaken to evaluate potential murine strain differences in the effects of serotonergic drugs on PPI and habituation. Two strains used most often as a genetic background for transgenic or knockout manipulations, C57BL/6 and 129Sv, and the outbred ICR strain were used. We assessed the effects of the 5-HT(1A/1B) agonist 5-methoxy-3(1,2,3,6)tetrahydropyridin-4-yl-1H-indole (RU24969), the 5-HT(1A) agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), the 5-HT(2A/2C) agonist (+/-)2,5-dimethoxy-4-methylamphetamine (DOM), and the serotonin releaser (+)3, 4-methylenedioxy-N-methylamphetamine (MDMA) on PPI and habituation of acoustic startle in the three strains. C57BL/6 mice exhibited lower baseline PPI levels than 129Sv and ICR mice, and 129Sv mice habituated less than C57BL/6 and ICR mice. MDMA decreased PPI in C57BL/6 and ICR, but not 129Sv mice, and RU24969 disrupted habituation in C57BL/6 and 129Sv, but not ICR mice. Lastly, RU24969 decreased and 8-OH-DPAT increased PPI across all strains, although qualitative differences were observed. Thus, both baseline and serotonergic drug-induced effects on murine PPI and habituation are strain-dependent.

title: The Effects of Increased Central Serotonergic Activity on Prepulse Inhibition and Habituation of the Human Startle Response
abstract: Sensorimotor gating is critical to normal brain functioning, and disruptions are associated with certain mental illnesses, such as schizophrenia. Prepulse inhibition of the acoustic startle reflex (ASR) (PPI) is an operational measure of sensorimotor gating, of which evidence for a serotonergic modulation is currently inconsistent. In a double-blind placebo-controlled crossover design, 18 healthy male volunteers received either placebo or a dose of 10 mg of escitalopram (SSRI), after which they were tested in both PPI and habituation of the startle reflex paradigms. No significant differences between the two treatments were observed on PPI, although escitalopram was found to significantly delay habituation of the ASR. In the current study, escitalopram was found to delay habituation, but it did not affect PPI in healthy male volunteers. As escitalopram is a highly specific SSRI, the results suggest that an increased serotonergic activity disrupts habituation, but not PPI in healthy volunteers.

title: Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review
abstract: Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia.  This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats.  Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated.  Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications.  Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.

title: Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus.
abstract: Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampal-dependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging.

title: Sexually dimorphic effects of prenatal stress on cognition, hormonal responses, and central neurotransmitters.
abstract: Exposure to stress during gestation results in physiological and behavioral alterations that persist into adulthood. This study examined the effects of prenatal stress on the postnatal expression of sexually differentiated cognitive, hormonal, and neurochemical profiles in male and female rats. Pregnant dams were subjected to restraint stress three times daily for 45 min during d 14-21 of pregnancy. The offspring of control and prenatally stressed dams were tested for anxiety-related and cognitive behaviors, stress and gonadal steroid hormone levels, as well as monoamines and metabolite levels in selected brain regions. Postnatal testosterone levels (measured at 1 and 5 d) did not differ between controls and prenatally stressed animals. In adulthood, the serum corticosterone response to stress was attenuated in prenatally stressed females, eliminating the sex difference normally observed in this parameter. Prenatally stressed females exhibited higher anxiety levels, evidenced by longer open field entry latencies. Prenatal stress had no effect on object recognition memory, but eliminated the advantage normally seen in the male performance of a spatial memory task. Neurochemical profiles of prenatally stressed females were altered toward the masculine phenotype in the prefrontal cortex, amygdala, and hippocampus. Thus, prenatal stress altered subsequent cognitive, endocrine, and neurochemical responses in a sex-specific manner. These data reinforce the view that prenatal stress affects multiple aspects of brain development, interfering with the expression of normal behavioral, neuroendocrine, and neurochemical sex differences. These data have implications for the effects of prenatal stress on the development of sexually dimorphic endocrine and neurological disorders.

title: Behavior ontogeny in the elevated plus-maze: prenatal stress effects
abstract: Prenatal stress is a putative model for studying some psychopathological disorders. Indeed, submitting pregnant animals to stress leads to enhanced anxiety in the adult offspring. However, little is known about how prenatal stress effects interacts with anxiety throughout development. To study this issue, prenatally stressed rats were tested in the elevated plus‐maze at different ages. During pregnancy female rats were submitted to uncontrollable electric foot shock sessions every other day or kept undisturbed (controls). After delivery, litters from control and stressed dams were left undisturbed from the 3rd to the 14th postnatal days. Male and female rats were tested in the elevated plus‐maze at the ages of 30, 45 or 60 days. The following measures were taken in the elevated plus‐maze: number of entries and time spent in the arms (or their extremities) and frequency and time spent in naturalistic behaviors (stretching, rearing, end exploring, grooming and head dipping). Decreases in the percentage of entries into and in the time spent (only females) in the open arms were shown by 60‐day‐old prenatally stressed rats, but not by 30‐ and 45‐day old. Increased open arm ends exploration was shown by 45‐day‐old prenatally stressed males. Rearing behavior was found to increase with age, a phenomenon more pronounced in females. Additionally, at the younger ages prenatally stressed rats were heavier than controls, an effect which disappeared at young adulthood. In conclusion, anxiogenic prenatal stress effects in the elevated plus‐maze could only be detected at early adulthood, not before. Nonetheless, at late adolescence (45 days of age) prenatal stress leaded to an anxiolytic‐like effect which can be interpreted as increased risk‐taking behavior.

title: Prenatal stress and subsequent exposure to chronic mild stress in rats; interdependent effects on emotional behavior and the serotonergic system
abstract: Exposure to prenatal stress (PS) can predispose individuals to the development of psychopathology later in life. We examined the effects of unpredictable chronic mild stress (CMS) exposure during adolescence on a background of PS in male and female Sprague-Dawley rats. PS induced more anxiety-like behavior in the elevated zero maze in both sexes, an effect that was normalized by subsequent exposure to CMS. Moreover, PS was associated with increased depression-like behavior in the forced swim test in males only. Conversely, sucrose intake was increased in PS males, whilst being decreased in females when consecutively exposed to PS and CMS. Hypothalamo-pituitary-adrenal (HPA) axis reactivity was affected in males only, with higher stress-induced plasma corticosterone levels after PS. Markedly, CMS normalized the effects of PS on elevated zero maze behavior as well as basal and stress-induced plasma corticosterone secretion. At the neurochemical level, both PS and CMS induced various sex-specific alterations in serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) immunoreactivity in the dorsal raphe nucleus, hippocampus and prefrontal cortex with, in line with the behavioral observations, more profound effects in male offspring. In conclusion, these findings show that prenatal maternal stress in Sprague-Dawley rats induces various anxiety- and depression-related behavioral and neuroendocrine changes, as well as alterations in central 5-HT and TPH2 function, predominantly in male offspring. Moreover, CMS exposure partially normalized the effects of previous PS experience, suggesting that the outcome of developmental stress exposure largely depends on the environmental conditions later in life and vice versa.

title: A selective test for antidepressant treatments using rats bred for stress-induced reduction of motor activity in the swim test
abstract: Rationale and objectiveThis paper describes a new procedure for detecting effective antidepressant treatments. The procedure uses the swim-test susceptible (Susceptible) rat which has been selectively bred to show decreased struggling behavior in a swim test after exposure to a mild stressor. The ability of treatments to block this decrease in swim-test activity was assessed as a method for detecting effective antidepressants.ResultsIn both male and female Susceptible rats, chronic (14-day) treatment with different antidepressant drugs delivered via osmotic minipump [i.e., three tricyclics (desmethylimipramine, imipramine, amitriptyline), two selective serotonin reuptake inhibitors (fluoxetine and sertraline), a monoamine oxidase inhibitor (phenelzine), and two atypical antidepressants (venlafaxine and bupropion)] all prevented the stress-induced decrease in swim-test struggling normally shown by these rats. Electroconvulsive shock had a similar effect. Unlike antidepressant drugs, 14-day treatment with various nonantidepressant drugs [i.e., a stimulant (amphetamine), an anxiolytic (chlordiazepoxide), an antihistamine (chlorpheniramine), and an anticholinergic (scopolamine)] did not have this effect. Antidepressant drug treatment for 1 day (i.e., acute treatment) was also ineffective in this test. The procedure described above requires use of the Susceptible rat—swim test resistant rats (i.e., rats selectively bred to be resistant to decreased swim-test activity after exposure to stressful conditions) showed no significant differences in swim-test behavior between stress and nonstress conditions after 14-day drug treatment, and randomly bred Sprague–Dawley rats did not show a decrease in swim-test activity following exposure to the mild stressor that is the basis for the test.ConclusionThese results suggest that the procedure described here, which uses a rat subject that has been bred for vulnerability to stressful conditions, may be a selective screening technique for effective antidepressant treatments.

title: Sex differences in stress-induced social withdrawal: role of brain derived neurotrophic factor in the bed nucleus of the stria terminalis
abstract: Depression and anxiety disorders are more common in women than men, and little is known about the neurobiological mechanisms that contribute to this disparity. Recent data suggest that stress-induced changes in neurotrophins have opposing effects on behavior by acting in different brain networks. Social defeat has been an important approach for understanding neurotrophin action, but low female aggression levels in rats and mice have limited the application of these methods primarily to males. We examined the effects of social defeat in monogamous California mice (Peromyscus californicus), a species in which both males and females defend territories. We demonstrate that defeat stress increases mature brain-derived neurotrophic factor (BDNF) protein but not mRNA in the bed nucleus of the stria terminalis (BNST) in females but not males. Changes in BDNF protein were limited to anterior subregions of the BNST, and there were no changes in the adjacent nucleus accumbens (NAc). The effects of defeat on social withdrawal behavior and BDNF were reversed by chronic, low doses of the antidepressant sertraline. However, higher doses of sertraline restored social withdrawal and elevated BDNF levels. Acute treatment with a low dose of sertraline failed to reverse the effects of defeat. Infusions of the selective tyrosine-related kinase B receptor (TrkB) antagonist ANA-12 into the anterior BNST specifically increased social interaction in stressed females but had no effect on behavior in females naïve to defeat. These results suggest that stress-induced increases in BDNF in the anterior BNST contribute to the exaggerated social withdrawal phenotype observed in females.

title: Sertraline. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive-compulsive disorder.
abstract: Sertraline is a selective inhibitor of central serotonin reuptake. Thus, it enhances serotoninergic transmission--a property which appears to explain its antidepressant activity. Its elimination half-life (approximately 26 hours) makes it suitable for once daily administration. Although clinical experience with sertraline is limited, it appears to possess antidepressant efficacy similar to that of amitriptyline and dothiepin, marginally better than imipramine, and significantly better than placebo. Additionally, sertraline is the only antidepressant licensed in the UK for the prevention of recurrence of depression, and preliminary findings suggest that the drug may also be effective in the treatment of obsessive-compulsive disorder. Sertraline and other serotonin reuptake inhibitors possess tolerability advantages over tricyclic antidepressants. Sertraline has minimal anticholinergic activity, is essentially devoid of cardiovascular effects, has a wide therapeutic index and may be administered to elderly patients or those with underlying cardiovascular disorders. However, as with other serotonin reuptake inhibitors, sertraline has been associated with gastrointestinal disturbances (nausea, diarrhoea/loose stools) and male sexual dysfunction (primarily ejaculatory disturbance), although each of these effects is usually mild and transient, decreasing in frequency with continued treatment. As a drug class, serotonin reuptake inhibitors such as sertraline appear to provide significant advantages compared with the more established antidepressant agents, particularly in terms of tolerability. Although much broader clinical experience is required before sertraline's full therapeutic potential can be realised, if future studies confirm the encouraging initial findings, sertraline will undoubtedly become an important option in the treatment of depression.

title: Chronic administration of risperidone to healthy rats: A behavioural and morphological study
abstract: Taking into account that most of the experimental research into the effects of antipsychotic drugs has mainly focused on behavioural aspects, the aim of the present work is to investigate the effects of a chronic therapeutic dose of risperidone (1 mg/kg/day during 140 days) on both behavioural and morphological aspects in healthy rats. The behavioural results revealed only minor modifications in prepulse inhibition, showing the risperidone-treated group higher values at 70 days of treatment with respect to the vehicle group. Moreover, in the open-field test, this group showed a greater incidence of grooming. In the active avoidance test, no differences were found between the groups studied. Additionally, in the morphological study performed to analyse cortical thickness and the number of GFAP-, CaBP-, PV- and Fos-immunostained cells no differences were seen between the two groups studied. It is important to note that the risperidone-treated group showed a slight increase in the total number of cells counted, although this increase was not significant. Our results indicate that the chronic administration of therapeutic doses of risperidone does not produce any dramatic behavioural or morphological changes in healthy animals.

title: Correlation of growth hormone secretion during pregnancy with circulating prolactin in rats.
abstract: Growth hormone (GH) concentrations were measured throughout pregnancy in rats. The effects of surgical stress, ovariectomy, and treatments with the antiprogesterone mifepristone (RU 486) or the antioestrogen tamoxifen on serum GH, progesterone and prolactin were studied. GH concentrations were low during the first 18 days of pregnancy, except on the morning of day 5, and increased progressively from day 19 reaching peak values on the mornings of days 21 and 22. Thereafter GH concentrations decreased progressively, reaching very low values at 24.00 h on day 22, in parallel with a rise in serum prolactin concentrations. Surgical stress, performed at 12.00 h on day 20 of pregnancy, diminished serum GH concentrations 10 min later, but these returned to values similar to those of the non-operated rats 1-24 h later. Surgical stress did not modify serum prolactin concentrations at any time. Ovariectomy performed on the morning of day 19 produced the expected fall in serum progesterone and a rise in prolactin which lasted until the night of day 20. Serum GH concentrations were significantly diminished with respect to controls on day 20 and the morning of day 21 and then increased. Treatment with mifepristone on day 19 produced a simultaneous rise in serum prolactin and a fall in serum progesterone and GH by 08.00 h on day 21. Treatment with tamoxifen on days 3 and 4, or given daily from day 17 onwards did not modify prolactin concentrations but diminished serum GH concentrations at 08.00 on day 5 and on days 19-22, with the exception of a peak on day 22 (08.00 h). Tamoxifen also decreased serum progesterone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Acute Stress in Pregnant Rats Effects on Growth Rate, Learning, and Memory Capabilities of the Offspring
abstract: Growth rate of the offspring of female rats stressed by the presence of a cat at the 10th or the 19th gestational day was lower than that of controls whereas footshocks administered at the same periods did not significantly influence growth rate of the young. Whatever the nature of the stress and the time when it was administered to the mother, the death rate of the young rats was much greater than that in controls. When adult, the offspring of stressed mothers exhibited learning and memory impairments in a delayed alternation task as well as in passive avoidance conditioning. Alteration of these cognitive functions is interpreted in terms of subtle dysfunctions in the development of the nervous system through modifications of the hormonal components of the mothers, particularly eventual alterations of the nervous system biochemistry of the offspring.

title: Prenatal stress induces body weight deficit and behavioural alterations in rats: the effect of diazepam
abstract: Prenatal stress may induce intrauterine growth retardation, but it is not known whether a treatment with the anxiolytic benzodiazepine, diazepam may interfere with this phenomenon. A daily physical stress consisting of a forced immersion for 15 min in cold water was applied to pregnant rats of the Wistar strain from gestational day 5 until parturition. Animals were treated either with physiological saline or with diazepam (0.1 or 1 mg/kg/day) injected intraperitoneally 1 h prior to stress application. Control animals received injections of physiological saline but were not subjected to physical stress. Newborn pups subjected to prenatal stress showed reduced body weight as compared to control animals. Offspring were also examined for the appearance day of the following reflexes: cliff aversion, startle, righting, forelimb placing, forelimb grasping and bar holding. Hair growth, and first day of ears and eyes opening was also scored. At 60 days of age, male rats from the three experimental groups were subjected to behavioural tests, i.e., constrained swim (despair test) and step-through passive avoidance response. Animals subjected to prenatal stress showed a delayed appearance of all neonatal reflexes and behavioural deficits in adulthood, namely increased immobility in the despair test and reduced retention of a passive avoidance task. The prenatal treatment with diazepam totally counteracted the effect of stress, normalizing the time-course of neonatal reflexes and the behavioural responses in adulthood. No difference was seen between the effects of the two drug doses. It is concluded that prenatal physical stress may induce body growth retardation and may be considered as a model for human intrauterine growth retardation. The treatment with an anxiolytic benzodiazepine, such as diazepam, may counteract the effects of prenatal stress interfering with the biological consequences of stress concerning probably cerebral neurotransmitters in both the unborn foetus and the pregnant rat.

title: Long-Term Effects of Prenatal Stress on Dopamine and Glutamate Receptors in Adult Rat Brain
abstract: Prenatal stress greatly influences the ability of an individual to manage stressful events in adulthood. Such vulnerability may result from abnormalities in the development and integration of forebrain dopaminergic and glutamatergic projections during the prenatal period. In this study, we assessed the effects of prenatal stress on the expression of selective dopamine and glutamate receptor subtypes in the adult offsprings of rats subjected to repeated restraint stress during the last week of pregnancy. Dopamine D2-like receptors increased in dorsal frontal cortex (DFC), medial prefrontal cortex (MPC), hippocampal CA1 region and core region of nucleus accumbens (NAc) of prenatally stressed rats compared to control subjects. Glutamate NMDA receptors increased in MPC, DFC, hippocampal CA1, medial caudate-putamen, as well as in shell and core regions of NAc. Group III metabotropic glutamate receptors increased in MPC and DFC of prenatally stressed rats, but remained unchanged in all other regions examined. These results indicate that stress suffered during the gestational period has long lasting effects that extend into the adulthood of prenatally stressed offsprings. Changes in dopamine and glutamate receptor subtype levels in different forebrain regions of adult rats suggest that the development and formation of the corticostriatal and corticolimbic pathways may be permanently altered as a result of stress suffered prenatally. Maldevelopment of these pathways may provide a neurobiological substrate for the development of schizophrenia and other idiopathic psychotic disorders.

title: Differential adaptive responses to chronic stress of maternally stressed male mice offspring.
abstract: It is well established that stress in early life can alter the activity of the hypothalamus-pituitary-adrenal (HPA) axis, but most studies to date have focused on HPA reactivity in response to a single acute stress. The present study addressed whether stress in pregnant mice could influence the adaptive responses of their offspring to chronic stress. Male offspring were exclusively used in this study. Elevated plus maze tests revealed that 14 d of repeated restraint stress (6 h per day; from postnatal d 50-63) significantly increased anxiety-like behavior in maternally stressed mice. NBI 27914, a CRH receptor antagonist, completely eliminated anxiety-related behaviors in a dose-dependent manner, indicating an involvement of a hyperactive CRH system. In accordance with increased anxiety, CRH contents in the hypothalamus and amygdala were significantly higher in these mice. Despite an increased basal activity of the CRH-ACTH system, the combination of chronic prenatal and postnatal stress resulted in a significant reduction of basal plasma corticosterone level, presumably because of a defect in adrenal function. Along with alterations in hypothalamic and hippocampal corticosteroid receptors, it was also demonstrated that a dysfunction in negative feedback inhibition of the HPA axis could be deteriorated by chronic stress in maternally stressed male mice. Taken together, these results indicate that exposure to maternal stress in the womb can affect an animal's coping capacity to chronic postnatal stress.

title: Impact of prenatal stress on long term body weight is dependent on timing and maternal sensitivity
abstract: Stress experienced during pregnancy increases the risk for altered birth weights. Recent studies have revealed a link between abnormal birth weights and a future predisposition toward developing overweight or obesity. To determine the gestational time window when stress exposure produces the greatest impact on offspring body weight regulation, we have examined the birth weights and long-term body weight changes in offspring exposed to chronic variable stress (CVS) early, mid-, or late in gestation. As it is likely that the influences of prenatal stress on development stem from a complex interaction between both environmental and genetic factors, our study has included comparisons with offspring born to stress-sensitive (corticotropin-releasing factor receptor-2 deficient) mice. Stress experienced late in pregnancy significantly elevated offspring birth weights in wild type mice compared to unstressed controls. However, this weight difference diminished postnatally. In contrast, stress experienced mid- to late in pregnancy produced significant and long-term effects on body weight in offspring from stress-sensitive dams, were the male offspring were 15% heavier as adults. Adult offspring plasma glucose and leptin levels were also dependent on the timing of stress exposure, indicating that alterations in energy homeostasis may be influencing long-term body weight. Results from these studies support our hypothesis that the ultimate effect of prenatal stress on offspring long-term outcome is dependent on the timing of exposure and maternal sensitivity.

title: Prenatal psychological stress causes higher emotionality, depression-like behavior, and elevated activity in the hypothalamo-pituitary-adrenal axis
abstract: In humans, stressful events during pregnancy may raise the risk of psychiatric disorders in offspring, and studies with rodents have found that physical prenatal stress can cause changes in the physiology, neurobiology, and behavior of offspring. In the present study, we examined whether psychological prenatal stress with little physical stress could cause changes in the neurobiology and behavior of offspring in Sprague-Dawley rats, as physical prenatal stress did. Dams received psychological stress by observing a rat being electrically shocked behind a transparent wall in the social communication box during the last trimester of gestation but were not exposed to any physical stress. Male offspring from the dams exposed to psychological stress showed enhanced emotionality in an open field test, depression-like behavior in a forced swim test, and enhanced activity in the hypothalamo-pituitary-adrenal axis, compared with rats from untreated dams. However, the prenatally stressed rats showed intact ability to acquire context conditioning. This is the first report that psychological prenatal stress in the communication box can cause changes in the neurobiology and behavior of offspring in rodents.

title: The weight gain response to stress during adulthood is conditioned by both sex and prenatal stress exposure
abstract: Food intake and weight gain are known to be affected by stress. However, the type and duration of the stress may have variable effects, with males and females responding differently. We report the short-term and long-term effects of prenatal and adult immobilization stress, as well as the combination of these two stresses, on weight gain and food intake in male and female rats and the role of post-pubertal gonadal hormones in this process. No long-term effect of prenatal stress on food intake or weight gain was found in either sex. However, during the period of adult stress [at postnatal day (P) 90; 10 days duration] stressed male rats gained significantly less weight than controls and previous exposure to prenatal stress attenuated this effect (control: 31.2+/-2.1g; prenatal stress: 24.6+/-3.8g; adult stress: 8.1+/-3.4g; prenatal and adult stress: 18.2+/-3.3g; p<0.0001). There was no change in food intake in response to either prenatal or adult stress. Adult stress increased circulating corticosterone levels during the initial part of the stress period, in both male and female rats with this rise being greater in male rats. No effect on corticosterone levels was observed on the last day of stress in either sex. No effect on weight gain or food intake was observed in female rats. Following adult stress, male rats increased their weight gain, with no change in food intake, such that 1 month later they reached control levels. At the time of sacrifice (P180), there were no differences in weight or circulating metabolic hormone levels between any of the male groups. Although castration alone modulated body weight in both male and female rats, it did not affect their weight gain response to adult stress. These results indicate that the weight gain response to adult stress is sexually dimorphic and that this is not dependent on post-pubertal gonadal steroids. Furthermore, the outcome of this response closely depends on the time at which the change in weight is analyzed, which could help to explain different results reported in the literature. Indeed, weight and metabolic hormone levels were normalized by the end of the study.

title: Fetal programming of appetite and obesity
abstract: Obesity and related metabolic disorders are prevalent health issues in modern society and are commonly attributed to lifestyle and dietary factors. However, the mechanisms by which environmental factors modulate the physiological systems that control weight regulation and the aetiology of metabolic disorders, which manifest in adult life, may have their roots before birth. The 'fetal origins' or 'fetal programming' paradigm is based on the observation that environmental changes can reset the developmental path during intrauterine development leading to obesity and cardiovascular and metabolic disorders later in life. The pathogenesis is not based on genetic defects but on altered genetic expression as a consequence of an adaptation to environmental changes during fetal development. While many endocrine systems can be affected by fetal programming recent experimental studies suggest that leptin and insulin resistance are critical endocrine defects in the pathogenesis of programming-induced obesity and metabolic disorders. However, it remains to be determined whether postnatal obesity is a consequence of programming of appetite regulation and whether hyperphagia is the main underlying cause of the increased adiposity and the development of metabolic disorders.

title: Poor fetal growth followed by rapid postnatal catch-up growth leads to premature death
abstract: It is widely accepted that individuals with a low birth weight are at increased risk of developing type 2 diabetes, insulin resistance and cardiovascular disease. This risk is amplified if the poor fetal growth is followed by rapid postnatal catch-up growth. We have shown recently that poor fetal growth, resulting from maternal protein restriction, followed by postnatal catch-up growth is associated with reduced average longevity in mice. Here, we show that in addition to reduced average longevity, mice which have been growth restricted in utero and then grown rapidly during the lactation period have a reduced maximum longevity. Maximum longevity of these mice was, further, reduced when the animals were weaned onto an obesity-inducing cafeteria-style diet. This reduced maximum longevity was associated with early age-related weight loss. These results demonstrate that maternal nutrition during critical periods of development has a major impact on quantity as well as quality of life.

title: Serotonin alterations in anorexia and bulimia nervosa: New insights from imaging studies
abstract: Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders with relatively homogenous presentations such as age of onset and gender distribution. In addition, they share symptoms, such as extremes of food consumption, body image distortion, anxiety and obsessions, and ego-syntonic neglect, raises the possibility that these symptoms reflect disturbed brain function that contributes to the pathophysiology of this illness. Recent brain imaging studies have identified altered activity in frontal, cingulate, temporal, and parietal cortical regions in AN and BN. Importantly, such disturbances are present when subjects are ill and persist after recovery, suggesting that these may be traits that are independent of the state of the illness. Emerging data point to a dysregulation of serotonin pathways in cortical and limbic structures that may be related to anxiety, behavioral inhibition, and body image distortions. In specific, recent studies using PET with serotonin specific radioligands implicate alterations of 5-HT1A and 5-HT2A receptors and the 5-HT transporter. Alterations of these circuits may affect mood and impulse control as well as the motivating and hedonic aspects of feeding behavior. Such imaging studies may offer insights into new pharmacology and psychotherapy approaches.

title: Role of central serotonin and melanocortin systems in the control of energy balance.
abstract: Body weight homeostasis is critically dependent upon the convergence and integration of multiple central and peripheral signalling systems that collectively function to detect and elicit physiological and behavioural responses to nutritional state. To date, only a minority of these signals have been pharmacologically targeted for the treatment of human obesity. One signal that has been effectively manipulated to reduce body weight is the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT); however, the relevant downstream signalling pathways are incompletely understood. Recently, the melanocortin system, a nexus for multiple modulators of energy balance, has emerged as one key mediator of serotonin's effects on appetite. Here we review the serotonin and melanocortin systems with reference to their roles in energy balance and discuss the evidence that the two systems are functionally linked.

title: Dysregulation of brain reward systems in eating disorders: Neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa
abstract: Food intake is mediated, in part, through brain pathways for motivation and reinforcement. Dysregulation of these pathways may underlay some of the behaviors exhibited by patients with eating disorders. Research using animal models of eating disorders has greatly contributed to the detailed study of potential brain mechanisms that many underlie the causes or consequences of aberrant eating behaviors. This review focuses on neurochemical evidence of reward-related brain dysfunctions obtained through animal models of binge eating, bulimia nervosa, or anorexia nervosa. The findings suggest that alterations in dopamine (DA), acetylcholine (ACh) and opioid systems in reward-related brain areas occur in response to binge eating of palatable foods. Moreover, animal models of bulimia nervosa suggest that while bingeing on palatable food releases DA, purging attenuates the release of ACh that might otherwise signal satiety. Animal models of anorexia nervosa suggest that restricted access to food enhances the reinforcing effects of DA when the animal does eat. The activity-based anorexia model suggests alterations in mesolimbic DA and serotonin occur as a result of restricted eating coupled with excessive wheel running. These findings with animal models complement data obtained through neuroimaging and pharmacotherapy studies of clinical populations. Information on the neurochemical consequences of the behaviors associated with these eating disorders will be useful in understanding these complex disorders and may inform future therapeutic approaches, as discussed here. This article is part of a Special Issue entitled 'Central Control of Food Intake'.

title: Brain serotonin system in the coordination of food intake and body weight
abstract: An inverse relationship between brain serotonin and food intake and body weight has been known for more than 30 years. Specifically, augmentation of brain serotonin inhibits food intake, while depletion of brain serotonin promotes hyperphagia and weight gain. Through the decades, serotonin receptors have been identified and their function in the serotonergic regulation of food intake clarified. Recent refined genetic studies now indicate that a primary mechanism through which serotonin influences appetite and body weight is via serotonin 2C receptor (5-HT(2C)R) and serotonin 1B receptor (5-HT(1B)R) influencing the activity of endogenous melanocortin receptor agonists and antagonists at the melanocortin 4 receptor (MC4R). However, other mechanisms are also possible and the challenge of future research is to delineate them in the complete elucidation of the complex neurocircuitry underlying the serotonergic control of appetite and body weight.

title: Reduction of feeding behavior by the serotonin uptake inhibitor sertraline
abstract: Administration of the selective serotonin (5-HT) uptake inhibitor sertraline produced a dose-dependent reduction of food intake in rats. Doses of sertraline of 10 mg/kg or greater reduced the intake of solid pellets significantly (P<0.01) during the 1st hour of a 4-h feeding test in rats deprived of food and water for 24 h. Food intake during the remaining 3 h and water intake during the feeding test was unaffected by sertraline. Sertraline (2–18 mg/kg IP) also reduced milk consumption in food-deprived rats. Pretreatment with the nonselective 5-HT antagonists metergoline (2 mg/kg IP) or methysergide (3.3 mg/kg IP) blocked sertraline's inhibition of dry food intake, whereas pretreatment with the selective 5-HT2 receptor antagonist ketanserin (3.3 mg/kg IP) or the peripheral 5-HT2 antagonist xylamidine (2.5 mg/kg IP) failed to block sertraline's anorexic effect. The feeding-suppressant effect of 10 mg/kg sertraline was prevented following the destruction of central 5-HT neurons by the 5-HT neurotoxic agent, 5,7-dihydroxytryptamine (200 μg ICV). This result is consistent with sertraline's anorexic effect depending on intact 5-HT neurotransmission. Therefore, sertraline appears to reduce feeding by enhancing the action of endogenous serotonin at central synapses mediated by 5-HT1 rather than 5-HT2 receptors.

title: Sertraline, a selective serotonin reuptake inhibitor, affects thirst, salt appetite and plasma levels of oxytocin and vasopressin in rats
abstract: We investigated the effects of chronic administration of sertraline (SERT; ∼20 mg kg−1 day−1 in drinking water), a selective serotonin reuptake inhibitor, on water and sodium intake and on plasma levels of oxytocin (OT) and vasopressin (AVP) in basal and stimulated conditions. Basal water intake was reduced in SERT‐treated rats. After 24 h of water deprivation, rats treated with SERT for 21 days ingested less water than the control rats (9.7 ± 0.5 versus 20.0 ± 0.9 ml, respectively, at 300 min after water presentation, P < 0.0001). Subcutaneous injection of 2 m NaCl or isoproterenol evoked a lower dipsogenic response in rats treated with SERT for 21 days. Fluid and food deprivation also induced a weaker dipsogenic response in SERT‐treated rats (1.6 ± 0.5 versus 10.2 ± 1.2 ml, at 300 min, P < 0.0001) but had no effect on saline intake. Sodium depletion induced a higher natriorexigenic response in the SERT group (5.6 ± 1.3 versus 1.2 ± 0.3 ml, at 300 min, P < 0.0002). Higher urinary density and lower plasma sodium levels were observed after SERT treatment. Sertraline also increased plasma levels of vasopressin and oxytocin (AVP, 2.65 ± 0.36 versus 1.31 ± 0.16 pg ml−1, P < 0.005; OT, 17.16 ± 1.06 versus 11.3 ± 1.03 pg ml−1, P < 0.0009, at the third week post‐treatment). These data constitute the first evidence that chronic SERT treatment affects water and sodium intake in rats. These effects seem to be related to the hyponatraemia caused by the higher plasma levels of AVP and OT.

title: Effects of sertraline on autonomic and cognitive functions in healthy volunteers
abstract: RationaleThough sertraline, a selective serotonin reuptake inhibitor (SSRI), causes autonomic and cognitive adverse events such as dry mouth and somnolence, there is a paucity of appropriately designed studies on the cognitive and autonomic effects of the drug in the literature.ObjectiveTo compare the effects of sertraline on cognitive and autonomic functions with those of placebo in healthy humans.MethodA randomized, double blind, cross over study of 12 healthy male volunteers aged 24 (21– 32; median; range) years. Subjects orally received 50 mg sertraline and placebo once daily for periods of 14 days each with at least 14 days in between. Heart rate variability (HRV), skin conductance level (SCL) and skin conductance response (SCR) following sudden deep respiration were employed as parameters for autonomic function. Quantitative EEG (qEEG) and psychometric tests served as parameters for cognitive function. Measurements were performed repeatedly before the start of drug administration and on the last treatment day.ResultsSertraline caused a significant reduction of heart rate and SCL (P<0.05), whereas HRV and SCR were not changed. Cognitive functions such as flicker fusion frequency, memory, choice reaction time and psychomotor performance were not influenced by sertraline but slow and fast beta power density in the qEEG was increased.ConclusionCognitive and psychomotor performance are not altered in healthy humans receiving multiple dosing with sertraline. The observed decreases in heart rate and SCL may be due to a sympatho-inhibitory effect of sertraline.

title: Effects of prenatal stress on vulnerability to stress in prepubertal and adult rats
abstract: This study investigated the hypotheses that unpredictable prenatal stress has effects on the offspring, similar to those induced by perinatal administration of glucocorticoids and increases the vulnerability to stressful situations at adulthood. Rats were exposed to random noise and light stress throughout pregnancy. Offspring were tested for the development of spontaneous alternation behavior (SA) and at adulthood, their response to novel or aversive situations, open field, extinction and punishment following acquisition of an appetitive response and two-way active avoidance, were assessed. In prenatally stressed rats, the development of SA was significantly delayed. On repeated exposure to an open field they were less active; control rats had elevated plasma corticosterone (CCS) on days 2 and 4 of open field exposure, while prenatally stressed rats had significantly raised plasma CCS after each exposure (days 1-8). Furthermore, punishment-induced suppression of an appetitive response was enhanced. Acquisition of active avoidance was faciliated in female but reduced in male prenatally stressed offspring. It is suggested that random prenatal noise and light stress may cause impairment of development of hippocampal function which lasts into adulthood. This impairment is manifested as an increase in vulnerability and a decrease in habituation to stressful stimuli.

title: Anterior pituitary response to stress : time-related changes and adaptation
abstract: A wide array of physical and psychological stressors alter the secretion of anterior pituitary hormones. However, both the qualitative and the quantitative features of the stressors as well as its duration markedly influence the final endocrine response. In addition, among all anterior pituitary hormones, only ACTH and prolactin levels appear to reflect the intensity of the stress experienced by the animals. Although physical stressors show a somewhat specific neuroendocrine profile, the response of the pituitary‐adrenal (PA) and sympathomedulloadrenal axes are common to almost all stressors. After an initial stimulatory effect of stress, an inhibition of all anterior pituitary hormones, except ACTH, can be found provided the stressor is intense enough. The mechanisms responsible for this biphasic response to stress are likely to be located at sites above the pituitary. When the animals are repeatedly exposed to the same stressor, some behavioural and physiological consequences of stress exposure are reduced, suggesting that the animals become adapted to the stimulus. This process has been also termed habituation. Among all the pituitary hormones, only ACTH and prolactin levels are reduced as a consequence of repeated exposure to the same (homotypic) stressor, although some negative results have been reported. However, it has been recently reported that subtle changes in the characteristics of the stressors or in their regularity can greatly influence adaptation, and these factors might explain failure to find adaptation of ACTH and prolactin in some works. Habituation of ACTH and prolactin, when observed, appears to be specific for the chronically applied stressor so that the potentiality of the PA axis and prolactin to respond to a novel (heterotypic) stressor can be preserved. In the case of the PA axis, an intact or potentiated response to a novel stressor is observed in spite of presumably negative feedback exerted by daily stress‐induced glucocorticoid release and the high resting levels of glucocorticoids. This phenomenon has been termed as facilitation and can be unmasked alternating stress. Although with the exception of the PA axis, developmental aspects of anterior pituitary response to stress have been poorly studied, available data suggest that dramatic changes occur in some hormones during weaning, with some, but less profound, changes thereafter. Responsiveness to stressors appears to mature with age, but developmental patterns differ among the various anterior pituitary hormones.

title: Prenatal and adult stress interplay — behavioral implications
abstract: The origin of adult behavior and the possible pathogenesis of psychiatric disorders remain elusive, but extensive research indicates that interaction of genes and environment play a crucial role for adult phenotype. Differences in susceptibility may arise by earlier experiences and genomic variables, either alone or in combination. The acoustic startle response (ASR) has been shown to be altered in patients with several psychiatric diseases, a change that could result from a persistent sensitization caused by chronic arousal secondary to a traumatic incident. The current work hypothesized that a single aversive procedure would induce long-term hyperactivity in the HPA-axis of rats that had become vulnerable by prenatal stress, and thereby change reactivity in the ASR. Prenatal stress was achieved by maternal gestational exposure to Chronic Mild Stress (CMS). At age 3 months, the offspring were blood sampled by a stressful procedure, and subsequently tested in the acoustic startle paradigm. Prenatal CMS strongly reduced prepulse inhibition (PPI) whereas postnatal blood sampling under restraint generally increased PPI. Our data demonstrate interplay between pre- and postnatal stressful events, but also that this interaction is complex and could influence the interplay between PPI and basal startle. Our results suggest that circumstances dating back to early development may have implications for adult life behavior, and based on this we propose a new theory of a threshold in the induction of a stress response in the ASR test, which influences whether the PPI or basal startle response will be affected.

title: Acoustic startle amplitude predicts vulnerability to develop post-traumatic stress hyper-responsivity and associated plasma corticosterone changes in rats
abstract: Following exposure to trauma, a vulnerable sub-population of individuals develops post-traumatic stress disorder (PTSD) with characteristic persistent autonomic hyper-responsivity, associated increased startle response, and commonly altered hypothalamo-pituitary-adrenal regulation. A goal of this investigation was to identify a predictive marker for this vulnerability. Previous investigators have developed a model for PTSD in which male mice were exposed to a single brief episode of inescapable footshock followed by 1-min contextual reminders of this trauma at weekly intervals for 6 weeks. Exposure to these reminders induced a progressive and persistent increase in the amplitude of acoustic startle consistent with the persistently increased acoustic startle of individuals exhibiting PTSD. We adapted this model to adult male Wistar rats, with added characterization of initial (pre-trauma) startle response. After one episode of inescapable footshock (10 s, 2 mA) or control treatment followed by six weekly 1-min contextual reminders, acoustic startle was re-tested. Data were analyzed after dividing rats within each treatment into LOW vs MID vs HIGH (33% in each group) pre-treatment startle responders. Rats which exhibited pre-treatment LOW- and MID-range acoustic startle responses did not develop increased acoustic startle responses following subsequent traumatic stress+reminders ([TS+R]) treatment. However, rats which exhibited HIGH pre-treatment startle responses exhibited further significant (p<0.01) [TS+R]-induced persistent enhancement of this already elevated startle response. Furthermore, rats exhibiting HIGH pre-treatment startle responses were also the only subgroup which exhibited increased basal plasma corticosterone levels following [TS+R] treatment. These results suggest that initial pre-stress acoustic startle response can identify subgroups of rats which are predisposed to, or resistant to, developing a PTSD-like syndrome following subsequent trauma.

title: Lack of effect of an early stressful life event on sensorimotor gating in adult rats
abstract: Hypotheses of the etiology of schizophrenia emphasize the important role of perinatal insults in predisposing individuals to the development of the disease, so that an animal model in which a discrete postnatal manipulation of the infant social environment yields schizophrenia-like behavior in adulthood would be valuable in terms of the study of the neural substrate and treatment of schizophrenia. Schizophrenics demonstrate a deficit in sensorimotor gating (prepulse inhibition), and a similar phenomenon has been described in adult rats following the administration of direct and indirect dopamine agonists. Recently it has been reported that a 24 h separation of rat pups from the mother results in a disruption of prepulse inhibition at adulthood. Here we report a study which investigated the same phenomenon but which, in contrast to the previous study, utilized unrelated subjects all derived from different dams. Maternal separation was conducted for 24 h with pups aged 4, 9 or 18 days and these subjects, together with non-separated controls, were tested at age 3 months in terms of their prepulse inhibition in the acoustic startle response paradigm. Maternal separation did not disrupt prepulse inhibition. Comparison of males and females (with a maximum of one opposite-sex sibling) demonstrated that acoustic startle response and prepulse inhibition of this response was enhanced in males relative to females. This study indicates that 24 h maternal separation does not provide a robust model for studying the effects of early environmental insults on the long-term abnormal development of sensorimotor gating.

title: The differential effects of prenatal stress in rats on the acoustic startle reflex under baseline conditions and in response to anxiogenic drugs
abstract: The prenatal stress syndrome (PS) is characterized by exaggerated behavioral and physiological responses to stressful stimuli and anxiogenic agents.  To characterize the behavioral effects of PS on the acoustic startle reflex (ASR) and to determine the possible role of PS-induced alterations in noradrenergic control of ASR by determining the effects of the α2-adrenoceptor antagonists, yohimbine, idazoxan, and RS79948–197.  PS was induced by exposing pregnant dams to a mild stressor of handling and saline injection (0.1 ml, s.c.) from gestational days 14 to 21. Control dams were left undisturbed throughout pregnancy. Using adult male offspring, all ASR studies consisted of either a 30- or 60-min testing period containing 60 or 120 acoustic startle stimuli trials (95 dB, 50 ms noise burst) at a fixed intertrial interval of 30 s after a 5-min acclimation period. For drug studies, a 3-day repeated measures design was implemented.  With the exception of the response to the first startle stimulus on the first day of testing, there were no significant differences in baseline ASR between control and PS offspring. Low doses of yohimbine, idazoxan, and RS79948–197 were anxiogenic in the ASR test in both control and PS offspring. PS offspring were less responsive to higher doses of yohimbine (5 mg/kg) and idazoxan (8 mg/kg) but did not differ from control in their responses to any dose of RS79948–197.  Anxiogenic effects of yohimbine, idazoxan, and RS79978–197, likely mediated via α2-adrenoceptor blockade, are similar in control and PS rats. Differences between control and PS rats occurred in the response to higher doses of yohimbine and idazoxan. Non-specific effects of these drugs, such as actions at 5HT1A receptors, may cause their behavioral profile to be altered by PS, and to differ from the highly selective RS79948–197.

title: Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia
abstract: Exposure to stress during gestation induces marked changes in the behavior of the affected offspring. Examining the consequences of prenatal stress may prove useful in understanding more about the origins of schizophrenia because a number of clinical investigations have suggested that developmental insults are associated with an increased incidence of schizophrenia. The purpose of these studies is to investigate the effects of stress during gestation on the behaviors of the adult male rat offspring with an emphasis on developing a heuristic animal model of schizophrenia. Pregnant female Sprague-Dawley rats were exposed to a novel variable stress paradigm during either the second or third week of gestation. Behavioral and neuroendocrinological consequences of prenatal stress exposure were evaluated in the male offspring on postnatal day 35 or 56. Prenatal stress exposure during the third week of pregnancy caused adult male rats to exhibit prolonged elevation in plasma glucocorticoid levels following acute exposure to restraint stress indicative of diminished glucocorticoid negative feedback. Similarly, exposure to stress during the third week of pregnancy elicited an enhanced locomotor response to the psychomotor stimulant amphetamine on postnatal day 56 but not on postnatal day 35. In addition, prepulse inhibition of the acoustic startle response was diminished across a range of prepulse stimulus intensities in prenatally stressed adult male rats. Similarly, prenatally stressed rats showed evidence of a disruption in auditory sensory gating as measured by the N40 response. Taken together, these findings suggest that prenatal stress exposure significantly changed many facets of adult rat behavior. Interestingly, the behaviors that are altered have been used to validate animal models of schizophrenia and therefore, suggest that this preparation may be useful to learn more about some aspects of the pathophysiology of schizophrenia.

title: Sensitization and habituation of the acoustic startle reflex in patients with schizophrenia
abstract: Assessments of prepulse inhibition and habituation of the acoustic startle response have proved to be valuable tools for assessing deficits of sensorimotor gating and information processing in schizophrenia patients. Recent studies, however, have reported inconsistent results regarding startle habituation deficits in schizophrenia using block-to-block analyses. Some of these inconsistencies may be due to abnormal initial sensitization effects to startle-eliciting stimuli. In a longitudinal study during the course of an acute psychotic episode, 34 medicated inpatients were examined with regard to sensitization and habituation effects in a trial-by-trial analysis and compared with 18 normal control subjects. On two examinations--10 days after admission and after psychopathological improvement 2-3 weeks later--schizophrenia patients exhibited an exaggerated magnitude increment across the first few startle-eliciting stimuli and habituation deficits that were evident when the effect of sensitization was removed from analysis. In the present study, both increased sensitization and reduced habituation appeared to be trait markers of schizophrenic psychoses. The enhanced sensitization effect--presumably due to an abnormal arousal modulation--reflects abnormal stimulus processing in schizophrenia, i.e. the diminished ability to learn the irrelevance of simple identical stimuli. In addition, the present data have important implications for designing startle studies to assess sensitization, habituation and prepulse inhibition in one session.

title: Differential effects of mild repeated restraint stress on behaviors and GABAA receptors in male and female rats
abstract: We previously reported that the very mild stress of individual housing influenced seizure risk and gamma-amino butyric acid (GABA(A)) receptor activity differentially between male and female rats. The aim of the present set of studies was to assess sex differences in behavioral responses to a more pronounced type of stressor, repeated restraint stress. We also wanted to determine the role of GABA(A) receptors in effects of this stressor. Our data suggest that repeated restraint stress afforded short-term protection against seizure induction in both male and female rats. Moreover, this protection was more persistent in female than male rats. This stress paradigm also elicited a reduction in general activity in male rats, whereas female rats displayed prolonged increased activity following the repeated restraint stress exposure. However, there were limited effects on anxiety-like behaviors, as determined by time spent in the open arms on the elevated plus maze. Sex differences in stress-induced increases in plasma corticosterone levels were observed, which generally correlated with sex differences in behavioral measures. There were no significant effects of the repeated restraint stress exposure on benzodiazepine/GABA(A) receptor density or affinity nor on receptor function. Taken together, these findings provide additional evidence to support the important influences of sex in responding to stress and highlight the need to consider this context when addressing the role of stress in health issues for women and men.

title: Restraint stress in biobehavioral research: Recent developments
abstract: In the 15 years since the publication of two previous reviews on restraint stress much advancement has been made in the field. However, while previous reviews have focused mainly on drug effects, recent research has focused on broader implications in the health fields. This research has placed an increased emphasis on stress effects in physiological, immunological, endocrine and developmental processes as well as the impact of stress on numerous disorders. A major problem with our review was the inability to identify a large number of articles focusing on restraint and immobilization, since those keywords were often omitted from the title or not referred to within the body of the article. It seems likely that additional reviews with extended literature research of this field are required.

title: Effects of prenatal exposure to chronic mild stress and toluene in rats.
abstract: The aim of the present study was to elucidate whether prenatal chronic stress, in combination with exposure to a developmental neurotoxicant, would increase effects in the offspring compared with the effects of either exposure alone. Development and neurobehavioral effects were investigated in female offspring of pregnant rats ( exposed to chronic mild stress (CMS) during gestational days (GD) 9-20, or 1500 ppm toluene, 6 h/day during gestational days 7-20, or a combination of the two. Prenatal CMS was associated with decreased thymic weight and increased auditory startle response. The corticosterone response to restraint seemed modified by prenatal exposure to toluene. Lactational body weight was decreased in offsprings subjected to CMS, primarily due to effects in the combined exposure group. Cognitive function was investigated in the Morris water maze, and some indications of improved function due to CMS were observed. In the present experimental setting, there was no indication of the two exposures potentiating each other with respect to adverse effects on the nervous system. However, the effects of prenatal CMS indicate that stress during fetal life may interfere with the development of the thymus and increase the reactivity (startle reflex) of the offspring.

title: Effects of repeated fluoxetine on anxiety-related behaviours, central serotonergic systems, and the corticotropic axis in SHR and WKY rats
abstract: In keeping with the anxiolytic property of selective serotonin reuptake inhibitors (SSRIs) in humans, we have examined in the spontaneously hypertensive rat (SHR) and the Wistar-Kyoto (WKY) rat, which display low and high anxiety, respectively, some psychoneuroendocrine effects of a repeated treatment with the SSRI fluoxetine (5 or 10 mg/kg daily, for 3 weeks). Two days after the last injection, plasma levels of fluoxetine were not detectable whereas those of its metabolite, norfluoxetine, were present to similar extents in both strains. By means of the elevated plus-maze test (29-30 h after the 13th administration of fluoxetine) and an open field test (48 h after the last injection of fluoxetine), it was observed that fluoxetine pretreatment did not yield anxiolysis; hence, some, but not all, behaviours were indicative of anxiety and hypolocomotion (as assessed through principal component analyses and acute diazepam studies). In both strains, the 10 mg/kg dose of fluoxetine decreased hypothalamus 5-HT and 5-HIAA levels, and reduced midbrain and/or hippocampus [3H]citalopram binding at 5-HT transporters, but did not affect [3H]8-hydroxy-2-(di-N-propylamino)tetralin binding at hippocampal 5-HT1A receptors. However, the fluoxetine-elicited reduction in hippocampal 5-HT transporter binding was much more important in WKY than in SHR rats, this strain-dependent effect being associated in WKY rats with a reduction in cortical [3H]ketanserin binding at 5-HT2A receptors. Lastly, in WKY rats, repeated fluoxetine administration increased adrenal weights and the plasma corticosterone response to open field exposure, but did not affect the binding capacities of hippocampal mineralocorticoid and glucocorticoid receptors. These data show that key psychoneuroendocrine responses to repeated fluoxetine administration may be strain-dependent, and that repeated fluoxetine administration does not yield anxiolysis, as assessed by two standard tests of emotivity.

title: The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review.
abstract: The open field is a very popular animal model of anxiety-like behavior. An overview of the literature on the action elicited by effective or putative anxiolytics in animal subjected to this procedure indicates that classical treatments such as benzodiazepine receptor full agonists or 5-HT(1A) receptor full or partial agonists elicit an anxiolytic-like effect in this procedure in most cases (approximately 2/3). However, compounds (triazolobenzodiazepines such as adinazolam and alprazolam, selective serotonin reuptake inhibitors) that have a different spectrum of therapeutic efficacy in anxiety disorders such as panic attacks, generalized anxiety disorder or obsessive-compulsive disorder were poorly effective as anxiolytics in the open field test, suggesting that this paradigm may not model features of anxiety disorders. The procedure is also relevant for the study of compounds endowed with anxiogenic effects, as such effects were detected after treatments with benzodiazepine receptor inverse agonists or with corticotropin releasing factor (CRF) receptor agonists.

title: Fluoxetine during Development Reverses the Effects of Prenatal Stress on Depressive-Like Behavior and Hippocampal Neurogenesis in Adolescence
abstract: Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

title: Neonatal handling reverses behavioral abnormalities induced in rats by prenatal stress
abstract: The aim of this study was to see whether neonatal handling can reverse the behavioral deficits induced in rats by unpredictable prenatal stress. Rats (24) were exposed to random noise and light stress (RS) on a random basis throughout pregnancy. Half the litters of RS and control (C) dams were subjected to neonatal handling (NH), 3' daily for 21 days. Behavioral measures, open field in both sexes and plus maze test in females only were conducted at 1.5-2 months, and spatial lateralization by amphetamine-induced rotation, in females at 3 months. RS caused significant increases in emotionality and timidity (higher incidence of defecation and less time in open arms of plus maze), and a change in directional bias towards the left. NH completely reversed all these behavioral abnormalities in RS rats but had little effect in C. It is concluded that NH can influence postnatal development of brain organisation in the opposite direction to that induced by prenatal stress.

title: Sex differences in corticolimbic dopamine and serotonin systems in the rat and the effect of postnatal handling
abstract: Stress-related psychopathology is particularly prevalent in women, although the neurobiological reason(s) for this are unclear. Dopamine (DA) and serotonin (5-HT) systems however, are known to play important adaptive roles in stress and emotion regulation. The aims of the present study included examination of sex differences in stress-related behaviour and neuroendocrine function as well as post mortem neurochemistry, with the main hypothesis that corticolimbic DA and 5-HT systems would show greater functional activity in males than females. Long-Evans rats of both sexes were employed. Additional factors incorporated included differential postnatal experience (handled vs. nonhandled) and adult mild stress experience (acute vs. repeated (5) restraint). Regional neurochemistry measures were conducted separately for left and right hemispheres. Behaviourally, females showed more exploratory behaviour than males in the elevated plus maze and an openfield/holeboard apparatus. Females also exhibited significantly higher levels of adrenocorticotrophic hormone and corticosterone at all time points in response to restraint stress than males across treatment conditions, although both sexes showed similar habituation in stress-induced ACTH activation with repeated mild stress. Neurochemically, females had significantly higher levels of DA (in ventromedial prefrontal cortex (vmPFC), insular cortex and n. accumbens) and 5-HT (in vmPFC, amygdala, dorsal hippocampus and insula) than males. In contrast, males had higher levels of the DA metabolite DOPAC or DOPAC/DA ratios than females in all five regions and higher levels of the 5-HT metabolite 5-HIAA or 5-HIAA/5-HT ratios in vmPFC, amygdala and insula, suggesting greater neurotransmitter utilization in males. Moreover, handling treatment induced a significant male-specific upregulation of 5-HT metabolism in all regions except n. accumbens. Given the adaptive role of 5-HT and DAergic neurotransmission in stress and emotion regulation, the intrinsic sex differences we report in the functional status of these systems across conditions, may be highly relevant to the differential vulnerability to disorders of stress and emotion regulation.

title: Periodic Maternal Deprivation Induces Gender-Dependent Alterations in Behavioral and Neuroendocrine Responses to Emotional Stress in Adult Rats
abstract: There is evidence that stressful events during the neonatal "stress hyporesponsive period" may influence both emotional behavior and the maturation of the hypothalamic-pituitary-adrenal (HPA) axis in rats. We tested whether periodic maternal deprivation (180 min daily on postnatal days 3-10, PMD) caused chronic changes in emotional behavior and HPA axis activity in either male or female adult rats, or both. In addition, HPA secretory responses to human/rat corticotropin-releasing factor (CRH, 50 ng/kg i.v.) were determined in the adult males. In the elevated plus-maze test, adult (4-5 months of age) PMD-treated animals of both sexes displayed increased anxiety-related behavior compared to control rats. This was indicated by a reduction in the number of entries (male: 70% reduction, p < 0.01; female: 31% reduction, p < 0.01) and amount of time spent on the open arms (male: 86% reduction, p < 0.01; female: 40% reduction, NS). Neuroendocrine parameters were also altered in PMD-treated rats in a gender-dependent manner. Whereas basal plasma adrenocorticotropin (ACTH) and corticosterone levels did not differ significantly between PMD and control groups of either sex, the ACTH response to elevated plus-maze exposure, a predominantly emotional stressor, was higher in male (p < 0.01), but not female, PMD animals than in the respective controls. In contrast, PMD had no effect on behavioral (duration of struggling) or HPA axis responses to forced swimming (90 s, 19 degrees C), a complex and predominantly physical stressor, in either male or female rats. In response to CRH stimulation, PMD-treated males did not show differences in the ACTH secretion compared to controls, indicating alterations in HPA axis regulation at a suprapituitary level. Thus, PMD caused long-term changes in the emotional behavior of adult rats of both sexes, although to a differing degree in males and females, whereas it appeared to cause predominantly alterations in the HPA axis response in males, depending on the characteristics of the stressor used.

title: Prenatal stress and postnatal development of neonatal rats — sex-dependent effects on emotional behavior and learning ability of neonatal rats
abstract: Maternal sound stress (800 Hz; 77 dB, every other minute for 15 min/day, from day 10 to 18 of gestation), combined with forced swimming stress (15 min/day), was found to cause potentiation of sound‐induced loss of locomotor activity, referred to as emotional behavior, of male offspring, but not that of female offspring, at 4 weeks of age. Maternal stress also caused an increase in the total number of errors by male, but not female offspring in the water‐maze test at 6 weeks of age. These effects of stress on emotional behavior and learning behavior were abolished when dams were pretreated with buspirone (30 min before the stress, from day 8 to 18 of gestation). Thus, prenatal stress might have sex‐dependent effects on emotional behavior and learning ability of neonatal rats.

title: Prenatal Restraint Stress Generates Two Distinct Behavioral and Neurochemical Profiles in Male and Female Rats
abstract: Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS (“PRS rats”) showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.

title: Tests for emotionality in rats and mice: a review.
abstract: This paper examines the concept of emotionality, particularly in relation to measures taken in ‘novel environment’ tests (e.g. the open field). Evidence of several different types is reviewed to assess the validity of the measures in relation to common assumptions underlying their use. In response to increased light and noise, open field defecation increases and ambulation decreases, and thus on this basis they may be termed emotional responses. In many cases defecation and ambulation in the open field showed a fairly low but significant inverse correlation. Nevertheless, a number of limitations to this relationship were found, depending on the species, strain, sex, sample size, and early experience; other, presumed, measures of emotionality in the open field showed little consistent relationship to defecation, but the evidence here was sparse. Studies measuring heart-rate responses provided insufficient evidence to relate open field defecation to this other response presumed to be under sympathetic nervous control. Ambulation showed little descriptive validity as a measure of exploration; owing to the occurrence of both immobility and escape behaviour as alternative forms of emotional behaviour, ambulation also provided an inadequate indication of emotional responses. Thus, conceptual frameworks which suggested that emotionality energized ambulation in a consistent manner were criticized. Open field defecation showed little relationship to supposed measures of emotionality taken in other types of tests (e.g. emergence tests, active avoidance learning); these findings clearly failed to support the use of emotionality as a consistent constitutional trait, with unitary drive properties. Two alternative methods were suggested, for testing: (a) responses to novel environments, and (b) emotional behaviour, without making assumptions that the measures represent unitary major motivational constructs.

title: Differences in open-field behavior and in learning tasks between two rat strains differing in their reactivity to stressors
abstract: The study characterizes differences between inbred Wistar-Kyoto (WKYs) and Brown-Norway (BNs) rats in open-field behavior, and in discriminative learning and acquisition of an avoidance learning task. Hyper-reactivity of WKYs to novelty was demonstrated in an open-field test. Discriminative learning and retention thereof was slower in WKYs, but as efficient as in BNs. Acquisition of avoidance learning was also slower in WKYs, but their maximal avoidance score was much higher (approximately 85%) than in BNs. Also, recall of avoidance learning was slower for WKYs. We conclude: (1) hyper-reactivity of WKYs to novelty is expressed by their exceptional immobility and excess defecation in the open-field and is paralleled by their known hyper-reactivity to stressful stimuli, and (2) no strain differences exist in the ability to learn a discriminative task, but both acquisition and recall of an avoidance task are slower in WKYs. This may imply that the degree of reactivity to stressful environmental stimuli may play an important role in the acquisition of learning.

title: The adolescent brain and age-related behavioral manifestations
abstract: To successfully negotiate the developmental transition between youth and adulthood, adolescents must maneuver this often stressful period while acquiring skills necessary for independence. Certain behavioral features, including age-related increases in social behavior and risk-taking/novelty-seeking, are common among adolescents of diverse mammalian species and may aid in this process. Reduced positive incentive values from stimuli may lead adolescents to pursue new appetitive reinforcers through drug use and other risk-taking behaviors, with their relative insensitivity to drugs supporting comparatively greater per occasion use. Pubertal increases in gonadal hormones are a hallmark of adolescence, although there is little evidence for a simple association of these hormones with behavioral change during adolescence. Prominent developmental transformations are seen in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems. Developmental changes in these stressor-sensitive regions, which are critical for attributing incentive salience to drugs and other stimuli, likely contribute to the unique characteristics of adolescence.

title: Stress and the developing adolescent brain
abstract: Adolescence is a time of continued brain maturation, particularly in limbic and cortical regions, which undoubtedly plays a role in the physiological and emotional changes coincident with adolescence. An emerging line of research has indicated that stressors experienced during this crucial developmental stage may affect the trajectory of this neural maturation and contribute to the increase in psychological morbidities, such as anxiety and depression, often observed during adolescence. In this review, we discuss the short- and long-term effects of periadolescent stress exposure on the structure and function of the brain. More specifically, we examine how stress at prepubertal and early adolescent stages of development affects the morphological plasticity of limbic and cortical brain regions, as well as the enduring effects of adolescent stress exposure on these brain regions in adulthood. We suggest that, due to a number of converging factors during this period of maturation, the adolescent brain may be particularly sensitive to stress-induced neurobehavioral dysfunctions with important consequences on an individual's immediate and long-term health and well-being.

title: The cellular neurobiology of depression
abstract: Major depressive disorders, long considered to be of neurochemical origin, have recently been associated with impairments in signaling pathways that regulate neuroplasticity and cell survival. Agents designed to directly target molecules in these pathways may hold promise as new therapeutics for depression.

title: Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats.
abstract: Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for depression. Recent reports in the literature describe differences in antidepressant effects among SSRIs. Although each SSRI apparently has different pharmacological actions aside from serotonin reuptake inhibition, the relations between antidepressant effects and unique pharmacological properties in respective SSRIs remain unclear. This study was designed to compare abilities of three systemically administered SSRIs to increase the extracellular levels of serotonin, dopamine, and noradrenaline acutely in three brain regions of male Sprague-Dawley rats. We examined effects of sertraline, fluvoxamine, and paroxetine on extracellular serotonin, dopamine, and noradrenaline levels in the medial prefrontal cortex, nucleus accumbens and striatum of rats using in vivo microdialysis. Dialysate samples were collected in sample vials every 20 min for 460 min. Extracellular serotonin, dopamine, and noradrenaline levels were determined using high-performance liquid chromatography with electrochemical detection. All SSRI administrations increased extracellular serotonin levels in all regions. Only sertraline administration increased extracellular dopamine concentrations in the nucleus accumbens and striatum. All SSRI administrations increased extracellular noradrenaline levels in the nucleus accumbens, although fluvoxamine was less effective. These results suggest that neurochemical differences account for the differences in clinical antidepressant effects among SSRIs.

title: The glucocorticoid receptor: Pivot of depression and of antidepressant treatment?
abstract: Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis and increased levels of glucocorticoid hormones in patients with depression have mostly been ascribed to impaired feedback regulation of the HPA axis, possibly caused by altered function of the receptor for glucocorticoid hormones, the glucocorticoid receptor (GR). Antidepressants, in turn, ameliorate many of the neurobiological disturbances in depression, including HPA axis hyperactivity, and thereby alleviate depressive symptoms. There is strong evidence for the notion that antidepressants exert these effects by modulating the GR. Such modulations, however, can be manifold and range from regulation of receptor expression to post-translational modifications, which may result in differences in GR nuclear translocation and GR-dependent gene transcription. The idea that the therapeutic action of antidepressants is mediated, at least in part, by restoring GR function, is consistent with studies showing that decreased GR function contributes to HPA axis hyperactivity and to the development of depressive symptoms. Conversely, excessive glucocorticoid signalling, which requires an active GR, is associated with functional impairments in the depressed brain, especially in the hippocampus, where it results in reduced neurogenesis and impaired neuroplasticity. In this review, we will focus on the GR as a key player in the precipitation, development and resolution of depression. We will discuss potential explanations for the apparent controversy between glucocorticoid resistance and the detrimental effects of excessive glucocorticoid signalling. We will review some of the evidence for modulation of the GR by antidepressants and we will provide further insight into how antidepressants may regulate the GR to overcome depressive symptoms.

title: The neurobiology of depression and antidepressant action
abstract: We present a comprehensive overview of the neurobiology of unipolar major depression and antidepressant drug action, integrating data from affective neuroscience, neuro- and psychopharmacology, neuroendocrinology, neuroanatomy, and molecular biology. We suggest that the problem of depression comprises three sub-problems: first episodes in people with low vulnerability ('simple' depressions), which are strongly stress-dependent; an increase in vulnerability and autonomy from stress that develops over episodes of depression (kindling); and factors that confer vulnerability to a first episode (a depressive diathesis). We describe key processes in the onset of a 'simple' depression and show that kindling and depressive diatheses reproduce many of the neurobiological features of depression. We also review the neurobiological mechanisms of antidepressant drug action, and show that resistance to antidepressant treatment is associated with genetic and other factors that are largely similar to those implicated in vulnerability to depression. We discuss the implications of these conclusions for the understanding and treatment of depression, and make some strategic recommendations for future research.

title: Remodeling of Hippocampal Spine Synapses in the Rat Learned Helplessness Model of Depression
abstract: Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications.



We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm.



Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for 6 days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared with nonstressed control rats. Shorter, 1-day or 3-day desipramine treatments, however, had neither synaptic nor behavioral effects.



These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression.

title: Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms
abstract: Increasing evidence demonstrates that neuroplasticity, a fundamental mechanism of neuronal adaptation, is disrupted in mood disorders and in animal models of stress. Here we provide an overview of the evidence that chronic stress, which can precipitate or exacerbate depression, disrupts neuroplasticity, while antidepressant treatment produces opposing effects and can enhance neuroplasticity. We discuss neuroplasticity at different levels: structural plasticity (such as plastic changes in spine and dendrite morphology as well as adult neurogenesis), functional synaptic plasticity, and the molecular and cellular mechanisms accompanying such changes. Together, these studies elucidate mechanisms that may contribute to the pathophysiology of depression. Greater appreciation of the convergence of mechanisms between stress, depression, and neuroplasticity is likely to lead to the identification of novel targets for more efficacious treatments.

title: Role of the Amygdala in Antidepressant Effects on Hippocampal Cell Proliferation and Survival and on Depression-like Behavior in the Rat
abstract: The stimulation of adult hippocampal neurogenesis by antidepressants has been associated with multiple molecular pathways, but the potential influence exerted by other brain areas has received much less attention. The basolateral complex of the amygdala (BLA), a region involved in anxiety and a site of action of antidepressants, has been implicated in both basal and stress-induced changes in neural plasticity in the dentate gyrus. We investigated here whether the BLA modulates the effects of the SSRI antidepressant fluoxetine on hippocampal cell proliferation and survival in relation to a behavioral index of depression-like behavior (forced swim test). We used a lesion approach targeting the BLA along with a chronic treatment with fluoxetine, and monitored basal anxiety levels given the important role of this behavioral trait in the progress of depression. Chronic fluoxetine treatment had a positive effect on hippocampal cell survival only when the BLA was lesioned. Anxiety was related to hippocampal cell survival in opposite ways in sham- and BLA-lesioned animals (i.e., negatively in sham- and positively in BLA-lesioned animals). Both BLA lesions and low anxiety were critical factors to enable a negative relationship between cell proliferation and depression-like behavior. Therefore, our study highlights a role for the amygdala on fluoxetine-stimulated cell survival and on the establishment of a link between cell proliferation and depression-like behavior. It also reveals an important modulatory role for anxiety on cell proliferation involving both BLA-dependent and –independent mechanisms. Our findings underscore the amygdala as a potential target to modulate antidepressants' action in hippocampal neurogenesis and in their link to depression-like behaviors.

title: Prenatal stress has pro-inflammatory consequences on the immune system in adult rats
abstract: The in utero environment is critical for initiating the ontogeny of several physiological systems, including the immune surveillance. Yet, little is known about adverse early experiences on the offspring's immunity and vulnerability to disease. The present work aimed at investigating the impact of restraint prenatal stress (PS) on the development and responsiveness of in vitro and in vivo cellular and humoral immunity of male progeny aged 7 weeks and 6 months. In adult 6-month-old rats, we detected increased circulating CD8(+)-expressing and NK cells in PS rats as compared to controls, associated with higher mRNA expression of IFN-gamma. In addition, in vitro stimulation with phytohemagglutinin-A induced an increase in both the proliferation of T lymphocytes and the secretion of IFN-gamma in PS rats. Interestingly, these alterations were undetectable in younger PS rats (7-week old), except for a slight increase in the mRNA expression of several pro-inflammatory cytokines in peripheral blood mononuclear cells. Moreover, in vivo neutralization of IFN-gamma in young rats had no effects in PS group. In conclusion, we report for the first time long-lasting pro-inflammatory consequences of PS in rats.

title: Prenatal stress, fetal imprinting and immunity
abstract: A comprehensive number of epidemiological and animal studies suggests that prenatal and early life events are important determinants for disorders later in life. Among them, prenatal stress (i.e. stress experienced by the pregnant mother with impact on the fetal ontogeny) has programming effects on the hypothalamic-pituitary-adrenocortical axis, brain neurotransmitter systems and cognitive abilities of the offspring. This review focuses on the impact of maternal stress during gestation on the immune function in the offspring. It compares results from different animal species and highlights potential mechanisms for the immune effects of prenatal stress, including maternal glucocorticoids and placental functions. The existence of possible windows of increased vulnerability of the immune system to prenatal stress during gestation is discussed. Several gaps in the present knowledge are pointed out, especially concerning the time when prenatal stress effects are expressed during postnatal life, why this expression is delayed after birth and whether prenatal stress predisposes to immune-related pathologies later in life.

title: Influence of prenatal maternal stress on the immunocompetence of the offspring
abstract: To evaluate the effects of prenatal maternal stress on the development of humoral immunocompetence in the offspring and on their hormonal and immunologic responses to postnatal stress, gravid Sprague-Dawley rats were exposed daily on gestational days 15-21 to prenatal environmental stress [(PES) 15 unsignaled, inescapable electric foot-shocks (0.05 mA for 0.5 s)] or prenatal psychological stress [(PPS) pregnant rats were placed in the nonelectrified section of the apparatus and allowed to see, hear, and smell a nonpregnant partner being environmentally stressed]. Pregnant controls (PC) were placed in the apparatus for 30 min. Serum corticosterone (CCS) and immunoglobulin G (IgG) levels were measured in the offspring every 7 days from birth to postnatal day (PND) 28. On PND 29-33, offspring were environmentally stressed; hormonal and immune status were determined on PND 34. Levels of IgG were reduced in PES and PPS offspring on PND 0 and in PES offspring on PND 7 and 28. These changes were unrelated to differences in CCS and did not reflect altered maternal-pup interactions or nutritional factors. Postnatal stress was immunosuppressive in PC pups but did not alter immune parameters in PPS offspring. In PES females, postnatal stress was also immunosuppressive. However, in PES males with already reduced IgG levels postnatal stress enhanced immune function. These data provide the first experimental evidence that prenatal maternal stress can alter immune parameters in the rat offspring.

title: Maternal Glucocorticoid Secretion Mediates Long-Term Effects of Prenatal Stress
abstract: There is growing evidence that stressors occurring during pregnancy can impair biological and behavioral adaptation to stress in the adult offspring. Mechanisms by which stress in the pregnant rat can influence development of the offspring are still unknown. In the present study, we investigated the involvement of maternal corticosterone secretion during pregnancy on the hypothalamo–pituitary–adrenal axis activity of adult offspring. We investigated stress-induced corticosterone secretion and hippocampal type I and type II corticosteroid receptors in male adult rats submitted to prenatal stress born to either mothers with intact corticosterone secretion or mothers in which stress-induced corticosterone secretion was blocked by adrenalectomy with substitutive corticosterone therapy. Repeated restraint during the last week of pregnancy was used as prenatal stressor. Furthermore, the specific role of an injection of corticosterone before the restraint stress on adrenalectomized mothers with substitutive corticosterone treatment was also studied. We report here that blockade of the mother’s stress-induced glucocorticoid secretion suppresses the prolonged stress-induced corticosteroid response and the decrease in type I hippocampal corticosteroid receptors usually observed in prenatally stressed adults. Conversely, corticosterone administered during stress, to mothers in which corticosterone secretion is blocked, reinstates the effects of prenatal stress. These results suggest for the first time that stress-induced increases in maternal glucocorticoids may be a mechanism by which prenatal stress impairs the development of the adult offspring’s glucocorticoid response.

title: Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators.
abstract: Stress begins in the brain and affects the brain, as well as the rest of the body. Acute stress responses promote adaptation and survival via responses of neural, cardiovascular, autonomic, immune and metabolic systems. Chronic stress can promote and exacerbate pathophysiology through the same systems that are dysregulated. The burden of chronic stress and accompanying changes in personal behaviors (smoking, eating too much, drinking, poor quality sleep; otherwise referred to as "lifestyle") is called allostatic overload. Brain regions such as hippocampus, prefrontal cortex and amygdala respond to acute and chronic stress and show changes in morphology and chemistry that are largely reversible if the chronic stress lasts for weeks. However, it is not clear whether prolonged stress for many months or years may have irreversible effects on the brain. The adaptive plasticity of chronic stress involves many mediators, including glucocorticoids, excitatory amino acids, endogenous factors such as brain neurotrophic factor (BDNF), polysialated neural cell adhesion molecule (PSA-NCAM) and tissue plasminogen activator (tPA). The role of this stress-induced remodeling of neural circuitry is discussed in relation to psychiatric illnesses, as well as chronic stress and the concept of top-down regulation of cognitive, autonomic and neuroendocrine function. This concept leads to a different way of regarding more holistic manipulations, such as physical activity and social support as an important complement to pharmaceutical therapy in treatment of the common phenomenon of being "stressed out". Policies of government and the private sector play an important role in this top-down view of minimizing the burden of chronic stress and related lifestyle (i.e. allostatic overload).

title: Enhancing versus Suppressive Effects of Stress on Immune Function: Implications for Immunoprotection and Immunopathology
abstract: Stress is known to suppress immune function and increase susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate asthma, and allergic, autoimmune and inflammatory diseases, although such diseases should be ameliorated by immunosuppression. Moreover, the short-term fight-or-flight stress response is one of nature’s fundamental defense mechanisms that enables the cardiovascular and musculoskeletal systems to promote survival, and it is unlikely that this response would suppress immune function at a time when it is most required for survival (e.g. in response to wounding and infection by a predator or aggressor). These observations suggest that stress may suppress immune function under some conditions while enhancing it under others. The effects of stress are likely to be beneficial or harmful depending on the type (immunoprotective, immunoregulatory/inhibitory, or immunopathological) of immune response that is affected. Studies have shown that several critical factors influence the direction (enhancing vs. suppressive) of the effects of stress or stress hormones on immune function: (1) Duration (acute vs. chronic) of stress: Acute or short-term stress experienced at the time of immune activation can enhance innate and adaptive immune responses. Chronic or long-term stress can suppress immunity by decreasing immune cell numbers and function and/or increasing active immunosuppressive mechanisms (e.g. regulatory T cells). Chronic stress can also dysregulate immune function by promoting proinflammatory and type-2 cytokine-driven responses. (2) Effects of stress on leukocyte distribution: Compartments that are enriched with immune cells during acute stress show immunoenhancement, while those that are depleted of leukocytes, show immunosuppression. (3) The differential effects of physiologic versus pharmacologic concentrations of glucocorticoids, and the differential effects of endogenous versus synthetic glucocorticoids: Endogenous hormones in physiological concentrations can have immunoenhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immunosuppressive. (4) The timing of stressor or stress hormone exposure relative to the time of activation and time course of the immune response: Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response. We propose that it is important to study and, if possible, to clinically harness the immunoenhancing effects of the acute stress response, that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve. In view of the ubiquitous nature of stress and its significant effects on immunoprotection as well as immunopathology, it is important to further elucidate the mechanisms mediating stress-immune interactions and to meaningfully translate findings from bench to bedside.

title: Evidence for an inhibitory immunomodulatory effect of selected antidepressants on rat splenocytes: possible relevance to depression and hyperactive-immune disorders.
abstract: Antidepressants have been found to possess antiproliferative effect. In the immune system depression may activate pro-inflammatory cytokines. Therefore, the aim of this study was to assess the immunomodulatory activity of antidepressants in naïve rat. Rat splenocytes were activated with con A and treated with paroxetine, sertraline or clomipramine ex vivo. We found that the antidepressants inhibit cell viability and proliferation at IC50 of 5-8 microM of mitogen-stimulated rat splenocytes. This inhibitory effect was accompanied by cell cycle arrest and increase in apoptotic events as assayed by FACS. Moreover, antidepressants decrease the secretion of the TH1 factor--TNFalpha. In addition, the antidepressants reduced the expression of the enzyme cyclooxygenase2 which is involved in inflammation. On the cellular level we show the up-regulation of MAPK death signaling pathway and suppression of the anti-apoptotic factor--Bcl-2. These findings reveal the immunomodulatory effect of the selected antidepressants. These data suggest a novel use of antidepressants or their derivatives.

title: The interaction between prenatal stress and neonatal handling on nociceptive response latencies in male and female rats
abstract: Neonatal handling produces physiological and behavioral changes that persist into adulthood. These effects are opposite to those resulting from prenatal stress (PS). We examined the interaction between PS and handling on nociception in adult male and female rats. Randomly selected pregnant rats were subjected to restraint stress on days 13-17 of gestation for 25 min each day, or left undisturbed. At birth, selected stressed/nonstressed litters were assigned to be handled. handling consisted of 15 min of separation from the dam, once per day, from postnatal days 1-14. At 4 months of age, rats were placed on a 50 degrees C hot plate, and their latencies to paw lick were recorded. Prenatal stress and handling interacted to affect latencies in male rats. Handled (H)/PS rats had significantly lower paw lick latencies than nonhandled (NH)/PS rats (p < 0.05). However, handling had no effect on the male offspring of control dams. Handling elevated paw lick latencies in the female offspring of control dams, an effect that was most pronounced in diestrous vs. estrous rats. The NH/PS rats showed significantly elevated latencies compared to NH/NS rats (p < 0.05). These results suggest that handling effects on nociception are most apparent in rats subjected to PS; in males at least, these effects would otherwise not be present.

title: Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors.
abstract: Selective serotonin reuptake inhibitors (SSRIs), in addition to their antidepressant effects, have been reported to have antiinflammatory effects. The aim of this study was to assess the antiarthritic potential of 2 SSRIs, fluoxetine and citalopram, in murine collagen-induced arthritis (CIA) and in a human ex vivo disease model of rheumatoid arthritis (RA).



Following therapeutic administration of SSRIs, paw swelling was assessed and clinical scores were determined daily in DBA/1 mice with CIA. Joint architecture was examined histologically at the end of the treatment period. Cultures of human RA synovial membranes were treated with SSRIs, and cytokine production was measured. Toll-like receptor (TLR) function was examined in murine and human macrophages, human B cells, and human fibroblast-like synovial cells treated with SSRIs.



Both SSRIs significantly inhibited disease progression in mice with CIA, with fluoxetine showing the greatest degree of efficacy at the clinical and histologic levels. In addition, both drugs significantly inhibited the spontaneous production of tumor necrosis factor, interleukin-6, and interferon-gamma-inducible protein 10 in human RA synovial membrane cultures. Fluoxetine and citalopram treatment also inhibited the signaling of TLRs 3, 7, 8, and 9, providing a potential mechanism for their antiinflammatory action.



Fluoxetine and citalopram treatment selectively inhibit endosomal TLR signaling, ameliorate disease in CIA, and suppress inflammatory cytokine production in human RA tissue. These data highlight the antiarthritic potential of the SSRI drug family and provide further evidence of the involvement of TLRs in the pathogenesis of RA. The SSRIs may provide a template for potential antiarthritic drug development.

title: Gender-specific effects of prenatal stress on emotional reactivity and stress physiology of goat kids
abstract: The aims of this study were to investigate the effects of maternal stress during pregnancy on the emotional reactivity, the hypothalamo-pituitary-adrenocortical (HPA) axis, and the sympatho-adrenomedullary (SAM) system of goat offspring according to their gender, and to investigate the role of maternal cortisol in prenatal stress effects. Goats were exposed to ten transports in isolation or ten ACTH injections (0.125 IU/kg body weight) during the last third of pregnancy. Control goats remained undisturbed. No effect of repeated transport during the last third of pregnancy was found on basal cortisol concentrations of the offspring. However, an increase in phenylethanolamine N-methyl transferase activity in the adrenals was observed in prenatally stressed kids compared to control kids (P = 0.031). In the presence of novelty, prenatally stressed female kids were more active (P = 0.049) than control females; they also showed more signs of arousal (P = 0.039) and tended to explore more of their environment (P = 0.053) in reaction to a startling stimulus. On the contrary, prenatally stressed male kids tended to be less active (P = 0.051) than control male kids but showed more signs of distress (P = 0.047) in the presence of novelty. Intermediate effects were found on the emotional reactivity to novelty of kids born from dams given injections of ACTH. In conclusion, transport stress in pregnant goats affects the sympatho-adrenomedullary system and the emotional reactivity of their offspring in a gender-specific manner. Moreover, the effects of prenatal transport and ACTH injections showed some similarities but differed in some critical details.