bluuebunny/crossref_metadata_2025 huggingface dataset:
Apoptosis in Isolated Adult Cardiomyocytes Exposed to Adriamycina
Authors: KUMAR DINENDER , KIRSHENBAUM LORRIE , LI TIMAO , DANELISEN IGOR , SINGAL PAWAN
Published: February 2006

Abstract: Adriamycin (doxorubicin) is a highly potent antineoplastic agent, but its use is limited by the risk of developing cardiomyopathy and congestive heart failure. Available evidence suggests that adriamycin‐induced congestive heart failure is mediated by oxidative stress. We examined the possibility of adriamycin‐induced apoptosis in isolated adult rat cardiomyocytes and its inhibition by trolox, a water‐soluble antioxidant. Cardiomyocytes isolated from rat hearts were exposed to 20 μM adriamycin for 1 h and examined at different post‐treatment durations (0–23 h). Adriamycin caused a significant decrease in rod‐shaped cells and an increase in round cells. Both Hoechst 33258 staining and TUNEL assay revealed a significantly increased number of apoptotic myocytes and nucleosomal fragmentation upon exposure to adriamycin. In agarose gel electrophoresis, DNA laddering was found to be more intense in adriamycin‐exposed myocytes. A bright smear at the leading edge of the gels suggested indiscriminate fragmentation of DNA and myocyte necrosis by adriamycin. Both types of DNA degradations due to adriamycin were significantly reduced by trolox. We suggest that adriamycin‐induced cell death involves both apoptosis and necrosis and these may be mediated by oxidative stress.
Physical Exercise and Antioxidant Defenses in the Hearta
Authors: ATALAY MUSTAFA , SEN CHANDAN K.
Published: February 2006

Abstract: Cardiac muscle relies highly on aerobic metabolism. Heart muscle has a high oxygen uptake at resting conditions, which increases many fold during exhaustive physical exercise. Such a high rate of oxidative metabolism is often associated with enhanced production of reactive oxygen metabolites. A single bout of strenuous exercise has been demonstrated to induce oxidative damage in heart. Such oxidant insult may lead to adaptive responses and strengthen antioxidant defenses in the heart tissue. Endurance exercise training has indeed been shown to upregulate heart tissue antioxidant defenses. Recently, we have observed that even predominantly anaerobic sprint training regimens may enhance cardiac antioxidant defenses. Regular physical exercise may beneficially influence cardiac antioxidant defenses and promote overall cardiac function.
New Insights into Cardioprotection by Ischemic Preconditioning and Other Forms of Stressa
Authors: ZEEUW SANDRA DE , VAN DEN DOEL MIRELLA A. , DUNCKER DIRK J. , VERDOUW PIETER D.
Published: February 2006

Abstract: Ischemic preconditioning has not only received wide attention in heart research, but has also been a topic of extensive studies involving other organs. In several of these studies, it has been shown that in spite of differences in the endpoints used to assess protection, the same mediators as in myocardial ischemic preconditioning may be involved. However, several of the putative mediators do not require ischemia to become activated. This has guided us and others to investigate whether the myocardium can also be protected by brief ischemia in other organs and whether other non‐pharmacological forms of stress, which do not produce ischemia but are capable of activating these potential mediators, are also cardioprotective.
Role of KATPChannel in Heat Shock and Pharmacological Preconditioninga
Authors: KUKREJA RAKESH C.
Published: February 2006

Abstract:Heat shock (HS) and 4‐monophosphoryl lipid A (MLA, a non‐toxic analogue of endotoxin) protects the myocardium against ischemia‐reperfusion injury. We studied the involvement of ATP‐sensitive potassium channel (KATPchannel) in ischemic protection induced by these stimuli. Anesthetized rabbits were preconditioned with either HS (by raising temperature to 42°C for 15 min) or intravenous pretreatment with MLA (35 μg/kg). After 24 h, animals were re‐anesthetized and subjected to 30‐min regional ischemia followed by 180‐min reperfusion (I/R). KATPchannel blockers glibenclamide and/or 5‐hydroxydecanoate (5‐HD) were used to inhibit channel function. The 72 kD heat shock protein (HSP‐72) was measured by Western blots. HS produced a marked reduction in infarct size (39.4 ± 8.1% to 14.3 ± 2.5%,p< 0.05) that was abolished by glibenclamide (42.3 ± 3.2%) and 5‐HD (33.7 ± 4.8%) when given before I/R. These drugs failed to block HS protection when given before HS. Expression of HSP‐72 was increased in all HS groups as compared to non‐HS groups in both glibenclamide and 5‐HD‐treated rabbits. Similarly, pretreatment with MLA reduced infarct size from 40 ± 8.6% to 15.1 ± 1.5% (p< 0.05). The infarct size increased to 51.9 ± 5.8 with 5‐HD in MLA‐treated rabbits. 5‐HD did not alter infarct size significantly when given in vehicle‐treated control rabbits. These data suggest that HS and MLA exert their anti‐ischemic effect through activation of KATPchannel.
Metabolic Changes in the Normal and Hypoxic Neonatal Myocardium
Authors: ABDEL‐ALEEM SALAH , ST. LOUIS JAMES D. , HUGHES G. CHAD , LOWE JAMES E.
Published: February 2006

Abstract: Hypoxia is characterized by inadequate oxygen delivery to the myocardium with a resulting imbalance between oxygen demand and energy supply. Several adaptive mechanisms occur to preserve myocardial survival during hypoxia. These include both short‐ and long‐term mechanisms, which serve to achieve a new balance between myocardial oxygen demand and energy production. Short‐term adaptation includes downregulation of myocardial function along with upregulation of energy production via anaerobic glycolysis following an increase in glucose uptake and glycogen breakdown. Long‐term adaptation includes genetic reprogramming of key glycolytic enzymes. Thus, the initial decline in high‐energy phosphates following hypoxia is accompanied by a decrease in myocardial contractility and myocardial energy requirements are subsequently met by ATP supplied from anaerobic glycolysis. Thus, a downregulation in cardiac function and/or enhanced energy production via anaerobic glycolysis are the major mechanisms promoting myocardial survival during hypoxia. In contrast to the aforementioned metabolic changes occurring in adult myocardium, the effects of chronic hypoxia on neonatal myocardial metabolism remain undefined. Studies from our laboratory using a novel neonatal piglet model of chronic hypoxia have shown a shift in cardiac myocyte substrate utilization towards the newborn state with a preference for glucose utilization. We have also shown, using this same model, that chronically hypoxic neonatal hearts were more tolerant to ischemia than non‐hypoxic hearts. This ischemic tolerance is likely due to adaptive metabolic changes in the chronically hypoxic hearts, such as increased anaerobic glycolysis and glycogen breakdown.
Regulation of Cardiovascular Development and Physiology by Hypoxia‐Inducible Factor 1a
Authors: SEMENZA GREGG L. , AGANI FATON , IYER NARAYAN , KOTCH LORI , LAUGHNER ERIK , LEUNG SANDRA , YU AIMEE
Published: February 2006

Abstract: Hypoxia is an essential pathophysiologic component of ischemic cardiovascular disease. A better understanding of the molecular mechanisms underlying adaptive responses to hypoxia may lead to novel therapeutic strategies. Hypoxia‐inducible factor 1 (HIF‐1) is a heterodimeric basic‐helix‐loop‐helix‐PAS domain transcription factor that mediates changes in gene expression in response to changes in O2 concentration. Genes that are transcriptionally activated by HIF‐1 in hypoxic cells encode proteins that increase O2 delivery or allow metabolic adaptation to limited O2 availability. HIF‐1 target genes include those encoding vascular endothelial growth factor (VEGF), erythropoietin, glucose transporters, and glycolytic enzymes. In anemic fetal sheep, increased myocardial vascularization was associated with concomitant increases in the expression of HIF‐1 and VEGF. Expression of HIF‐1 target genes was not induced by hypoxia in embryonic stem cells lacking expression of the O2‐regulated HIF‐1αa subunit. Mouse embryos lacking HIF‐1α expression arrested in their development by E9.0 and died by E10.5 with cardiovascular malformations and massive cell death throughout the embryo. These studies indicate that HIF‐1 functions as a master regulator of O2 homeostasis that controls the establishment of essential physiologic systems during embryogenesis as well as their subsequent utilization during fetal and postnatal life.
Activity of Cytochrome c Oxidase in the Right and Left Ventricular Myocardium of Male and Female Rats Exposed To Intermittent High Altitude Hypoxiaa
Authors: STIEGLEROVÁ A. , DRAHOTA Z. , HOUSTEK J. , MILEROVÁ M. , PELOUCH V. , OSTADAL B.
Published: February 2006

Abstract: The aim of the present study was to compare the capacity of the oxidative metabolism (total activity of cytochrome c oxidase, COX) in the right and left ventricular myocardium of adult rats exposed to intermittent high altitude (IHA) hypoxia simulated in a barochamber (5,000 m, 8 h/day, 5 days/wk, for a total of 32 exposures). In male and female rats, IHA induced significant increases of the right ventricular (RV) weight and protein content, whereas left ventricular (LV) weight and protein content remained unaffected. Consequently, the RV/LV ratio in both sexes markedly increased. Similarly, IHA induce an increase of the total activity of COX in RV in both sexes. The specific activities of COX in homogenate as well as in isolated mitochondria were not changed in IHA‐exposed animals, which indicates that the increase of total activity of COX is proportional to the increase of total protein content and RV weight.
Alternatives for Myocardial Protection: Adenosine‐Enhanced Ischemic Preconditioninga
Authors: MCCULLY JAMES D. , LEVITSKY SIDNEY
Published: February 2006

Abstract: Intrinsic to the development of new myoprotective protocols for use in cardiac surgery are the requirements of new protocols to be equal to or better than conventional cardioplegia in providing for enhanced postischemic functional recovery and decreased myocardial infarct size. Our data suggest that adenosine‐enhanced ischemic preconditioning, in which a bolus injection of adenosine to the myocardium is used coincident with ischemic preconditioning, meets these requirements, providing equal cardioprotection as that of cold blood cardioplegia, significantly decreasing myocardial infarct size and significantly enhancing postischemic myocardial functional recovery in both the isolated perfused rabbit heart and in the in situ blood‐perfused sheep heart. These results further suggest that adenosine‐enhanced ischemic preconditioning may provide an effective, alternative myocardial protective protocol to reduce the morbidity and mortality in cardiac surgery.
Nitric Oxide and the Vascular Endothelium in Myocardial Ischemia‐Reperfusion Injurya
Authors: VINTEN‐JOHANSEN JAKOB , ZHAO ZHI‐QING , NAKAMURA MASANORI , JORDAN JAMES E. , RONSON RUSSELL S. , THOURANI VINOD H. , GUYTON ROBERT A.
Published: February 2006

Abstract: The normal coronary vascular endothelium (VE) tonically releases nitric oxide (NO) by converting L‐arginine to citrulline by a constitutive NO synthase. Reperfusion after myocardial ischemia reduces basal and stimulated release of NO. This “vascular reperfusion injury” is mediated largely by neutrophils (PMN) through specific interactions between adhesion molecules on the endothelium and the PMN, an interaction that precedes myocyte injury. NO inhibits the PMN‐mediated reperfusion injury by direct effects on both the PMN and the vascular endothelium. Cardioprotective strategies include augmentation of endogenous NO by the precursor L‐arginine and the administration of exogenous NO donors at the time of perfusion, which (1) attenuates PMN adherence to the coronary artery and venous endothelium, (2) reduces PMN‐mediated endothelial dysfunction, (3) reduces PMN accumulation in the area at risk, and (4) reduces infarct size. Hence, NO represents a powerful therapeutic tool with which to attenuate the consequences of ischemia‐reperfusion injury on vascular injury and infarction.
Nitric Oxide Prevents Myoglobin/tert‐Butyl Hydroperoxide‐Induced Inhibition of Ca2+ Transport in Skeletal and Cardiac Sarcoplasmic Reticulum
Authors: MENSHIKOVA ELIZABETH V. , RITOV VLADIMIR B. , GORBUNOV NIKOLAJ V. , SALAMA GUY , CLAYCAMP H. GREGG , KAGAN VALERIAN E.
Published: February 2006

Abstract: Interaction of hydrogen peroxide or organic hydroperoxides with hemoproteins is known to produce oxoferryl hemoprotein species that act as very potent oxidants. Since skeletal and cardiac muscle cells contain high concentrations of myoglobin this reaction may be an important mechanism of initiation or enhancement of oxidative stress, which may impair their Ca2+ transport systems. Using skeletal and cardiac sarcoplasmic reticulum (SR) vesicles, we demonstrated by EPR the formation of alkoxyl radicals and protein‐centered peroxyl radicals in the presence of myoglobin (Mb) and tert‐butyl hydroperoxide (t‐BuOOH). The low temperature EPR signal of the radicals was characterized by a major feature at
g= 2.016

and a shoulder at
g= 2.036

. In the presence of SR vesicles, the magnitude of the protein‐centered peroxyl radical signal decreased, suggesting that the radicals were involved in oxidative modification of SR membranes. This was accompanied by SR membrane oxidative damage, as evidenced by accumulation of 2‐thiobarbituric acid‐reactive substances (TBARS) and the inhibition of Ca2+ transport. We have shown that nitric oxide (NO), reacting with redox‐active heme iron, can prevent peroxyl radical formation activated by Mb/t‐BuOOH. Incubation of SR membranes with an NO donor, PAPA/NO (a non‐thiol compound that releases NO) at 200–500 μM completely prevented the t‐BuOOH‐dependent production of peroxyl radicals and formation of TBARS, and thus protected against oxidative inhibition of Ca2+ transport.
Role for NADPH/NADH Oxidase in the Modulation of Vascular Tonea
Authors: MÜNZEL THOMAS , HINK ULRICH , HEITZER THOMAS , MEINERTZ THOMAS
Published: February 2006

Abstract: The endothelium modulates vascular tone by producing vasodilator andvasoconstrictor substances. Of these, the best characterized and potentially most important are nitric oxide (NO•) and O2−•. These small molecules exhibit opposing effects on vascular tone and chemically react with each other in a fashion that negates their individual effects and leads to the production of potentially toxic substances, such as peroxynitrite (ONOO−). These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis. The precise O2−• source within vascular tissue remains to be determined. Recent work demonstrated that in endothelial cells as well as in vascular smooth muscle cells, a membrane‐associated NAD(P)H‐dependent oxidase represents the most significant O2−• source. Interestingly, this oxidase is activated upon stimulation with angiotensin II, suggesting that under all conditions of an activated circulating and/or local renin‐angiotensin system endothelial dysfunction secondary to increased vascular O2−• production is expected.
Differential Regulation of Apoptosis by Ischemia‐Reperfusion and Ischemic Adaptationa
Authors: MAULIK NILANJANA , SASAKI HIROAKI , GALANG NATHANIEL
Published: February 2006

Abstract: Ischemia and reperfusion injure the heart, as manifested by myocardial infarction, postischemic ventricular functional dysfunctions, arrhythmias, and cardiomyocyte apoptosis. Hearts can be adapted to ischemicreperfusion injury by subjecting them to non‐lethal cyclic episodes of shortterm ischemia and reperfusion. The adapted myocardium becomes resistant to subsequent lethal ischemic injury. Reactive oxygen species and oxidative stress play crucial roles in the pathophysiology of ischemic‐reperfusion injury. The adapted hearts, when subjected to subsequent ischemia and reperfusion, generate a reduced amount of oxygen free radicals compared to the nonadapted hearts. The number of cardiomyocytes undergoing apoptotic cell death is reduced in the adapted hearts subjected to ischemia and reperfusion. In concert, the adapted myocardium is associated with increased antioxidant gene Bcl‐2, increased binding activity of the nuclear transcription factor NFκB, and reduced binding activity of AP‐1 compared to nonadapted hearts. Yet when nonadapted hearts are subjected to ischemia and reperfusion, Bcl‐2 is downregulated while NFκB is moderately upregulated and AP‐1 is significantly upregulated.
Apoptosis in Myocardial Ischemia‐Reperfusion
Authors: GOTTLIEB ROBERTA A. , ENGLER ROBERT L.
Published: February 2006

Abstract: The signal transduction pathways by which ischemia‐reperfusion leads to apoptosis may involve the JNK pathway, ceramide generation, and inhibition of protective PKC pathways. The biochemical events associated with apoptosis include mitochondrial inactivation, cytochrome c dislocation, caspase activation, and cytoplasmic acidification. Through the concerted efforts of multiple classes of enzymes, apoptosis is accomplished, resulting in the death of a cell in which potentially transforming oncogenes have been degraded and inflammatory contents are contained within the plasma membrane until the fragments can be ingested by phagocytes. This non‐inflammatory mode of cell death permits tissue remodeling with minimal scar formation, and so is preferable to necrotic cell death. The distinction between apoptosis and necrosis, which implies different mechanisms of cell death, is blurred in the case of a pathologic insult such as ischemia‐reperfusion. It is suggested that it is more useful to view cell death in the context of whether or not it can be prevented
Stress Signal to Survival and Apoptosisa
Authors: TAKEDA ATSUSHI , TAKEDA NOBUAKIRA
Published: February 2006

Abstract: This investigation focused on whether apoptosis can be observed in some heart diseases. Apoptosis was examined immunochemically using monoclonal antibodies such as p53, Bcl‐2 and cyclin E, A, and B1 in parallel with flow cytometry. Left ventricular myocardium was obtained at autopsy from 40 patients with acute myocarditis (AM;
N= 10

, 6 males, 4 females, mean age 56 ± 13 years), chronic myocarditis (CM;
N= 10,

5 males, 5 females, mean age 48 ± 16 years), dilated cardiomyopathy (DCM;
N= 10,

7 males, 3 females, mean age 60 ± 11 years), and no heart disease (Cont;
N= 10,
5 males, 5 females, mean age 63 ± 14 years). Cell cycle analysis of myocytes by flow cytometry revealed that the relative content of G2M phase in acute myocarditis was far higher than those in other heart diseases (AM, 12.3 ± 3.7%; CM, 5.2 ± 4.5%; DCM, 6.3 ± 4.0%; Cont, 3.4 ± 1.8%; Mean ± SD). Expression of p53 was observed mainly in myocytes from chronic myocarditis. Expression of Bcl‐2, on the other hand, was detected in myocytes from acute myocarditis. Results suggest that apoptosis may play some role in the repairing process of myocardial inflammation.
The Concepts of the Ventral Striatopallidal System and Extended Amygdala
Authors: DE OLMOS JOSE S. , HEIMER LENNART
Published: February 2006

ABSTRACT: The concepts of the ventral striatopallidal system and extended amygdala have significantly improved our understanding of basal forebrain organization. As a result of these and other advances during the last twenty years, many of the most prominent basal forebrain structures, including the nucleus accumbens, olfactory tubercle, and amygdaloid body, have all but lost their relevance as independent functional anatomical units. In order to appreciate the distinct differences that exist between the ventral striatopallidal system and the extended amygdala, and as a way of explaining the choice of the terms ventral striatopallidal system and extended amygdala, we will review the discovery and subsequent elaboration of these two systems. On the background of these discussions, we will then proceed to dispel some recently published misgivings regarding the usefulness of the extended amygdaloid concept.
The Concept of the Ventral Striatum in Nonhuman Primates
Authors: HABER SUZANNE N. , McFARLAND NIKOLAUS R.
Published: February 2006

ABSTRACT: The concept of the ventral striatum was first put forth by Heimer and Wilson to describe the extension of basal ganglia elements into the olfactory tubercle. The ventral striatum includes the conventional nucleus accumbens, which has been closely associated with reward and motivation. This paper uses the afferent connections to the ventral striatum to define this region in monkeys. Furthermore the shell and core subterritories are discussed with respect to their histochemistry and specific connections.
Mesolimbic Neuronal Activity across Behavioral States
Authors: WOODWARD DONALD J. , CHANG JING‐YU , JANAK PATRICIA , AZAROV ALEXEY , ANSTROM KRISTIN
Published: February 2006

ABSTRACT:A goal of neurophysiology of the mesolimbic system is to determine the activity patterns within the regions in the prefrontal cortex, ventral neostriatum, and amygdala that regulate behavioral patterns to seek rewards. A new technology has been introduced in which arrays of microwires are implanted in different brain regions while activity patterns of ensembles of neurons are recorded for long periods of time during freely moving behaviors. Multichannel instrumentation and software is used for data acquisition and analysis. An initial hypothesis was that neural signals would be encountered in the nucleus accumbens and associated regions specifically related to reward. However, an initial study of neural activity and behavioral patterns during a simple lever press for intravenous cocaine (1 mg/kg) revealed that phasic excitatory or inhibitory neural activity patterns often appear prior to the reward phase. Individual neurons throughout the mesolimbic system appear to code information specific to sensory and motor events, tones, or lever presses in the chain of tasks leading to all rewards so far studied. Different spatial temporal patterns also appear within the same neural populations, as reward is changed from injected cocaine to heroin, from ingested pure water to ethanol in water or sucrose. Overall, patterns of activity for each neuron are found to shift dynamically during the operant task as changes are made in the target reward. Significant shifts in activity of mesolimbic neurons that are unrelated to specific sensory‐motor events also appear during complex sessions, such as during a bout of ethanol consumption to reach satiation or during progressive ratio tasks with increasing difficulty. An emerging hypothesis is that some candidate neural elements in the mesolimbic system code the anticipated reward, whereas others serve internal logic functions of motivation that mediate extinction or resumption of specific goal‐directed behaviors.
Regulation of Neurotransmitter Interactions in the Ventral Striatum
Authors: McGINTY JACQUELINE F.
Published: February 2006

ABSTRACT:Transsynaptic activation of neuronal circuits originating in the basal forebrain contributes to psychostimulant‐evoked dopamine and glutamate release and consequent changes in medium spiny neuronal gene expression in the ventral striatum. New evidence from microdialysis studies indicates that amphetamine‐induced dopamine and glutamate releasein vivois partially calcium dependent. The calcium‐dependent component is totally blocked by a kappa opioid receptor agonist, indicating that endogenous opioids may regulate dopamine‐glutamate interactions in the ventral striatum. Further, muscarinic receptor blockade increases, and muscarinic receptor stimulation decreases, dialysate glutamate levels in the striatum. Pre‐ and postsynaptic muscarinic receptors contribute to the ability of the muscarinic antagonist, scopolamine, to augment D1receptor‐stimulated immediate early and neuropeptide gene expression. Moreover, scopolamine prevents a D2antagonist from blocking D1agonist‐induced gene expression, indicating that activation of cholinergic interneurons contributes to D1/D2interactions in the striatum. Thus, transsynaptic activity and presynaptic muscarinic and kappa opioid receptors regulate dopamine and glutamate interactions that switch on and off multiple intracellular signaling cascades. Changes in immediate early and neuropeptide gene expression that result from activation of these cascades are mediated by such nuclear transcription factors as phosphorylated cyclase response element‐binding protein. In addition, a novel signaling pathway involving the RAR/RXR nuclear hormone receptor complex is implicated in the control of dopamine receptor and neuropeptide gene expression in the striatum.
The Synaptic Framework for Chemical Signaling in Nucleus Accumbens
Authors: MEREDITH G. E.
Published: February 2006

ABSTRACT: Our knowledge of the organization of the nucleus accumbens has been greatly advanced in the last two decades, but only now are we beginning to understand the complex neural circuitry that underlies the mix of behaviors attributed to this nucleus. Superimposed on the neurochemically defined territories of the shell and core are four or more conduits for information flow. Each of these behaviorally relevant pathways can be characterized by the spatial distribution of inputs to its central unit: the GABAergic projection neuron, a spiny cell that also contains the opioid peptides, enkephalin or dynorphin. In this review, current models of accumbal circuits will be examined and, with the aid of recent anatomical findings, further extended to shed light on how functionally diverse information is processed in this nucleus. However complex, accumbal wiring is not fixed, and, as we will show, psychostimulants, dopamine‐deleting lesions, and chronic blockade of dopaminergic receptors can alter the anatomical substrate, synaptology, and neurotrophic factors that govern circuits through the shell and core.
The Intrinsic Organization of the Central Extended Amygdala
Authors: CASSELL MARTIN D. , FREEDMAN LORIN J. , SHI CHANGJUN
Published: February 2006

ABSTRACT: The central component of the extended amygdala (CEA) comprises the central amygdaloid nucleus (Ce), the dorsal substantia innominata (SI), and the bed nucleus of the stria terminalis (BNST). Anatomical studies have suggested the presence of an intrinsic system of GABAergic neurons that not only connects homologous subareas of the Ce, SI, and BNST but that also acts as an interface between sensory afferents and brain stem‐projecting neurons. CEA outputs, with a few exceptions, arise from separate populations of neurons, but all, including GABAergic neurons themselves, are heavily innervated by GABAergic terminals. GABAergic neurons may serve to integrate output activity of the CEA, though GABAergic neurons form a heterogeneous population whose differential intrinsic connections appear related to their peptide content. Afferents from the dysgranular insular cortex and lateral parabrachial complex preferentially innervate GABAergic neurons, suggesting these neurons may also integrate afferent activity. Afferents from the basolateral amygdala (BL) appear to innervate both output neurons and intrinsic GABAergic neurons. Evidence will be presented to show that BL afferents form synaptic complexes with cortical, GABAergic, and TH‐immunoreactive terminal boutons on GABAergic dendritic spines. These complexes may be a key element in control of CEA output activity.
The Medial Extended Amygdala in Male Reproductive Behavior A Node in the Mammalian Social Behavior Network
Authors: NEWMAN SARAH WINANS
Published: February 2006

ABSTRACT: Hormonal and chemosensory signals regulate social behaviors in a wide variety of mammals. In the male Syrian hamster, these signals are integrated in nuclei of the medial extended amygdala, where olfactory and vomeronasal system transmission is modulated by populations of androgen‐ and estrogen‐sensitive neurons. Evidence from behavioral changes following lesions and from immediate early gene expression supports the hypothesis that the medial extended amygdala and medial preoptic area belong to a circuit that functions selectively in male sexual behavior. However, accumulated behavioral, neuroanatomical, and neuroendocrine data in hamsters, other rodents, and other mammals indicate that this circuit is embedded in a larger integrated network that controls not only male mating behavior, but female sexual behavior, parental behavior, and various forms of aggression. In this context, perhaps an individual animal's social responses can be more eaisly understood as a repertoire of closely interrelated, hormone‐regulated behaviors, shaped by development and experience and modulated acutely by the environmental signals and the hormonal milieu of the brain.
The Extended Amygdala and Salt Appetite
Authors: JOHNSON ALAN KIM , de OLMOS JOSE , PASTUSKOVAS CINTHIA V. , ZARDETTO‐SMITH ANDREA M. , VIVAS LAURA
Published: February 2006

ABSTRACT:Both chemo‐ and mechanosensitive receptors are involved in detecting changes in the signals that reflect the status of body fluids and of blood pressure. These receptors are located in the systemic circulatory system and in the sensory circumventricular organs of the brain. Under conditions of body fluid deficit or of marked changes in fluid distribution, multiple inputs derived from these humoral and neural receptors converge on key areas of the brain where the information is integrated. The result of this central processing is the mobilization of homeostatic behaviors (thirst and salt appetite), hormone release, autonomic changes, and cardiovascular adjustments. This review discusses the current understanding of the nature and role of the central and systemic receptors involved in the facilitation and inhibition of thirst and salt appetite and on particular components of the central neural network that receive and process input derived from fluid‐ and cardiovascular‐related sensory systems. Special attention is paid to the structures of the lamina terminalis, the area postrema, the lateral parabrachial nucleus, and their association with the central nucleus of the amygdala and the bed nucleus of the stria terminalis in controlling the behaviors that participate in maintaining body fluid and cardiovascular homeostasis.
The Extended Amygdala: Are the Central Nucleus of the Amygdala and the Bed Nucleus of the Stria Terminalis Differentially Involved in Fear versus Anxiety?
Authors: DAVIS MICHAEL , SHI CHANGJUN
Published: February 2006

ABSTRACT:Although there is a close correspondence between fear and anxiety, and the study of fear in animals has been extremely valuable for under‐standing the neural basis of anxiety, it is also clear that a richer animal model of human anxiety disorders would include measures of both stimulus‐specific fear and something less stimulus specific, more akin to anxiety. Patients with posttraumatic stress syndrome seem to show normal fear reactions but abnormal anxiety measured with the acoustic startle reflex. Studies in rats, also using the startle reflex, indicate that highly processed explicit cue information (lights, tones) activates the central nucleus of the amygdala, which projects to and modulates the acoustic startle pathway in the brain stem. Less explicit information, such as that produced by exposure to a threating environment or by intraventricular administration of corticotropin‐releasing hormone, may activate another part of the extended amygdala, the bed nucleus of the stria terminalis, which also projects to the startle pathway. Because this information may be less specific and of long duration, activation of the bed nucleus of the stria terminalis may mediate anxiety, whereas activation of the central nucleus of the amygdala may mediate stimulus‐specific fear.
Brain and Sexual Behavior
Authors: LARSSON KNUT , AHLENIUS SVEN
Published: February 2006

ABSTRACT: This chapter will give personal accounts of the neural basis of male rat sexual behavior from two somewhat different perspectives, one tilted towards neuroanatomy (K.L.), and one tilted towards monoaminergic pharmacology (S.A.). Both perspectives were strongly influenced by the Zeitgeist, the former imperceptibly merging into the latter as relations between the neural substrate for monoaminergic neurotransmission was elucidated. 1
The Basal Forebrain Corticopetal System Revisited
Authors: ZABORSZKY L. , PANG K. , SOMOGYI J. , NADASDY Z. , KALLO I.
Published: February 2006

ABSTRACT:The medial septum, diagonal bands, ventral pallidum, substantia innominata, globus pallidus, and internal capsule contain a heterogeneous population of neurons, including cholinergic and noncholinergic (mostly GABA containing), corticopetal projection neurons, and interneurons. This highly complex brain region, which constitutes a significant part of the basal forebrain has been implicated in attention, motivation, learning, as well as in a number of neuropsychiatric disorders, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Part of the difficulty in understanding the functions of the basal forebrain, as well as the aberrant information‐processing characteristics of these disease states lies in the fact that the organizational principles of this brain area remained largely elusive. On the basis of new anatomical data, it is proposed that a large part of the basal forebrain corticopetal system be organized into longitudinal bands. Considering the topographic organization of cortical afferents to different divisions of the prefrontal cortex and a similar topographic projection of these prefrontal areas to basal forebrain regions, it is suggested that several functionally segregated cortico‐prefronto‐basal forebrain‐cortical circuits exist. It is envisaged that such specific “triangular” circuits could amplify selective attentional processing in posterior sensory cortical areas.
Prefrontal Cortical Networks Related to Visceral Function and Mood
Authors: PRICE JOSEPH L.
Published: February 2006

ABSTRACT: At least twenty‐two architectonic areas can be distinguished within the orbital and medial prefrontal cortex (OMPFC). Although each of these areas has a distinct structure and connections, they can be grouped into two “networks,” defined by cortico‐cortical connections that primarily interconnect areas within each network. The networks also have different connections to the striatum, medial thalamus, and other brain regions. The orbital network consists of most of the areas in the orbital cortex. It receives several sensory inputs (olfactory, gustatory, visceral afferent, somatic sensory, and visual) that appear to be related to feeding. It also receives many limbic inputs from the amygdala, entorhinal and perirhinal cortex, and subiculum, including a specific projection from the ventrolateral part of the basal amygdaloid nucleus. The orbital network may therefore serve as a substrate to integrate viscerosensory information with affective signals. The medial network consists of areas on the medial frontal surface together with a few select areas in the orbital cortex. These areas have few direct sensory inputs, and their limbic inputs are somewhat different than those to the orbital network (e.g., from the ventromedial part of the basal amygdaloid nucleus). However, they provide the major output from the OMPFC to the hypothalamus and brain stem (especially the periaqueductal gray). The medial network may therefore serve as a visceromotor system to provide frontal cortical influence over autonomic and endocrine function. Connections between the networks presumably allow information flow from viscerosensory to visceromotor systems. In addition to a probable role in eating behavior, this system appears to be involved in guiding behavior and regulation of mood. Lesions of the ventromedial prefrontal cortex result in sociopathic behavior and difficulty in making appropriate choices, whereas functional imaging studies indicate that subjects with unipolar and bipolar depression have abnormal activity in medial and orbital prefrontal areas. Many of these areas also show volume changes and decreased glial number and density in mood‐disordered subjects.
The Role of Dopamine, Dynorphin, and CART Systems in the Ventral Striatum and Amygdala in Cocaine Abuse
Authors: HURD YASMIN L. , SVENSSON PERNILLA , PONTÉN MARJAN
Published: February 2006

ABSTRACT: Disturbance of the mesolimbic dopamine system has long been hypothesized for the underlying neurobiology of cocaine addiction. Recently, increased attention has been directed towards the opioid neuropeptide system, in particular dynorphin; inasmuch as opioid peptide‐containing neurons are regulated by dopamine, these peptides have potent effects on mood and reward, and cocaine consistently modulates dynorphin activity. Our experiments have been directed towards characterizing the specific alterations of dopamine and dynorphin systems during different stages following cocaine administration, as well as assessing the contribution of nucleus accumbens and amygdala dopamine levels to cocaine‐intake behavior. We have used the techniques of in vivo microdialysis to measure and manipulate extracellular concentrations of dopamine in animals that self‐administer cocaine, and in situ hybridization to study mRNA expression levels of prodynorphin and dopamine receptors. It is clear from these studies that different stages of the cocaine use cycle are characterized by distinct patterns of prodynorphin and dopamine D1 mRNA expression levels. Moreover, cocaine‐intake behavior is sensitive to very specific concentrations of dopamine in the nucleus accumbens as well as in the amygdala. Recently, the CART (cocaine and amphetamine‐regulated transcript) peptide was proposed as a novel target for the actions of psychostimulant drugs. We have noted differences between male and female rats in the mesolimbic mRNA expression of CART that might be relevant for gender differences apparent in drug abuse.
D3 Dopamine and Kappa Opioid Receptor Alterations in Human Brain of Cocaine‐overdose Victims
Authors: MASH DEBORAH C. , STALEY JULIE K.
Published: February 2006

ABSTRACT: Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry, which affects motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blockade of DA uptake, reciprocal signaling between DA and endogenous opioids has important implications for understanding cocaine dependence. We have used in vitro autoradiography and ligand binding to map D3 DA and kappa opioid receptors in the human brains of cocaine‐overdose victims. The number of D3 binding sites was increased one‐ to threefold over the nucleus accumbens and ventromedial sectors of the caudate and putamen from cocaine‐overdose victims, as compared to age‐matched and drug‐free control subjects. D3 receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased sixfold in cocaine‐overdose victims over control values, suggesting that cocaine exposure also affects the expression of D3 receptor mRNA. The number of kappa opioid receptors in the nucleus accumbens and other corticolimbic areas from cocaine fatalities was increased twofold as compared to control values. Cocaine‐overdose victims exhibiting preterminal excited delirium had a selective upregulation of kappa receptors measured also in the amygdala. Understanding the complex regulatory profiles of DA and opioid synaptic markers that occur with chronic misuse of cocaine may suggest multitarget strategies for treating cocaine dependence.
Mesolimbic Activity Associated with Psychosis in Schizophrenia: Symptom‐specific PET Studies
Authors: EPSTEIN JANE , STERN EMILY , SILBERSWEIG DAVID
Published: February 2006

ABSTRACT: Hallucinations and paranoid delusions are prominent among the positive symptoms of schizophrenia. Such psychotic symptoms are notable for their aberrant representations of, and relation to, the external world and for the emotional/motivational valence associated with the representations. As mesolimbic structures, including the amygdala and ventral striatum, are thought to play a significant role in imparting emotional valence to external stimuli, we here examine the mesolimbic findings of H215O PET studies designed to probe the functional neuroanatomy of psychosis.

Patients with schizophrenia (including those with active hallucinations, those with active paranoid delusions, and those without active positive symptoms at the time of scanning) and healthy control subjects were studied. An event‐related PET paradigm was used to identify the neural correlates of hallucinations, and a modified emotional stroop paradigm (with threat versus neutral words) was used to test the hypothesis that paranoid patients would have increased mesolimbic activity in response to threat, and even in response to neutral stimuli.

The findings suggest that the positive psychotic symptoms of hallucinations and delusions share similar functional neuroanatomical features of increased mesotemporal and ventral striatal activity in the setting of decreased prefrontal activity. The pattern is evident even in a neutral context, unlike the case for normal subjects, who show such features only in response to threat. The implications of these findings for a pathophysiology of psychosis will be discussed in the context of the behavioral neuroanatomical literature in animals and humans.
Prefrontal Cortical‐Amygdalar Metabolism in Major Depression
Authors: DREVETS WAYNE C.
Published: February 2006

ABSTRACT: Functional neuroimaging studies of the anatomical correlates of familial major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose metabolism in depression in the amygdala and the orbital and medial prefrontal cortical (PFC) areas that are extensively connected with the amygdala. The amygdala metabolism in MDD and BD is positively correcated with both depression severity and “stressed” plasma cortisol concentrations measured during scanning. During antidepressant drug treatment, the mean amygdala metabolism decreases in treatment responders, and the persistence of elevated amygdala metabolism during remission is associated with a high risk for the development of depressive relapse. The orbital C Metabolism is also abnormally elevated during depression, but is negatively correlated with both depression severity and amygdala metabolism, suggesting that this structure may be activated as a compensatory mechanism to modulate amygdala activity or amygdala‐driven emotional responses. The posterior orbital C and anterior cingulate C ventral to the genu of the corpus callosum (Subgenual PFC) have more recently been shown in morphometric MRI and/or post mortem histopathological studies to have reduced grey matter volume and reduced glial cell numbers (with no equivalent loss of neurons) in familial MDD and BD. These data suggest a neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli. Antidepressant drugs may compensate for this dysfunction by inhibiting pathological limbic activity.
Afferent Connections to the Ventral Striatum from the Medial Prefrontal Cortex (Area 25) and the Thalamic Nuclei in the Macaque Monkey
Authors: NAKANO K. , KAYAHARA T. , CHIBA T.
Published: February 2006

ABSTRACT: The ventral striatal inputs in the macaque monkey were studied in relation to the connections from the orbitofrontal cortex, focusing on the infralimbic area (IL or area 25), thalamic nuclei and the vagal‐solitary nuclear complex (NTS‐X). The IL projects to more restricted parts of the ventral striatum (shell and core of nucleus accumbens, Acb; ventricular margin of caudate nucleus, CN), whereas the striatal projections of the prelimbic area (PL) are more extended than those of IL. The dorsal midline nuclei project densely to area 13, agranular insular cortex (Ia), and Acb. The nucleus ventralis anterior pars magnocellularis (VAmc) projects to the IL, perigenual area and to the region of CN between the limbic and association striatum with partial overlapping, and seems to play a role as an interface between the limbic and motor systems. The distribution pattern of retrogradely labeled neurons was similar in the midline‐intralaminar thalamic nuclei following injections in the IL and ventral striatum.
Imidazoline Receptor Antisera‐Selected cDNA Clone and mRNA Distributiona
Authors: PILETZ JOHN E. , JONES JULIA CAY , ZHU HE , BISHARA OSAMA , ERNSBERGER PAUL
Published: February 2006

ABSTRACT: A novel cDNA, designated Imidazoline Receptor Antisera‐Selected cDNA‐1 (iras‐1), encodes a 167‐kD protein. Two of its predicted peptides (42–43 kD) are immunologically consistent with a previously reported 11‐imidazoline binding protein. In the present study, two forms of iras mRNA (6.0 and 9.5 kb) were quantified across fresh rat tissues. Highest levels were found in brain (almost exclusively 6.0 kb in size), followed by liver and lung (9.5 ≥ 6.0 kb iras mRNA), kidney (6.0 > 9.5 kb), heart (6.0 kb), spleen (6.0 ≥ 9.5 kb), testes (6.0 > 9.5 kb), and skeletal muscle (6.0 > 9.5 kb). A correlation exists (ρ= 0.71, p= 0.05) between total (6.0 + 9.5 kb) iras mRNA and I1 BMAX values across rat tissues, corrected for housekeeping gene expression. Thus, total iras mRNA appears to be roughly proportional to the density of I1‐imidazoline binding sites.
Pharmacologic Characterization of Imidazoline Receptor Proteins Identified by Immunologic Techniques and Other Methodsa
Authors: ESCRIBÁ PABLO V. , OZAITA ANDRÉS , GARCÍA‐SEVILLA JESÚS A.
Published: February 2006

ABSTRACT: Biochemical and pharmacologic evidence supports the heterogeneous nature of imidazoline receptors (IRs). However, only monoamine oxidase (MAO) (55‐ and 61‐kD) isozymes have been identified as imidazoline binding site‐containing proteins. Idazoxan‐binding proteins of ∼70‐ and ∼45‐kD of unknown amino acid sequences have been isolated from chromaffin cells and rat brain, respectively. Other proteins of ∼27–30 to > 80 kD have been visualized by immunologic and photoaffinity labeling techniques in different tissues and species. The specific antiserum that recognizes the ∼70‐, ∼45‐, and ∼29‐kD IR proteins, but not MAO, was used to quantitate these proteins in the rat brain cortex. Treatments (7 days) with the I2‐selective imidazoline drugs idazoxan (10 mg/kg), cirazoline (1 mg/kg), and LSL 60101 ([2‐(2‐benzofuranyl) imidazole; 10 mg/kg]) induced differential changes in these proteins: levels of the ∼29‐kD IR were increased by idazoxan and LSL 60101 (23%), levels of the ∼45‐kD protein only by cirazoline (44%), and those of the ∼66‐kD protein only by idazoxan (50%). These treatments also increased the densities of [3H]‐idazoxan (I2) binding sites (32–42%). Chronic treatment with efaroxan, RX821002, and yohimbine (10 mg/kg), which possess very low affinity for I2‐IRs, did not alter either their immunoreactivities or the density of I2 sites. Chronic treatment with MAO inhibitors clorgyline and phenelzine (10 mg/kg) and acute treatment with EEDQ (1.6 mg/kg, 6 h) induced decreases in the levels of these IR proteins (17–47%) and I2 sites (31–57%). Significant correlations were found when the mean percentage changes in immunoreactivity of IR proteins were related to the mean percentage changes in the density of I2 sites after treatment with the foregoing drug (r= 0.92, r= 0.69, and r= 0.75 for the ∼29‐, ∼45‐, and ∼66‐kD proteins, respectively). These results indicate that in the rat cerebral cortex, the I2 sites labeled by [3H]idazoxan are heterogeneous and that the related immunoreactive IR proteins contribute differently to the modulation of I2 sites after drug treatment.