bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of DNA Sequences that Confer Complement Resistance in Leishmania chagasi
Authors: Dahlin‐Laborde Rebecca R. , Scolaro Eric J. , Romine Nathan M. , Ramer‐Tait Amanda E. , Lei Soi Meng , Beetham Jeffrey K.
Published: August 2009

Serial passage of axenically cultured Leishmania chagasi promastigotes results in a progressive diminution in resistance to complement‐mediated lysis (CML), whereas high CML resistance is seen in infectious metacyclic promastigotes from the sandfly vector as well as metacyclic‐like promastigotes within low‐passage cultures at stationary growth phase. As we previously reported, in a screen seeking to identify novel genes involved in CML resistance: (1) a genomic cosmid library derived from DNA of CML‐resistant L. chagasi promastigotes was transfected into high‐passage (constitutively CML‐sensitive) L. chagasi promastigotes; (2) transformants were screened for acquisition of CML‐resistance; (3) multiple cosmid‐transfectants exhibited partial CML resistance; and (4) the sequence for one of the cosmids (Cosmid 51) was determined. This report extends the analysis of Cosmid 51, and identifies by deletion analysis a subregion of the cosmid insert that is critical to the CML‐resistance phenotype of Cosmid 51 transformants. We also report the sequence determination and initial CML‐resistance activity of another cosmid that also confers partial resistance to CML.
Connection between the Striatal Neurokinin‐1 Receptor and Nitric Oxide Formation during Methamphetamine Exposure
Authors: Wang Jing , Xu Wenjing , Ali Syed F. , Angulo Jesus A.
Published: August 2009

Methamphetamine (METH) is a widely used “club drug” that produces neural damage in the brain, including the loss of some neurons. METH‐induced striatal neuronal loss has been attenuated by pretreatment with the neurokinin‐1 receptor antagonist WIN‐51,708 in mice. Using a histologic method, we have observed the internalization of the neurokinin‐1 receptor into endosomes in the striatal somatostatin/NPY/nitric oxide synthase interneurons. To investigate the role of this interneuron in the striatal cell death induced by METH, we assessed by immunohistochemistry the number of striatal nitric oxide synthase–positive neurons in the presence of METH at 8 and 16 hours after systemic injection of a bolus of METH (30 mg/kg, i.p.). We found the number of striatal nitric oxide synthase–positive neurons unchanged at these time points after METH. In a separate experiment we measured the levels of striatal 3‐nitrotyrosine (3‐NT) by HPLC (high‐pressure liquid chromatography) as an indirect index of nitric oxide synthesis. METH increased the levels of 3‐nitrotyrosine in the striatum and this increase was significantly attenuated by pretreatment with a selective neurokinin‐1 receptor antagonist. These observations suggest a causal relationship between the neurokinin‐1 receptor and the activation of neuronal nitric oxide synthase that warrants further investigation.
Prenatal Ethanol Exposure Reduces the Expression of the Transcriptional Factor Pax6 in the Developing Rat Brain
Authors: Aronne María Paula , Evrard Sergio Gustavo , Mirochnic Sebastián , Brusco Alicia
Published: August 2009

Prenatal ethanol exposure (PEE) induces functional and structural disorders in the developing central nervous system (CNS). The relationship between radial glial cells (RGCs) and migrating neuroblasts is crucial for the establishment of normal CNS laminated structures. Pax6, a transcription factor involved in mammalian neuronal developmental processes, could be affected by PEE, as it is already known to occur in amphibians. From gestational day 10 to 18 (G10‐G18), pregnant Wistar rats were subjected to an intraperitoneal injection of a daily ethanol (EtOH) 3.5 g/kg dose. Control pregnant rats received equivalent volumes of saline solution. Fetal weights and cerebral cortex thickness were significantly lower in G18 PEE than in control fetuses, and neural tube defects were found in the G18 PEE fetuses. Cortical expression of vimentin (an RGC cytoskeletal marker), S‐100b protein (a neurotrophic factor and cytosolic marker of RGCs during embryonic development), and 68 kDa neurofilaments (a neuronal cytoskeletal marker) were also decreased in G18 PEE fetuses. At G14, a reduction in Pax6 cortical expression was found. Our results suggest that PEE reduces Pax6 expression in undifferentiated mammalian CNS cells. This could be one of the factors that induce RGCs and neuronal alterations at end‐gestation. These alterations could be involved in the pathophysiology of neurodevelopmental disorders observed in the children affected by the fetal alcohol syndrome.
Neuroimaging in Human MDMA (Ecstasy) Users
Authors: Cowan Ronald L. , Roberts Deanne M. , Joers James M.
Published: August 2009

MDMA (3,4 methylenedioxymethamphetamine) has been used by millions of people worldwide as a recreational drug. The terms “MDMA” and “Ecstasy” are often used synonymously, but it is important to note that the purity of Ecstasy sold as MDMA is not certain. MDMA use is of public health concern, not so much because MDMA produces a common or severe dependence syndrome, but rather because rodent and nonhuman primate studies have indicated that MDMA (when administered at certain dosages and intervals) can cause long‐lasting reductions in markers of brain serotonin (5‐HT) that appear specific to fine‐diameter axons arising largely from the dorsal raphe nucleus (DR). Given the popularity of MDMA, the potential for the drug to produce long‐lasting or permanent 5‐HT axon damage or loss, and the widespread role of 5‐HT function in the brain, there is a great need for a better understanding of brain function in human users of this drug. To this end, neuropsychological, neuroendocrine, and neuroimaging studies have all suggested that human MDMA users may have long‐lasting changes in brain function consistent with 5‐HT toxicity. Data from animal models leads to testable hypotheses regarding MDMA's effects on the human brain. Because neuropsychological and neuroimaging findings have focused on the neocortex, a cortical model is developed to provide a context for designing and interpreting neuroimaging studies in MDMA users. Aspects of the model are supported by the available neuroimaging data, but there are controversial findings in some areas and most findings have not been replicated across different laboratories and using different modalities. This paper reviews existing findings in the context of a cortical model and suggests directions for future research.
Sex Differences in Dopamine‐ and Vesicular Monoamine‐Transporter Functions
Authors: Dluzen D.E. , McDermott J.L.
Published: August 2009

Men and women differ with regard to their use of, and responses to, methamphetamine (MA). Analogous sex differences with regard to MA are observed in animal models. In this report, data from a series of experiments that focus upon dopamine transporter (DAT) and vesicular monoamine transporter2 (VMAT2) function are reviewed by way of providing some understanding for these sex differences to MA. The amount of dopamine (DA) recovered after infusion of DA into superfused striatal tissue was greater in females and an accentuated amount of extracellular DA was obtained from females after infusion of the DAT‐blocking drug, nomifensine. These data suggest a higher level of DAT activity in females. To evaluate the implications of this sex difference in DAT function as related to MA, the amount of DA evoked by an infusion of MA into superfused striatal tissue was tested and found to be significantly greater in males. In contrast, potassium chloride–stimulated DA release was greater in females. The results of these DA‐evoked experiments imply that the greater DAT activity of females, by itself, cannot explain the sex differences observed with MA, and our attention was then directed to the VMAT2. Administration of the VMAT2 blocker, reserpine,in vivoresulted in a significantly greater amount of striatal DA depletion within female mice and infusion of reserpinein vitrointo striatal tissue produced significantly greater levels of extracellular DA in females. The data of these reserpine experiments suggest that females possess a more active/efficient VMAT2 function. Collectively, the data provide evidence for sex differences in both DAT and VMAT2 functioning, and we propose that the interaction of these two transporter systems contributes to the differences in response to MA between males and females.
Methylphenidate‐Induced Alterations in Synaptic Vesicle Trafficking and Activity
Authors: Volz Trent J. , Farnsworth Sarah J. , Hanson Glen R. , Fleckenstein Annette E.
Published: August 2009

The psychostimulant, methylphenidate (MPD), is commonly prescribed to treat attention‐deficit hyperactivity disorder. MPD binds to the neuronal dopamine (DA) transporter, where it blocks the inward transport of DA. The present study expands upon these findings by examining the effects of in vivo MPD administration on the vesicular monoamine transporter‐2 (VMAT‐2) in membrane‐associated vesicle and cytoplasmic vesicle subcellular fractions (i.e., those vesicles that do and do not co‐fractionate with synaptosomal membranes after osmotic lysis, respectively) isolated from lysates of rat striatal synaptosomes. The results indicate that a single MPD administration redistributes VMAT‐2 and associated vesicles within nerve terminals away from the synaptosomal membranes and into the cytoplasm, as assessed 1 hour after treatment. DA transport is also increased by MPD in both vesicle fractions (on account of vesicle trafficking in the cytoplasmic vesicles and to kinetic upregulation of the VMAT‐2 in the membrane‐associated vesicles). This, in turn, leads to an increase in the DA content of both vesicle fractions as well as an increase in the velocity and magnitude of K+‐stimulated DA release from striatal suspensions. Taken together, these data show that the trafficking, DA sequestration function, DA content, and exocytotic DA release function of synaptic vesicles can all be pharmacologically manipulated by in vivo MPD treatment. These findings may provide important insights useful for understanding and treating disorders involving abnormal DA transmission including drug abuse, Parkinson's disease, and attention‐deficit hyperactivity disorder.
Screening for Marijuana and Cocaine Abuse by Immunoanalysis and Gas Chromatography
Authors: Garcia‐Jimenez Sara , Heredia‐Lezama Karina , Bilbao‐Marcos Fernando , Fuentes‐Lara Griselda , Monroy‐Noyola Antonio , Deciga‐Campos Myrna
Published: August 2009

Drug abuse among college students is characterized by lower academic performance and long‐term negative consequences. Screening to detect students at high risk of consuming drugs is of primary importance to insure early identification and appropriate levels of care. As a result, this study aimed to determine the current or past use of drug abuse through a questionnaire applied to a student population at the Universidad Autónoma del Estado de Morelos. The results were confirmed by immunoanalysis and gas chromatography of urine. We interviewed 181 students aged 15 to 21 (gender was not considered in this study), and urine samples were collected for analytical analysis. For detection of metabolites Delta9‐THCA‐A and benzoylecgonine from marijuana and cocaine, respectively, a homogenous enzymatic inmmunoanalysis was used; subsequent samples were analyzed by a mass spectrometer with quadrupole detector. Seven samples of the total (181) did not completely fit the inclusion criteria and were eliminated. The results showed 0.50% and 1.16% positive samples for benzoylecgonine and Delta9‐THCA‐A, respectively. These results are not different from those of the National Questionnaire on Addiction. We can establish a program for detecting drug consumption in our students. This kind of study is important in order to implement programs that can help us to decrease the abuse of drugs in our college population.
Prostate Apoptosis Response 4 Gene Is Not Associated with Methamphetamine‐Use Disorder in the Japanese Population
Authors: Kishi Taro , Ikeda Masashi , Kitajima Tsuyoshi , Yamanouchi Yoshio , Kinoshita Yoko , Kawashima Kunihiro , Inada Toshiya , Harano Mutsuo , Komiyama Tokutaro , Hori Toru , Yamada Mitsuhiko , Iyo Masaomi , Sora Ichiro , Sekine Yoshimoto , Ozaki Norio , Ujike Hiroshi , Iwata Nakao
Published: August 2009

Abnormal intracellular signaling molecules in dopamine signal transduction are thought to be associated with the pathophysiology of methamphetamine (METH)‐use disorder. A recent study reported that a new intracellular protein, prostate apoptosis response 4 (Par‐4), plays a critical role in dopamine 2 receptor signaling. We therefore analyzed the association between the Par‐4 gene (PAWR) and METH‐use disorder in a Japanese population (191 patients with METH‐use disorder and 466 healthy controls). Using the recommended “gene‐based” association analysis, we selected five tagging SNPs in PAWR from the HapMap database. No significant allele/genotype‐wise or haplotype‐wise association was found between PAWR and METH‐use disorder. These results suggest that PAWR does not play a major role in METH‐use disorders in the Japanese population.
Dopamine Disposition in the Presynaptic Process Regulates the Severity of Methamphetamine‐Induced Neurotoxicity
Authors: Kuhn Donald M. , Francescutti‐Verbeem Dina M. , Thomas David M.
Published: August 2009

Methamphetamine (METH) is well known for its ability to cause damage to dopamine (DA) nerve endings of the striatum. The mechanisms by which METH causes neurotoxicity are not fully understood, but likely candidates are increased oxidative and nitrosative stress and mitochondrial dysfunction. Microglial activation is also emerging as an important element of the METH neurotoxic cascade, and it appears that extensive cross‐talk between these cells and DA nerve endings is an early event in this process. It may seem paradoxical, but DA itself is also thought to be an essential factor in the neuronal damaging effects of METH, but issues relating to its precise role in this regard remain unanswered. We present in this overview a summary of studies that tested how alterations in the disposition of presynaptic DA (injections of reserpine, L‐DOPA, or clorgyline) modulate METH neurotoxicity. In all cases, these drugs significantly increased the magnitude of microglial activation as well as the severity of damage to striatal DA nerve endings caused by METH. The enhancement of METH effects in striatum by reserpine, L‐DOPA, and clorgyline persisted for 14 days and showed no evidence of recovery. These data establish that subtle shifts in the newly synthesized pool of DA can cause substantial changes in the severity of METH‐induced neurotoxicity. DA released into the synapse by METH is very likely the source of downstream reactants that provoke microglial activation and the ensuing damage to DA nerve endings.
Methamphetamine Changes NMDA and AMPA Glutamate Receptor Subunit Levels in the Rat Striatum and Frontal Cortex
Authors: Simões Patrícia F. , Silva Ana P. , Pereira Frederico C. , Marques Elsa , Milhazes Nuno , Borges Fernanda , Ribeiro Carlos F. , Macedo Tice R.
Published: August 2009

Methamphetamine (METH) is a powerful psychostimulant whose noxious effects depend largely on the pattern of abuse. METH‐induced glutamate release may overactivateN‐methyl‐d‐aspartate and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors (NMDAR and AMPAR, respectively) causing excitotoxicity. In the brain, these receptors are also known for their essential role in mediating memory consolidation. Therefore, we assessed glial fibrillary acidic protein (GFAP) expression as a marker for astrogliosis and neurodegeneration by using Fluoro‐Jade C (F‐J C) staining. Moreover, we investigated the effect of two METH regimens on NMDAR NR1 and NR2A and on AMPAR GluR2 subunit expression in the rat striatum and frontal cortex 24 h after drug treatment. Adult Sprague‐Dawley rats were injected subcutaneously (s.c.) on six consecutive days with saline (control and acute groups) or with an increasing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the seventh day, both METH groups were given a “bolus” of 30 mg/kg METH, whereas controls received saline. We evaluated the expression levels of GFAP by both Western blot and immunohistochemical assays and concluded that there was no difference from control levels. In addition, neither drug regimen resulted in neurodegeneration within 24 h of last METH administration. In the frontal cortex of the acute group, NR1 expression level was decreased, and both NR2A and GluR2 were increased. Also, in the striatum of the acute group, the expression level of GluR2 was significantly increased, and both GluR2 and NR2A levels were augmented in the striatum of the ED group. Taken together, these results suggest a protective mechanism by decreasing permeability and/or functionality of AMPAR and NMDAR to counteract METH‐induced glutamate overflow in the brain. Moreover, these results may explain, in part, the mnemonic deficits and psychotic behavior associated with METH abuse.
Development and Characterization of a Novel Animal Model of Intermittent MDMA (“Ecstasy”) Exposure during Adolescence
Authors: Meyer Jerrold S. , Piper Brian J. , Vancollie Valerie E.
Published: August 2009

Adult animals treated with high doses of MDMA (“ecstasy”) either on a single day or for several consecutive days show numerous behavioral changes as well as persistent reductions in brain serotonin (5‐HT) concentrations and 5‐HT transporter (SERT) protein expression. However, such dosing regimens do not adequately mimic the intermittent use patterns commonly seen in adolescent recreational ecstasy users. We have developed and characterized a rat model of intermittent adolescent MDMA exposure that simulates many of the features of human weekend use. Animals treated with our dosing regimen experience only small increases in core body temperature, and their plasma MDMA levels compare favorably with the levels reported for heavy ecstasy users under naturalistic conditions when species differences in drug clearance rates are taken into account. Intermittent adolescent MDMA exposure causes later deficits in object‐recognition memory, increased impulsivity in the elevated plus‐maze, and reduced sensitivity to a 5‐HT1A agonist challenge. SERT‐immunoreactive fiber density is significantly reduced in the hippocampus but not the neocortex, suggesting that the hippocampus may be particularly vulnerable to moderate MDMA exposure during adolescence. Finally, adolescent MDMA‐treated animals are protected (i.e., show tolerance) against the neurotoxic and depressant effects of a subsequent MDMA “binge” challenge. We believe that the present animal model has important clinical relevance based on the similarities between the model and the reported effects of regular ecstasy use.
Behavioral Effects of CB2 Cannabinoid Receptor Activation and Its Influence on Food and Alcohol Consumption
Authors: Onaivi E. S. , Carpio O. , Ishiguro H. , Schanz N. , Uhl G. R. , Benno R.
Published: August 2009

Consumers of marijuana typically feel a strong, compulsive desire to consume food. Although past research revealed that the CB1 cannabinoid receptor is a potent regulator of food intake, the functional presence of neuronal CB2 cannabinoid receptors in the brain has been controversial. The role of CB2 receptors in food and alcohol consumption and the behavioral effects of CB2 receptor ligands are not well characterized. This is because CB2 cannabinoid receptors were thought to be absent from the brain and expressed primarily in immune cells and in the periphery. We tested the effects of peripheral injections of CB2 antagonist AM 630, CB2 agonist PEA, and CB1 antagonist AM 251 on male C57BL/6, Balb/c, and DBA/2 mice at the beginning of the night cycle and after overnight 12‐hour fasts. We also investigated the effects of the putative CB2 agonist, JWH015, and CB2 antagonist, SR144528, in mouse motor function tests and in the two‐compartment black and white box. Under standard conditions, the CB2 antagonist AM 630 inhibited food consumption in C57BL/6 mice and DBA/2 mice, but failed to block food intake of Balb/c mice. The CB2 agonist PEA had no significant effect on food consumption in Balb/c mice, and reduced food intake in C57BL/6 and DBA mice. The CB1 antagonist AM 251 inhibited food ingestion in the three mouse strains at variable times. After 12‐hour food deprivation, the CB2 antagonist AM 630 increased food consumption in C57Bl/6 mice, but failed to produce significant changes in food intake for Balb/c and DBA/2 mice. The CB2 agonist PEA also reduced food consumption in all three mice strains at variable times. In comparison to the CB2 ligands, CB1 antagonist AM 251 inhibited food ingestion in the mouse strains. A general pattern of depression in locomotor activity was induced by JWH 015 in both males and females in the three mouse strains tested as the dose was increased. The development and enhancement of alcohol preference was observed after chronic treatment with CB2 agonist JWH 015 in stressed mice, but not in controls. In the DBA/2 strain, the spontaneous locomotor activity and stereotype behavior was enhanced by acute administration of low doses of SR144528. There was a reduction in CNR2 gene expression in the ventral mid‐brain region of mice that developed alcohol preference, but not in those that did not develop alcohol preference. These effects of CB2 cannabinoid receptor ligands in in vivo behavioral tests are provided as functional evidence that CB2‐Rs in the brain play a role in food and alcohol consumption and in the modification of mouse behavior.
Functional Expression of Brain Neuronal CB2 Cannabinoid Receptors Are Involved in the Effects of Drugs of Abuse and in Depression
Authors: Onaivi Emmanuel S. , Ishiguro Hiroki , Gong Jian‐Ping , Patel Sejal , Meozzi Paul A. , Myers Lester , Perchuk Alex , Mora Zoila , Tagliaferro Patricia A. , Gardner Eileen , Brusco Alicia , Akinshola B. Emmanuel , Liu Qing‐Rong , Chirwa Sanika S. , Hope Bruce , Lujilde Javier , Inada Toshiya , Iwasaki Shinya , Macharia David , Teasenfitz Lindsey , Arinami Tadao , Uhl George R.
Published: August 2009

Major depression and addiction are mental health problems associated with stressful events in life with high relapse and recurrence even after treatment. Many laboratories were not able to detect the presence of CB2 cannabinoid receptors (CB2‐Rs) in healthy brains, but CB2‐R expression has been demonstrated in rat microglial cells and other brain‐associated cells during inflammation. Thus, neuronal expression of CB2‐Rs has been ambiguous and controversial, and its role in depression and substance abuse is unknown. In this study we tested the hypothesis that genetic variants of theCB2gene might be associated with depression in a human population and that alteration inCB2gene expression may be involved in the effects of abused substances, including opiates, cocaine, and ethanol, in rodents. Here we demonstrate that a high incidence of Q63R but not H316Y polymorphism in theCB2gene was found in Japanese depressed subjects. CB2‐Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated after exposure to stressors and administration of abused drugs. Mice that developed an alcohol preference had reducedCB2gene expression, and chronic treatment with JWH015 a putative CB2‐R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 antisense oligonucleotide into the mouse brain reduced mouse aversions in the plus‐maze test, indicating the functional presence of CB2‐Rs in the brain that modifies behavior. Using electron microscopy we report the subcellular localization of CB2‐Rs that are mainly on postsynaptic elements in rodent brain. Our data demonstrate the functional expression of CB2‐Rs in the brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuroimmunocannabinoid activity.
Acute Increase of the Glutamate–Glutamine Cycling in Discrete Brain Areas after Administration of a Single Dose of Amphetamine
Authors: Pereira Frederico C. , Rolo Marta R. , Marques Elsa , Mendes Vera M. , Ribeiro Carlos F. , Ali Syed F. , Morgadinho Teresa , Macedo Tice R.
Published: August 2009

The glutamate–glutamine cycle between neurons and glia is tightly related to excitatory glutamatergic and inhibitory GABAergic regulation in brain. The role of this neuron–astrocyte cross‐talk on the neurotoxicity induced by amphetamines is not understood. Also, the impact of neurotoxic doses of amphetamines on the balance between glutamatergic and GABAergic circuits is largely unknown. The aim of this work was to assess the acute effect of a neurotoxic regimen of amphetamine (AMPH) on glutamine (GLN, an astrocytic marker) levels and on glutamine/glutamate (an index for glutamate–glutamine cycle) and GABA/glutamate ratios in rat brain. Sprague‐Dawley rats were sacrificed 4 and 24 h after a single‐dose regimen of AMPH (30 mg/kg, i.p.), and the caudate–putamen (CPu), frontal cortex (FC), and hippocampus (Hp) were dissected for analysis of glutamate (GLU), γ‐aminobutyric acid (GABA), and GLN. The total content of these amino acids was measured using a microbore HPLC electrochemical detector. Although AMPH did not change GLU levels, it increased both GLN content and GLN/GLU ratio (160–469%) at 4 h, but not at 24 h, in all regions after injection. Striatal GABA levels and GABA/GLU ratio were increased (46 and 100%, respectively) at 24 h. In hippocampus the GABA/GLU increase (60%) occurred as early as 4 h after treatment. To the contrary, AMPH exerted no effect in GABA/GLU balance in frontal cortex. These data strongly suggest that this neurotoxic AMPH regimen provoked an early increase in the glutamate–glutamine cycle between neurons and glia. This increase may ultimately lead to an upregulation of the inhibitory system as a compensatory response.
γ‐Hydroxybutyric Acid–Induced Cognitive Deficits in the Female Adolescent Rat
Authors: Sircar Ratna , Basak Ashim , Sircar Debashish
Published: August 2009

γ‐hydroxybutyric acid (GHB), a “club drug,” is abused for its euphoric, sedative, and anabolic effects. GHB use and abuse is most prevalent among adolescents and young adults. Most GHB users report amnesia. In the present study, we tested the hypothesis that GHB treatment in female adolescent rats causes deficits in spatial learning and memory. Adolescent female rats were treated daily with GHB (100 mg/kg) for 5 consecutive days. Control rats received isovolumetric saline. Experimental and control rats were tested in the hidden platform task (reference memory) of the Morris water maze. GHB‐treated adolescent female rats had significantly longer latencies than saline‐treated controls, and in the probe trial drug‐treated rats spent less time in the quadrant where the platform was present prior to its removal than did control adolescent rats. Together, these data indicate that GHB exposure in adolescent female rats has a negative impact on spatial learning and memory.
Injection of the Neuropeptide CNP into Dopaminergic Rat Brain Areas Decreases Alcohol Intake
Authors: Romieu Pascal , Gobaille Serge , Aunis Dominique , Zwiller Jean
Published: August 2009

Alcohol administration is known to alter several brain functions and behaviors in humans and in laboratory animals. One of the targets of ethanol is the mesocorticolimbic dopaminergic reward pathway. We used the “alcohol deprivation effect” test as a rat model of alcohol craving and relapse. The effect is characterized by increased alcohol intake and preference after several weeks of voluntary alcohol consumption followed by a withdrawal phase. The alcohol deprivation effect was found to be considerably reduced by the injection in dopaminergic brain structures of the neuropeptide CNP. This peptide is the most abundant natriuretic peptide in the brain, and signals via an intracellular rise in cyclic GMP. The effect of CNP was observed whether the peptide was injectedin situinto the ventral tegmental area or into the prefrontal cortex. It was partially reversed by the injection in the same structures of KT5823, a selective inhibitor of the cGMP‐dependent protein kinase. The results indicate that changes of cyclic GMP levels in dopaminergic rat brain areas participate in the neurobiological mechanisms underlying alcohol craving after withdrawal and/or alcohol dependence.
Correlating Human and Animal Studies of Cocaine Abuse and Gene Expression
Authors: Lull Melinda E. , Freeman Willard M. , Vrana Kent E. , Mash Deborah C.
Published: August 2009

Gene expression changes resulting from cocaine abuse in both humans and animal models have been studied for several decades. Although human studies have been very useful at illuminating cocaine‐related expression changes, there are many factors complicating these studies, including the difficulty of obtaining high‐quality postmortem brain tissue and patient comorbidities. Animal models of cocaine abuse have served as valuable additions to human data and allow examination of specific aspects of cocaine abuse, including immediate early gene expression and the molecular effects of abstinence and relapse. In total, human and animal studies of cocaine abuse have uncovered gene expression changes in the brain related to a number of molecular functions, including the extracellular matrix, synaptic communication and neuroplasticity, receptors, ion channels and transporters, oligodendrocytes and myelin, apoptosis and cell death, mitochondrial function, signal transduction, and transcription factors. In addition, the mitogen‐activated protein kinase and synaptic long‐term potentiation signal transduction pathways are highlighted as pathways in which multiple components are altered by cocaine. Pathways and processes affected by changes in gene expression that overlap among multiple species may be promising pharmacotherapeutic targets for reducing the behavioral effects of cocaine abuse and the relapse potential observed in humans.
Disrupting Nicotine Reinforcement
Authors: Rose Jed E.
Published: August 2009

Cigarette smoking is a tenacious addiction that is maintained to a significant extent by the reinforcing effects of nicotine. An emerging theme in smoking cessation treatment is the development of methods for interfering with these reinforcing effects. By attenuating nicotine reinforcement, treatments may enhance a smoker's chances of successfully remaining abstinent. Several treatment approaches will be described, including the use of denicotinized cigarettes, nicotine vaccines, nicotinic receptor agonists and antagonists, and modulators of brain reinforcement processes. These techniques highlight the numerous sites along the path between the cigarette and the brain that can be targeted for intervention. In addition to unimodal therapies, treatment combinations will be discussed that might more effectively block cigarette reward and thereby further enhance smoking abstinence.
Chronic Stress, Drug Use, and Vulnerability to Addiction
Authors: Sinha Rajita
Published: August 2009

Stress is a well‐known risk factor in the development of addiction and in addiction relapse vulnerability. A series of population‐based and epidemiological studies have identified specific stressors and individual‐level variables that are predictive of substance use and abuse. Preclinical research also shows that stress exposure enhances drug self‐administration and reinstates drug seeking in drug‐experienced animals. The deleterious effects of early life stress, child maltreatment, and accumulated adversity on alterations in the corticotropin releasing factor and hypothalamic‐pituitary‐adrenal axis (CRF/HPA), the extrahypothalamic CRF, the autonomic arousal, and the central noradrenergic systems are also presented. The effects of these alterations on the corticostriatal‐limbic motivational, learning, and adaptation systems that include mesolimbic dopamine, glutamate, and gamma‐amino‐butyric acid (GABA) pathways are discussed as the underlying pathophysiology associated with stress‐related risk of addiction. The effects of regular and chronic drug use on alterations in these stress and motivational systems are also reviewed, with specific attention to the impact of these adaptations on stress regulation, impulse control, and perpetuation of compulsive drug seeking and relapse susceptibility. Finally, research gaps in furthering our understanding of the association between stress and addiction are presented, with the hope that addressing these unanswered questions will significantly influence new prevention and treatment strategies to address vulnerability to addiction.
Basic and Clinical Immunology of Siglecs
Authors: Von Gunten Stephan , Bochner Bruce S.
Published: August 2009

Siglecs are cell‐surface proteins found primarily on hematopoietic cells. By definition, they are members of the immunoglobulin gene super‐family and bind sialic acid. Most contain cytoplasmic tyrosine motifs implicated in cell signaling. This review will first summarize characteristics common and unique to Siglecs, followed by a discussion of each human Siglec in numerical order, mentioning in turn its closest murine ortholog or paralog. Each section will describe its pattern of cellular expression, latest known immune functions, ligands, and signaling pathways, with the focus being predominantly on CD33‐related Siglecs. Potential clinical and therapeutic implications of each Siglec will also be covered.
The Thymus Medulla Slowly Yields Its Secrets
Authors: Tykocinski Lars‐Oliver , Sinemus Anna , Kyewski Bruno
Published: August 2009

The past few years have witnessed considerable advances in our understanding of the mechanisms underlying the induction of central tolerance. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process by virtue of promiscuous expression of tissue‐restricted autoantigens. This brief review covers progress of the last two years in deciphering the functional interrelationship among TEC development, promiscuous gene expression, and central tolerance. We discuss new insights into signaling pathways directing the differentiation and homeostasis of mTECs, and new clues to the molecular regulation of promiscuous gene expression (pGE), including the role of the transcriptional regulator autoimmune regulator (AIRE). Furthermore, we emphasize the importance of promiscuous expression of particular tissue‐restricted self‐antigens in preventing organ‐specific autoimmunity and evaluate new data supporting the threshold model of central tolerance.
CARD9 Signaling in the Innate Immune Response
Authors: Ruland Jürgen
Published: August 2009

CARD9 is a caspase recruitment domain‐containing signaling protein that is highly expressed in dendritic cells and in macrophages. Work over the last two years has identified CARD9 as a central regulator of innate immunity. Best characterized is CARD9's function downstream of ITAM‐bearing or ITAM‐coupled receptors in myeloid cells, including its essential role downstream of the antifungal pattern‐recognition receptor Dectin‐1. In the ITAM receptor pathway, CARD9 couples receptor proximal splenic tyrosine kinase SYK activation to the canonical NF‐κB pathway. In addition, CARD9 is involved in the activation of p38 and JNK kinases and it can function downstream of cytosolic pattern‐recognition receptors. CARD9 signaling mediates mammalian innate immune responses against selected fungi, bacteria, and viruses and can prime and shape adaptive immunity. This review will summarize current knowledge on CARD9 signaling and its function in the innate immune response.
Neuromyelitis Optica and Asian Phenotype of Multiple Sclerosis
Authors: Kira Jun‐ichi
Published: August 2009

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), whereas neuromyelitis optica (NMO) is an inflammatory disease of the CNS selectively affecting the optic nerves and spinal cord. The pathological hallmark in MS is sharply demarcated demyelinating plaque with axons relatively preserved, whereas in NMO both axons and myelin are involved, resulting in necrotic cavitation. The nosological position of NMO has long been a matter of debate. In Asians, MS is rare; however, when it appears, the selective but severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal MS (OSMS), has similar features to those of the relapsing form of NMO in Western populations. Recent discovery of a specific immunoglobulin G (IgG) against NMO, designated NMO‐IgG, suggests that NMO is a distinct disease entity with a fundamentally different etiology from that of MS. Because NMO‐IgG has been reported to be present in about 50%–60% of OSMS patients with longitudinally extensive spinal cord lesions (LESCLs), OSMS in Asians has been suggested to be the same entity as NMO. About half of the patients with the anti–aquaporin 4 (AQP4) antibody demonstrate brain lesions fulfilling the Barkhof criteria, whereas OSMS patients without the anti‐AQP4 antibody show significantly fewer brain lesions. These findings indicate that the mechanism of LESCLs in Asians is heterogeneous, both related and unrelated to anti‐AQP4 antibody, and that the disease condition with anti‐AQP4 antibody does not completely overlap OSMS in Asians. This review discusses possible mechanisms for OSMS and anti‐AQP4 autoimmune syndrome of the CNS.
Hemispheric Asymmetries in the Quasibiennial Oscillation Signature on the Mid‐ to High‐Latitude Circulation of the Stratosphere
Authors: Peña‐Ortiz C. , García‐Herrera R. , Ribera P. , Calvo N.
Published: August 2009

The quasibiennial oscillation (QBO) dominates the variability of the equatorial stratosphere and also affects the circulation and temperature of the extratropical region. In this paper we review previous work showing that the mid‐ to high‐latitude circulation is weaker (stronger) when QBO easterlies (westerlies) dominate in the low equatorial stratosphere. The accepted explanation for the extratropical QBO signature is based on the QBO modulation of upward propagating planetary Rossby waves. This mechanism is consistent with the strong seasonality observed in the extratropical QBO. The largest QBO signature in the northern extratropical stratosphere occurs during winter when the dominating westerly wind allows the penetration of planetary waves in the northern stratosphere. However, during the southern winter, planetary waves do not disrupt the southern stratospheric vortex and the largest QBO signature is found during the late spring (November). To further illustrate these mechanisms, we analyze the QBO signature on the mid‐ to high‐latitude circulation of the stratosphere using data from the ERA‐40 reanalysis. The extratropical signature in both hemispheres is evaluated as a function of the latitude–height structure of the zonal wind in the tropical region in order to determine how the extratropical response depends on the vertical phase structure of the tropical QBO. We also analyze the QBO impact on planetary wave activity in order to determine how this modulation can explain the observed extratropical QBO signal.
Daily Rainfall Variability over Northeastern Argentina in the La Plata River Basin
Authors: García Norberto O. , Pedraza Raúl A.
Published: August 2009

We did a brief description of the climatic behavior and after this we analyzed the temporal variation in the total number of days a year with rainfall and the number of days a year with rainfall above the 100 mm threshold at the rain gauging stations in northeastern Argentina south of the La Plata River basin. The results show an increase both in the frequency of daily rainfall, especially during the winter season, and the frequency of days with heavy rainfall starting in the early 1970s. The increase in frequency of occurrence is more significant in the case of heavy rainfall. The annual maximum rainfall was calculated for periods of 1, 3, 5, 7, and 10 consecutive days at regional rain gauging stations for the respective historical periods, and the rain intensity–duration–return period curves (IDT) were determined on a frequency analysis. The IDT curves were compared with rainfall intensity–duration data of critical storms occurring in the last decades. We noticed that the rain intensities of critical storms (mostly convective) widely exceeded the intensities given by the 100‐year IDT curves, particularly for short durations. The increase in both the frequency of heavy rainfall occurrence and rain intensity from the 1970s onward shows an increase in frequency and intensity of the meso‐scale convective systems in the region resulting from climatic change. These systems tend to produce rainfall of very high intensity that is spatially concentrated and which generally produces significant floods in the local rivers.
Advances in Urban Climate Modeling
Authors: Hidalgo Julia , Masson Valéry , Baklanov Alexander , Pigeon Grégoire , Gimeno Luis
Published: August 2009

Cities interact with the atmosphere over a wide range of scales from the large‐scale processes, which have a direct impact on global climate change, to smaller scales, ranging from the conurbation itself to individual buildings. The review presented in this paper analyzes some of the ways in which cities influence atmospheric thermodynamics and airborne pollutant transport. We present the main physical processes that characterize the urban local meteorology (the urban microclimate) and air pollution. We focus on small‐scale impacts, including the urban heat island and its causes. The impact on the lower atmosphere over conurbations, air pollution in cities, and the effect on meteorological processes are discussed. An overview of the recent principal advances in urban climatology and air quality modeling in atmospheric numerical models is also presented.
Identification and Climatology of Cut‐off Lows near the Tropopause
Authors: Nieto R. , Sprenger M. , Wernli H. , Trigo R. M. , Gimeno L.
Published: August 2009

Cut‐off  low pressure systems (COLs) are defined as closed lows in the upper troposphere that have become completely detached from the main westerly current. These slow‐moving systems often affect the weather conditions at the earth's surface and also work as a mechanism of mass transfer between the stratosphere and the troposphere, playing a significant role in the net flow of tropospheric ozone. In the first part of this work we provide a comprehensive summary of results obtained in previous studies of COLs. Following this, we present three long‐term climatologies of COLs. The first two climatologies are based on the conceptual model of a COL, using European Centre for Medium‐range Weather Forecasts (ECMWF) analyses (1958–2002) and National Centers for Environmental Prediction–National Center for Atmospheric Research (1948–2006) reanalysis data sets. The third climatology uses a different method of detection, which is based on using potential vorticity as the physical parameter of diagnosis. This approach was applied only to the ECMWF reanalysis data. The final part of the paper is devoted to comparing results obtained by these different climatologies in terms of areas of preferential occurrence, life span, and seasonal cycle. Despite some key differences, the three climatologies agree in terms of the main areas of COL occurrence, namely (1) southwestern Europe, (2) the eastern north Pacific coast, and (3) the north China–Siberian region. However, it is also shown that the detection of these areas of main COL occurrence, as obtained using the potential vorticity approach, depends on the level of isentropic analysis used.
Human Regulatory CD8+ T Cells
Authors: Ablamunits Vitaly , Bisikirska Brygida C. , Herold Kevan C.
Published: August 2009

Administration of a humanized monoclonal anti‐CD3 antibody (mAb) to patients with type 1 diabetes (T1D) increases their C‐peptide responses and the CD8/CD4 ratio. Incubation of human peripheral blood mononuclear cells (PBMC) with mAb in vitro has been shown to induce CD8+ regulatory T cells (Tregs) capable of inhibiting proliferation of CD4+ T cells. We hypothesized that CD8+ Tregs function through secretion of cytokines. To test that possibility, we generated CD8+ Tregs, sorted them by FACS, incubated them with syngeneic CD8‐depleted PBMC in the presence of staphylococcal enterotoxin B (SEB), and measured proliferation of T cells and cytokines. Using neutralizing anti‐cytokine mAbs, we show that the inhibitory effect of CD8+ Tregs could be partially alleviated by anti‐CCL‐4, anti‐TNF, and to a lesser extent anti‐IL2, suggesting that these cytokines contribute to CD8+ Treg function.
Innate Immune Pathways in Virus‐Induced Autoimmune Diabetes
Authors: Nair Anjali , Wolter Travis R. , Meyers Adam J. , Zipris Danny
Published: August 2009

We recently hypothesized that Toll‐like receptor‐induced innate upregulation by Kilham rat virus (KRV) in the BioBreeding diabetes‐resistant (BBDR) rat model plays a key role in the mechanism of diabetes induction. To address this hypothesis, we analyzed innate immune signaling pathways upregulated by KRV in vitro and in vivo. We demonstrate that KRV activates the signal transducer and activator of transcription (STAT)‐1 in spleen cells in vitro and that this activation can be blocked by TLR9 inhibition. We also show that KRV upregulates STAT‐1 in pancreatic lymph nodes early after virus infection. Our data may implicate TLR9‐induced STAT‐1 signaling pathways in KRV‐induced innate immune activation in the BBDR rat and raise the possibility that these pathways are involved in mediating autoimmune diabetes.
Lowered Expressions of the NF‐κB Family Members in Dendritic Cells from NOD Mice are Associated with a Reduced Expression of GATA‐2
Authors: Takahashi Kazuma , Satoh Jo , Oka Yoshitomo
Published: August 2009

In type 1 diabetes, dendritic cells (DCs) display defective phenotype and function and possibly play crucial roles in the pathogenesis of this disease. In the present study, we compared transcription profiles of CD11c+ bone marrow (BM)‐derived DCs from NOD mice with those from NON mice, focusing on the NF‐κB/Rel family members and associated molecules. The BMDCs from NOD mice displayed reduced mRNA expressions of NF‐κB components, p65, p50, p52, and RelB, compared to NON mice: the proportions of each molecule relative to those of NON DCs were 53.9, 54.1, 54.0, and 37.0%, respectively, which were accompanied with lowered expressions of downstream immunomodulatory molecules, including IL‐6, CD80, CD86, 4‐1BB, and CD40. The reduction of NF‐κB components possibly underlies the defective phenotype and function of DCs from NOD mice, and could predispose to autoimmunity.
Persistence of Residual Beta Cells and Islet Autoimmunity during Increasing Duration of Diabetes in NOD Mice and Experimental Approaches toward Reversing New‐Onset Disease with Bioactive Peptides
Authors: Reddy Shiva , Cheung Carlos Chun Ho , Chai Ryan Chau Chia , Rodrigues Jessica Astrid
Published: August 2009

The precise fate of beta cells and the presence of islet infiltrates after onset of type 1 diabetes have not yet been fully characterized. Recently we showed that in newly diabetic NOD mice an appreciable number of beta cells remain. This was also observed during the first 2 weeks of diabetes in NOD mice without treatment with insulin. However, the mean number of beta cells per unit islet cross‐sectional area decreased with increasing duration of disease. In contrast, glucagon and somatostatin cell numbers showed an increase. The persistence of insulitis in several islets until 4 weeks of diabetes suggests ongoing beta cell autoimmunity over a protracted phase. Combined daily treatment of newly diabetic NOD mice with epidermal growth factor (EGF) and gastrin for the first 14 days of diabetes resulted in temporary restoration of normoglycemia in 7 of 15 mice. We speculate that the residual beta cells present soon after onset of diabetes may respond to experimental regeneration. Treatment of newly diabetic NOD mice with the bioactive peptides EGF and gastrin resulted in partial and temporary reversal of diabetes. We propose that peptide therapies combined with other benign immunomodulatory approaches to rescue and preserve beta cells in the long term and to prevent recurring autoimmunity may be more effective than peptide therapy alone in reversing diabetes in NOD mice.