Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology)

Publisher: Nature Publishing Group, Nature Publishing Group

Journal description

Neuropsychopharmacology is an international scientific journal and the official publication of the American College of Neuropsychopharmacology. The journal focuses on clinical and basic science contributions that advance our understanding of the brain and behavior.

Current impact factor: 7.83

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 7.833
2012 Impact Factor 8.678
2011 Impact Factor 7.991
2010 Impact Factor 6.685
2009 Impact Factor 6.993
2008 Impact Factor 6.835
2007 Impact Factor 6.157
2006 Impact Factor 5.889
2005 Impact Factor 5.369
2004 Impact Factor 4.941
2003 Impact Factor 5.201
2002 Impact Factor 4.497
2001 Impact Factor 4.715
2000 Impact Factor 4.579
1999 Impact Factor 4.858
1998 Impact Factor 4.318
1997 Impact Factor 4.105
1996 Impact Factor 3.936
1995 Impact Factor 3.567
1994 Impact Factor 2.78
1993 Impact Factor 2.521
1992 Impact Factor 3.661

Impact factor over time

Impact factor

Additional details

5-year impact 9.25
Cited half-life 5.20
Immediacy index 1.65
Eigenfactor 0.06
Article influence 2.24
Website Neuropsychopharmacology website
Other titles Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
ISSN 1740-634X
OCLC 855449
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details

Nature Publishing Group

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 6 months embargo
  • Conditions
    • Authors retain copyright
    • Published source must be acknowledged and DOI cited
    • Must link to publisher version
    • Publisher's version/PDF cannot be used
    • On author's personal website and institutional repository
    • If funding agency rules apply, authors may post authors version to their relevant funding body's archive, 6 months after publication
    • This policy is an exception to the default policies of 'Nature Publishing Group'
  • Classification
    ​ yellow

Publications in this journal

  • Louise Witten, Jesper Frank Bastlund, Birte Y Glenthøj, Christoffer Bundgaard, Björn Steiniger-Brach, Arne Mørk, Bob Oranje
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    ABSTRACT: Sensory gating is the brain's ability to filter out irrelevant information before it reaches high levels of conscious processing. In the current study we aimed to investigate the involvement of the noradrenergic and dopaminergic neurotransmitter systems in sensory gating. Furthermore, we investigated cross-species reliability, by comparing effects in both healthy humans and rats while keeping all experimental conditions as similar as possible between the species. The design of the human experiment (n=21) was a double-blind, placebo-controlled, cross-over study where sensory gating was assessed following a dose of either reboxetine (8 mg), haloperidol (2 mg), their combination or placebo at four separate visits. Similarly in the animal experiment sensory gating was assessed in rats, (n=22) following a dose of reboxetine (2 mg/kg), haloperidol (0.08 mg/kg), their combination or placebo. The sensory gating paradigms in both experiments were identical. In humans we found significantly reduced P50 suppression following separate administration of reboxetine or haloperidol while their combined administration did not reach statistical significance compared with placebo. In the rats we found a similar significant reduction of sensory gating (N40) following treatment with haloperidol and the combination of haloperidol and reboxetine, but not with separate reboxetine treatment, compared with placebo. Our study indicates that even when experimental conditions are kept as similar as possible, direct human to rat cross-species translation of pharmacological effects on sensory gating is challenging, which calls for more focussed research in this important translational area.Neuropsychopharmacology accepted article preview online, 01 July 2015. doi:10.1038/npp.2015.194.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.194
  • Youna Vandaele, Lauriane Cantin, Fuschia Serre, Caroline Vouillac-Mendoza, Serge H Ahmed
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    ABSTRACT: Ample evidence shows that the setting can control drug choices in both humans and animals. Here we reveal in rats that a major mechanism of this control involves a regulation of the drug influence on other competing options at the time of choice. Briefly, rats were offered a choice between a drug dose (cocaine or heroin) and a brief access to water sweetened with saccharin in two different settings. In one setting, choosing under the influence was not possible and rats largely preferred saccharin over either cocaine or heroin. In contrast, when the same rats were shifted to a setting where choosing under the influence was possible, they chose the drug either non-exclusively or exclusively depending on whether the drug enhanced or suppressed sweet reward, respectively. Thus, when rats were under the orexigenic influence of heroin at the time of choice, they more frequently chose saccharin in alternation with heroin. In contrast, when rats were under the anorexic influence of cocaine, they stopped choosing saccharin and continued taking cocaine exclusively. These setting- and drug-specific changes in preference were rapid and reversible, and could be induced by passively administering cocaine or heroin before choice. Finally, rats behaved as if they were oblivious to the drug influence on their choices. This behavior could explain why rats are vulnerable to harm themselves, sometimes to the point of death, in settings where choices are made under the drug influence, notably if this influence excludes other important options or, conversely, enhances harmful ones.Neuropsychopharmacology accepted article preview online, 01 July 2015. doi:10.1038/npp.2015.195.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.195
  • Pauline Belujon, Nicole L Jakobowski, Hannah K Dollish, Anthony A Grace
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    ABSTRACT: Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic use; however, very few have examined the effect of acute administration on the negative affective state after acute drug withdrawal. One dose of amphetamine was injected into Sprague-Dawley rats. Despair behavior using the modified forced swim test (FST) and dopamine (DA) activity in the ventral tegmental area using in vivo electrophysiological recordings were studied 18 h, 48 h and 72 h after injection of amphetamine. The effects of inactivation of the BLA and ketamine administration on VTA DA neuron activity and passivity in the modified FST were examined. Eighteen hours following amphetamine withdrawal there was a substantial decrease in the number of active DA neurons, as well as an increase in time spent immobile in the modified FST, which returned to baseline after 72 h. Inactivation of the BLA after acute amphetamine prevented the decrease in DA neuron tonic activity. Injection of ketamine also prevented the decrease in DA population activity but had no effect on immobility measured in the modified FST. The data support a model in which the negative affective state following acute amphetamine withdrawal is associated with a decrease in DA neuron population activity, driven by hyperactivity of the BLA. Although ketamine reversed the hypodopaminergic state following withdrawal, the failure to reduce immobility in the modified FST indicates different processes underlying negative emotional state may exist between depression and drug withdrawal.Neuropsychopharmacology accepted article preview online, 01 July 2015. doi:10.1038/npp.2015.191.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.191
  • Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; 40(8):1813-1814. DOI:10.1038/npp.2015.82
  • Su Mi Park, Meng Chen, Claire M Schmerberg, Russell S Dulman, Ramona M Rodriguiz, Marc G Caron, Jian Jin, William C Wetsel
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    ABSTRACT: Current antipsychotic drugs (APDs) show efficacy with positive symptoms, but are limited in treating negative or cognitive features of schizophrenia. While all currently FDA-approved medications target primarily the dopamine D2 receptor (D2R) to inhibit Gi/o-mediated adenylyl cyclase, a recent study has shown that many APDs affect not only Gi/o- but they can also influence β-arrestin- (βArr) mediated signaling. The ability of ligands to differentially affect signaling through these pathways is termed functional selectivity. We have developed ligands that are devoid of D2R-mediated Gi/o protein signaling, but are simultaneously partial agonists for D2R/βArr interactions. The purpose of present study was to test the effectiveness of UNC9975 or UNC9994 on schizophrenia-like behaviors in phencyclidine-treated or NR1-knockdown hypoglutamatergic mice. We have found the UNC compounds reduce hyperlocomotion in the open field, restore PPI, improve novel object recognition memory, partially normalize social behavior, decrease conditioned avoidance responding, and elicit a much lower level of catalepsy than haloperidol. These preclinical results suggest that exploitation of functional selectivity may provide unique opportunities to develop drugs with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related conditions than medications that are currently available.Neuropsychopharmacology accepted article preview online, 01 July 2015. doi:10.1038/npp.2015.196.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.196
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    ABSTRACT: Brain imaging has revealed links between prefrontal activity during risky decision-making and striatal dopamine receptors. Specifically, striatal dopamine D2-like receptor availability is correlated with risk-taking behavior and sensitivity of prefrontal activation to risk in the Balloon Analogue Risk Task. The extent to which these associations, involving a single neurochemical measure, reflect more general effects of dopaminergic functioning on risky decision-making, however, is unknown. Here, 65 healthy participants provided genotypes and performed the Balloon Analogue Risk Task during functional magnetic resonance imaging. For each participant, dopamine function was assessed using a gene composite score combining known functional variation across five genes involved in dopaminergic signaling: DRD2, DRD3, DRD4, DAT1 and COMT. The gene composite score was negatively related to dorsolateral prefrontal cortical function during risky decision-making, and nonlinearly related to earnings on the task. Iterative permutations of all possible allelic variations (7,777 allelic combinations) was tested on brain function in an independently-defined region of the prefrontal cortex and confirmed empirical validity of the composite score, which yielded stronger association than 95% of all other possible combinations. The gene composite score also accounted for a greater proportion of variability in neural and behavioral measures than the independent effects of each gene variant, indicating that combined effects of functional dopamine pathway genes can provide a robust assessment, presumably reflecting cumulative and potentially interactive effects on brain function. Our findings support the view that the links between dopaminergic signaling, prefrontal function and decision-making vary as a function of dopamine signaling capacity.Neuropsychopharmacology accepted article preview online, 29 June 2015. doi:10.1038/npp.2015.192.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.192
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    ABSTRACT: Although craving states are important to both cocaine dependence (CD) and pathological gambling (PG), few studies have directly investigated neurobiological similarities and differences in craving between these disorders. We used functional magnetic resonance imaging (fMRI) to assess brain activity in 103 participants (30 CD, 28 PG, and 45 Controls) while they watched videos depicting cocaine, gambling, and sad scenarios to investigate the neural correlates of craving. We observed a three-way urge type x video-type x diagnostic group interaction in self-reported craving, with CD participants reporting strong cocaine cravings to cocaine videos, and PG participants reporting strong gambling urges to gambling videos. Neuroimaging data revealed a diagnostic group x video interaction in anterior cingulate cortex/ventromedial prefrontal cortex (mPFC) activating predominantly to cocaine videos in CD participants, and a more dorsal mPFC region that was most strongly activated for cocaine videos in CD participants, gambling videos in PG participants, and sad videos in control participants. Gender x diagnosis x video interactions identified dorsal mPFC and a region in posterior insula/caudate in which female but not male PG participants showed increased responses to gambling videos. Findings illustrate both similarities and differences in the neural correlates of drug cravings and gambling urges in CD and PG. Future studies should investigate diagnostic- and gender-specific therapies targeting the neural systems implicated in craving/urge states in addictions.Neuropsychopharmacology accepted article preview online, 29 June 2015. doi:10.1038/npp.2015.193.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.193
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    ABSTRACT: Post-traumatic stress disorder (PTSD) - a chronic, debilitating condition, broadly characterized by emotion dysregulation - is prevalent among U.S. military personnel who have returned from Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). Selective serotonin reuptake inhibitors (SSRIs) are a first line treatment for PTSD, but treatment mechanisms are unknown, and patient response varies. SSRIs may exert their effects by remediating emotion regulatory brain activity, and individual differences in patient response might be explained, in part, by pre-treatment differences in neural systems supporting the down-regulation of negative affect. Thirty-four OEF/OIF veterans, 17 with PTSD and 17 without PTSD underwent 2 functional magnetic resonance imaging (fMRI) scans 12 weeks apart. At each scan, they performed an emotion regulation task; in the interim, veterans with PTSD were treated with the SSRI, paroxetine. SSRI treatment increased activation in both the left dorsolateral prefrontal cortex (dlPFC) and supplementary motor area (SMA) during emotion regulation, although only treatment-related change in the SMA differed significantly from veterans without PTSD. Less activation of the right ventrolateral prefrontal cortex (vlPFC)/inferior frontal gyrus (IFG) during pre-treatment emotion regulation was associated with greater reduction in PTSD symptoms with SSRI treatment, irrespective of pre-treatment severity. Patients with the least recruitment of prefrontal emotion regulatory brain regions may benefit most from treatment with SSRIs, which appear to augment activity in these regions.Neuropsychopharmacology accepted article preview online, 26 June 2015. doi:10.1038/npp.2015.190.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.190
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    ABSTRACT: Schizophrenia patients exhibit deficits in signaling of the M1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long term depression (LTD). We report that selective activation of the M1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Further, discovery of a novel, systemically active M1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M1 PAMs as a novel approach for the treatment of schizophrenia.Neuropsychopharmacology accepted article preview online, 25 June 2015. doi:10.1038/npp.2015.189.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.189
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    ABSTRACT: MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction but labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.182.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.182
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    ABSTRACT: The neurobiological underpinnings of Intermittent Explosive Disorder (IED) are traditionally linked to deficiencies in the serotonergic system. In this study, we investigated the effects of escitalopram, a Selective Serotonin Reuptake Inhibitor (SSRI), on brain activation during face processing. We expected that escitalopram would reduce amygdala activity in IED, and in addition, we explored the effect in other social-emotional related brain regions. Seventeen subjects with current Intermittent Explosive Disorder and fourteen healthy controls participated in a randomized, double-blind, placebo-controlled, counterbalanced fMRI face processing study. The analysis focused on the faces compared to a fixation baseline contrast, and a factorial model with Group as between and Drug as within subject factor was tested. Group x Drug interaction effects were found in the amygdala (small volume corrected) and the left temporal parietal junction (TPJ; whole-brain corrected). Escitalopram increased amygdala activation in controls, but surprisingly not in IED. However, the TPJ showed increased activity in IED on escitalopram compared to placebo. The TPJ is associated with social-cognitive processes, such as perspective taking and empathy. The TPJ findings suggest that SSRI administration may reduce aggressive tendencies towards other people by enhancing social-cognitive processing of empathy and perspective taking of others during emotional face processing. Future research should further elucidate the long-term effects of SSRIs on various social-emotional tasks in IED.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.187.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.187
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    ABSTRACT: Motivated behavior can be characterized by behavioral activation and high work output. Moreover, people with depression and other disorders show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Effort-based decision making is studied using tasks offering choices between high effort options leading to highly valued reinforcers vs low effort/low reward options, and such tasks could be useful as animal models of motivational symptoms. In the present studies the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine (TBZ) were investigated. TBZ blocks vesicular storage and also produces depressive symptoms in humans. Moreover, TBZ alters effort-based choice in rats, biasing animals towards low effort alternatives. The present studies investigated the ability of acute administration of various monoamine uptake inhibitors to reverse the effects of TBZ. Effort-related effects of TBZ were attenuated by the catecholamine uptake inhibitor and antidepressant bupropion, and this effect of bupropion was reversed by either D1 or D2 family antagonism. The effort-related effects of TBZ also were attenuated by the selective dopamine uptake blocker GBR12909. The 5-HT uptake inhibitor fluoxetine and the norepinephrine uptake inhibitor desipramine failed to reverse the effects of TBZ, and higher doses of these drugs, given alone or in combination with TBZ, led to further behavioral impairments. These results indicate that drugs acting on dopamine transmission are relatively effective at reversing the effort-related effects of TBZ, and are consistent with the hypothesis that drugs that enhance dopamine transmission may be effective at treating effort-related psychiatric symptoms in humans.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.188.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.188
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    ABSTRACT: Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Adverse early-life experiences provoke the release and modify the expression of several stress mediators and neurotransmitters within specific brain regions. The interaction of these mediators with developing neurons and neuronal networks may lead to long-lasting structural and functional alterations associated with cognitive and emotional consequences. Whereas a vast body of work has linked quantitative and qualitative aspects of stress to adolescent and adult outcomes, a number of questions are unclear. What distinguishes 'normal' from pathologic or toxic stress? How are the effects of stress transformed into structural and functional changes in individual neurons and neuronal networks? Which ones are affected?. We review these questions in the context of established and emerging studies. We introduce a novel concept regarding the origins of toxic early-life stress, stating that it may derive from specific patterns of environmental signals, especially those derived from the mother or caretaker. Fragmented and unpredictable patterns of maternal care behaviors induce a profound chronic stress. The aberrant patterns and rhythms of early-life sensory input might also directly and adversely influence the maturation of cognitive and emotional brain circuits, in analogy to visual and auditory brain systems. Thus, unpredictable, stress-provoking early-life experiences may influence adolescent cognitive and emotional outcomes by disrupting the maturation of the underlying brain networks. Comprehensive approaches and multiple levels of analysis are required to probe the protean consequences of early-life adversity on the developing brain. These involve integrated human and animal-model studies, and approaches ranging from in vivo imaging to novel neuroanatomical, molecular, epigenomic and computational methodologies. Because early-life adversity is a powerful determinant of subsequent vulnerabilities to emotional and cognitive pathologies, understanding the underlying processes will have profound implications for the world's current and future children.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.181.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.181
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    ABSTRACT: Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder (AD/HD), learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.186.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.186
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    ABSTRACT: Local translation of mRNAs in the synapse plays a major role in synaptic structure and function. Chronic alcohol use causes persistent changes in synaptic mRNA expression, possibly mediated by microRNAs localized in the synapse. We profiled the transcriptome of synaptoneurosomes (SN) obtained from the amygdala of mice that consumed 20% ethanol (alcohol) in a 30-day continuous two-bottle choice test to identify the microRNAs that target alcohol-induced mRNAs. SN are membrane vesicles containing pre- and post-synaptic compartments of neurons and astroglia and are a unique model for studying the synaptic transcriptome. We previously showed that chronic alcohol regulates mRNA expression in a coordinated manner. Here, we examine microRNAs and mRNAs from the same samples to define alcohol-responsive synaptic microRNAs and their predicted interactions with targeted mRNAs. The aim of the study was to identify the microRNA-mRNA synaptic interactions that are altered by alcohol. This was accomplished by comparing the effect of alcohol in SN vs. total homogenate preparations from the same samples. We used a combination of unbiased bioinformatics methods (differential expression, correlation, co-expression, microRNA-mRNA target prediction, co-targeting and cell type specific analyses) to identify key alcohol-sensitive microRNAs. Prediction analysis showed that a subset of alcohol-responsive microRNAs was predicted to target many alcohol-responsive mRNAs, providing a bidirectional analysis for identifying microRNA-mRNA interactions. We found microRNAs and mRNAs with overlapping patterns of expression that correlated with alcohol consumption. Cell-type specific analysis revealed that a significant number of alcohol-responsive mRNAs and microRNAs were unique to glutamate neurons and were predicted to target each other. Chronic alcohol appears to perturb the coordinated microRNA regulation of mRNAs in SN, a mechanism that may explain the aberrations in synaptic plasticity affecting the alcoholic brain.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.179.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.179
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    ABSTRACT: Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP 101,606 and BMT-108908 along with the non-selective NMDA antagonists ketamine and AZD6765 in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP 101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.184.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.184
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    ABSTRACT: Chronic intermittent alcohol vapor exposure leads to increased dynorphin (DYN) A-like peptide expression and heightened kappa-opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA) and these neuroadaptive responses differentiate alcohol-dependent from non-dependent phenotypes. Important for therapeutic development efforts is understanding the nature of the stimulus that drives dependence-like phenotypes such as escalated alcohol self-administration. Accordingly, the present study examined the impact of intra-CeA KOR antagonism on escalated operant alcohol self-administration and physiological withdrawal symptoms during acute withdrawal and protracted abstinence in rats previously exposed to chronic intermittent alcohol vapor. Following operant training, rats were implanted with intra-CeA guide cannula and exposed to long-term intermittent alcohol vapor exposure that resulted in escalated alcohol self-administration and elevated physiological withdrawal signs during acute withdrawal. Animals received intra-CeA infusions of the KOR antagonist nor-binaltorphimine (nor-BNI; 0, 2, 4, or 6 μg) prior to operant alcohol self-administration sessions and physiological withdrawal assessment during acute withdrawal and protracted abstinence. The results indicated that site-specific KOR antagonism in the CeA ameliorated escalated alcohol self-administration during both acute withdrawal and protracted abstinence test sessions, whereas KOR antagonism had no effect on physiological withdrawal scores at either time point. These results dissociate escalated alcohol self-administration from physiological withdrawal symptoms in relation to KOR signaling in the CeA and help clarify the nature of the stimulus that drives escalated alcohol self-administration during acute withdrawal and protracted abstinence.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.183.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.183
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    ABSTRACT: Stress plays a critical role in the development and expression of many psychiatric disorders, and is a defining feature of post-traumatic stress disorder (PTSD). Stress also limits the efficacy of behavioral therapies, such as exposure therapy, aimed at limiting pathological fear. Here we examine emerging evidence that stress impairs recovery from trauma by impairing fear extinction, a form of learning thought to underlie the suppression of trauma-related fear memories. We describe the major structural and functional abnormalities in brain regions that are particularly vulnerable to stress, including the amygdala, prefrontal cortex, and hippocampus, which may underlie stress-induced impairments in extinction. We also discuss some of the stress-induced neurochemical and molecular alterations in these brain regions that are associated with extinction deficits, and the potential for targeting these changes to prevent or reverse impaired extinction. A better understanding of the neurobiology of deleterious stress effects on extinction promises to yield novel approaches to improving therapeutic outcomes for PTSD and other anxiety and trauma-related disorders.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.180.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.180
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    ABSTRACT: The anterior bed nucleus of the stria terminalis (BNST) has been recognized as a critical structure in regulating trait anxiety, contextual fear memory, and appetitive behavior, and is known to be sensitive to stress manipulations. As one of the most complex structures in the central nervous system, the intrinsic circuitry of the BNST is largely unknown, however recent technological developments have allowed researchers to begin to untangle the internal connections of the nucleus. This research has revealed the possibility of two opposing circuits, one anxiolytic and one anxiogenic, within the BNST, the relative strength of which determines the behavioral outcome. The balance of these pathways is critical in maintaining a normal physiological and behavioral state; however stress and drugs of abuse can differentially affect the opposing circuitry within the nucleus to shift the balance to a pathological state. In this review, we will examine how stress interacts with the neuromodulators, corticotropin releasing factor, norepinephrine, dopamine and serotonin, to affect the circuitry of the BNST as well as how synaptic plasticity in the BNST is modulated by stress, resulting in long lasting changes in the circuit and behavioral state.Neuropsychopharmacology accepted article preview online, 22 June 2015. doi:10.1038/npp.2015.178.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.178