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  • Interaction between noradrenergic and cholinergic signaling in amygdala regulates anxiety- and depression-related behaviors in mice
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-22
    Yann S. Mineur, Emma L. Cahuzac, Tenna N. Mose, Matthew P. Bentham, Margreet E. Plantenga, David C. Thompson, Marina R. Picciotto

    Medications that target the noradrenergic system are important therapeutics for depression and anxiety disorders. More recently, clinical studies have shown that the α2-noradrenergic receptor (α2AR) agonist guanfacine can decrease stress-induced smoking relapse during acute abstinence, suggesting that targeting the noradrenergic system may aid in smoking cessation through effects on stress pathways in the brain. Acetylcholine (ACh), like the nicotine in tobacco, acts at nicotinic acetylcholine receptors (nAChRs) to regulate behaviors related to anxiety and depression. We therefore investigated interactions between guanfacine and ACh signaling in tests of anxiolytic and antidepressant efficacy in female and male C57BL/6J mice, focusing on the amygdala as a potential site of noradrenergic/cholinergic interaction. The antidepressant-like effects of guanfacine were blocked by shRNA-mediated knockdown of α2AR in amygdala. Knockdown of the high-affinity β2 nAChR subunit in amygdala also prevented antidepressant-like effects of guanfacine, suggesting that these behavioral effects require ACh signaling through β2-containing nAChRs in this brain area. Ablation of NE terminals prevented the anxiolytic- and antidepressant-like effects of the nicotinic partial agonist cytisine, whereas administration of the cholinesterase antagonist physostigmine induced a depression-like phenotype that was not altered by knocking down α2AR in the amygdala. These studies suggest that ACh and NE have opposing actions on behaviors related to anxiety and depression and that cholinergic signaling through β2-containing nAChRs and noradrenergic signaling through α2a receptors in neurons of the amygdala are critical for regulation of these behaviors.

    更新日期:2018-02-23
  • A single, extinction-based treatment with a kappa opioid receptor agonist elicits a long-term reduction in cocaine relapse
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-22
    Jasper A. Heinsbroek, Amelia B. Furbish, Jamie Peters

    Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the therapeutic potential of the KOR agonist U50,488 (U50) to reduce cocaine seeking in a self-administration model. Following cocaine self-administration and 7 days of forced home-cage abstinence, rats were administered a single dose of U50 (5 mg/kg, i.p.) 30 min prior to the first extinction training session, wherein cocaine and the discrete cocaine-paired cues were no longer available. U50 reduced cocaine seeking on this first extinction session, but did not alter extinction training over subsequent days. 2 weeks after U50 treatment, rats underwent a test of cue-induced reinstatement, and rats that had received U50 reinstated less than controls. Central inhibition of p38 MAPK at the time of U50 administration prevented its long-term therapeutic effect on reinstatement, but not its acute reduction in drug seeking on extinction day 1. The long-term therapeutic effect of U50 required operant extinction during U50 exposure, extended to cocaine-primed reinstatement, and was not mimicked by another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction.

    更新日期:2018-02-23
  • Relapse prediction in schizophrenia through digital phenotyping: a pilot study
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-22
    Ian Barnett, John Torous, Patrick Staples, Luis Sandoval, Matcheri Keshavan, Jukka-Pekka Onnela

    Among individuals diagnosed, hospitalized, and treated for schizophrenia, up to 40% of those discharged may relapse within 1 year even with appropriate treatment. Passively collected smartphone behavioral data present a scalable and at present underutilized opportunity to monitor patients in order to identify possible warning signs of relapse. Seventeen patients with schizophrenia in active treatment at a state mental health clinic in Boston used the Beiwe app on their personal smartphone for up to 3 months. By testing for changes in mobility patterns and social behavior over time as measured through smartphone use, we were able to identify statistically significant anomalies in patient behavior in the days prior to relapse. We found that the rate of behavioral anomalies detected in the 2 weeks prior to relapse was 71% higher than the rate of anomalies during other time periods. Our findings show how passive smartphone data, data collected in the background during regular phone use without active input from the subjects, can provide an unprecedented and detailed view into patient behavior outside the clinic. Real-time detection of behavioral anomalies could signal the need for an intervention before an escalation of symptoms and relapse occur, therefore reducing patient suffering and reducing the cost of care.

    更新日期:2018-02-23
  • Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-14
    Nicole S. Hernandez, Kelsey Y. Ige, Elizabeth G. Mietlicki-Baase, Gian Carlo Molina-Castro, Christopher A. Turner, Matthew R. Hayes, Heath D. Schmidt

    Novel molecular targets are needed to develop new medications for the treatment of cocaine addiction. Here we investigated a role for glucagon-like peptide-1 (GLP-1) receptors in the reinstatement of cocaine-seeking behavior, an animal model of relapse. We showed that peripheral administration of the GLP-1 receptor agonist exendin-4 dose dependently reduced cocaine seeking in rats at doses that did not affect ad libitum food intake, meal patterns or body weight. We also demonstrated that systemic exendin-4 penetrated the brain where it putatively bound receptors on both neurons and astrocytes in the ventral tegmental area (VTA). The effects of systemic exendin-4 on cocaine reinstatement were attenuated in rats pretreated with intra-VTA infusions of the GLP-1 receptor antagonist exendin-(9–39), indicating that the suppressive effects of systemic exendin-4 on cocaine seeking were due, in part, to activation of GLP-1 receptors in the VTA. Consistent with these effects, infusions of exendin-4 directly into the VTA-reduced cocaine seeking. Finally, extinction following cocaine self-administration was associated with decreased preproglucagon mRNA expression in the caudal brainstem. Thus, our study demonstrated a novel role for GLP-1 receptors in the reinstatement of cocaine-seeking behavior and identified behaviorally relevant doses of a GLP-1 receptor agonist that selectively reduced cocaine seeking and did not produce adverse effects.

    更新日期:2018-02-14
  • Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-09
    Hisham Ziauddeen, Liam J Nestor, Naresh Subramaniam, Chris Dodds, Pradeep J Nathan, Sam R Miller, Bhopinder K Sarai, Kay Maltby, Disala Fernando, Liling Warren, Louise K Hosking, Dawn Waterworth, Anna Korzeniowska, Beta Win, Duncan B Richards, Lakshmi Vasist Johnson, Paul C Fletcher, Edward T Bullmore

    Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype, Published online: 09 February 2018; doi:10.1038/npp.2017.287 Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype

    更新日期:2018-02-09
  • Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-09
    Brian Reed, Eduardo R Butelman, Rebecca S Fry, Rachel Kimani, Mary Jeanne Kreek

    Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence, Published online: 09 February 2018; doi:10.1038/npp.2017.245 Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence

    更新日期:2018-02-09
  • Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-09
    Arthur L Brody, Robert Hubert, Ryutaro Enoki, Lizette Y Garcia, Michael S Mamoun, Kyoji Okita, Edythe D London, Erika L Nurmi, Lauren C Seaman, Mark A Mandelkern

    Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study, Published online: 09 February 2018; doi:10.1038/npp.2017.261 Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study

    更新日期:2018-02-09
  • Single-Subject Anxiety Treatment Outcome Prediction using Functional Neuroimaging
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-09
    Tali M Ball, Murray B Stein, Holly J Ramsawh, Laura Campbell-Sills, Martin P Paulus

    Single-Subject Anxiety Treatment Outcome Prediction using Functional Neuroimaging Single-Subject Anxiety Treatment Outcome Prediction using Functional Neuroimaging, Published online: 09 February 2018; doi:10.1038/npp.2017.272 Single-Subject Anxiety Treatment Outcome Prediction using Functional Neuroimaging

    更新日期:2018-02-09
  • mTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F-Actin polymerization, structural modifications, and consumption
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-07
    Sophie Laguesse, Nadege Morisot, Khanhky Phamluong, Samuel A. Sakhai, Dorit Ron

    Actin is highly enriched at dendritic spines, and actin remodeling plays an essential role in structural plasticity. The mammalian target of rapamycin complex 2 (mTORC2) is a regulator of actin polymerization. Here, we report that alcohol consumption increases F-actin content in the dorsomedial striatum (DMS) of mice, thereby altering dendritic spine morphology in a mechanism that requires mTORC2. Specifically, we found that excessive alcohol consumption increases mTORC2 activity in the DMS, and that knockdown of Rictor, an essential component of mTORC2 signaling, reduces actin polymerization, and attenuates the alcohol-dependent alterations in spine head size and the number of mushroom spines. Finally, we show that knockdown of Rictor in the DMS reduces alcohol consumption, whereas intra-DMS infusion of the mTORC2 activator, A-443654, increases alcohol intake. Together, these results suggest that mTORC2 in the DMS facilitates the formation of F-actin, which in turn induces changes in spine structure to promote and/or maintain excessive alcohol intake.

    更新日期:2018-02-08
  • Embryonic stem cell transplants as a therapeutic strategy in a rodent model of autism
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-07
    Jennifer J. Donegan, Angela M. Boley, Daniel J. Lodge

    Autism is a neurodevelopmental disorder characterized by disruptions in three core behavioral domains: deficits in social interaction, impairments in communication, and repetitive and stereotyped patterns of behavior or thought. There are currently no drugs available for the treatment of the core symptoms of ASD and drugs that target comorbid symptoms often have serious adverse side effects, suggesting an urgent need for new therapeutic strategies. The neurobiology of autism is complex, but converging evidence suggests that ASD involves disruptions in the inhibitory GABAergic neurotransmitter system. Specifically, people with autism have a reduction in parvalbumin (PV)-containing interneurons in the PFC, leading to the suggestion that restoring interneuron function in this region may be a novel therapeutic approach for ASD. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of PV-positive interneurons, which were transplanted into the medial prefrontal cortex (mPFC) of the Poly I:C rodent model of autism. PV interneuron transplants were able to decrease pyramidal cell firing in the mPFC and alleviated deficits in social interaction and cognitive flexibility. Our results suggest that restoring PV interneuron function in the mPFC may be a novel and effective treatment strategy to reduce the core symptoms of autism.

    更新日期:2018-02-08
  • Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-05
    Amandine Valomon, Sebastian C. Holst, Alessandro Borrello, Susanne Weigend, Thomas Müller, Wolfgang Berger, Michael Sommerauer, Christian R. Baumann, Hans-Peter Landolt

    Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans. We first quantified in 73 young male volunteers the impact of COMT genotype on the evolution of attentional lapses during 40 h of extended wakefulness. Subsequently, we tested in an independent group of 30 young men whether selective inhibition of COMT activity with tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a genotype-dependent manner. Neither COMT genotype nor tolcapone affected brain electrical activity in wakefulness and sleep. By contrast, COMT genotype and tolcapone modulated the sleep loss-induced impairment of vigilant attention. More specifically, Val/Met heterozygotes produced twice as many lapses after a night without sleep than Met/Met homozygotes. Unexpectedly, tolcapone further deteriorated the sleep loss-induced performance deficits when compared to placebo, particularly in Val/Met and Met/Met genotypes. The findings suggest that PFC dopaminergic tone regulates sustained attention after sleep loss according to an inverse U-shaped relationship, independently of neurophysiological markers of elevated sleep need.

    更新日期:2018-02-06
  • Accelerated repetitive transcranial magnetic stimulation in the treatment of depression
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-05
    Paul B. Fitzgerald, Kate E. Hoy, David Elliot, R. N. Susan McQueen, Lenore E. Wambeek, Zafiris J. Daskalakis

    Repetitive transcranial magnetic stimulation (rTMS) is increasingly used clinically in the treatment of patients with major depressive disorder (MDD). However, rTMS treatment response can be slow. Early research suggests that accelerated forms of rTMS may be effective but no research has directly evaluated a schedule of accelerated rTMS compared to standard rTMS. To assess the efficacy of accelerated rTMS compared to standard daily rTMS. 115 outpatients with MDD received either accelerated rTMS (n = 58) (i.e., 63,000 high frequency rTMS pulses delivered as 3 treatments per day over 3 days in week 1, 3 treatments over 2 days in week 2 and 3 treatments on a single day in week 3) or standard rTMS (n = 57) (i.e., 63,000 total high frequency rTMS pulses delivered over 5 days per week for 4 weeks) following randomization. There were no significant differences in remission or response rates (p > 0.05 for all analyses) or reduction in depression scores (Time by group interaction (F (5, 489.452) = 1.711, p = 0.130) between the accelerated and standard rTMS treatment groups. Accelerated treatment was associated with a higher rate of reported treatment discomfort. It is feasible to provide accelerated rTMS treatment for outpatients with depression and this is likely to produce meaningful antidepressant effects.

    更新日期:2018-02-06
  • Environmental, genetic and epigenetic contributions to cocaine addiction
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-05
    R. Christopher Pierce, Bruno Fant, Sarah E. Swinford-Jackson, Elizabeth A. Heller, Wade H. Berrettini, Mathieu E. Wimmer

    Decades of research on cocaine has produced volumes of data that have answered many important questions about the nature of this highly addictive drug. Sadly, none of this information has translated into the development of effective therapies for the treatment of cocaine addiction. This review endeavors to assess the current state of cocaine research in an attempt to identify novel pathways for therapeutic development. For example, risk of cocaine addiction is highly heritable but genome-wide analyses comparing cocaine-dependent individuals to controls have not resulted in promising targets for drug development. Is this because the genetics of addiction is too complex or because the existing research methodologies are inadequate? Likewise, animal studies have revealed dozens of enduring changes in gene expression following prolonged exposure to cocaine, none of which have translated into therapeutics either because the resulting compounds were ineffective or produced intolerable side-effects. Recently, attention has focused on epigenetic modifications resulting from repeated cocaine intake, some of which appear to be heritable through changes in the germline. While epigenetic changes represent new vistas for therapeutic development, selective manipulation of epigenetic marks is currently challenging even in animals such that translational potential is a distant prospect. This review will reveal that despite the enormous progress made in understanding the molecular and physiological bases of cocaine addiction, there is much that remains a mystery. Continued advances in genetics and molecular biology hold potential for revealing multiple pathways toward the development of treatments for the continuing scourge of cocaine addiction.

    更新日期:2018-02-06
  • Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-05
    E Domi, E Barbier, E Augier, G Augier, D Gehlert, R Barchiesi, A Thorsell, L Holm, M Heilig

    Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.

    更新日期:2018-02-06
  • Several behavioral traits relevant for alcoholism are controlled by ɣ2 subunit containing GABAA receptors on dopamine neurons in mice
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-05
    Andrea Stojakovic, Magdalena Walczak, Przemysław E Cieślak, Aleksandra Trenk, Johan Sköld, Joanna Zajdel, Elahe Mirrasekhian, Camilla Karlsson, Annika Thorsell, Markus Heilig, Jan Rodriguez Parkitna, Tomasz Błasiak, David Engblom

    The risk factors for developing alcohol addiction include impulsivity, high sensitivity to the rewarding action of ethanol, and low sensitivity to its sedative and intoxicating effects. Genetic variation in GABAA receptor subunits, including the ɣ2 subunit (Gabrg2), affects the risk for developing alcoholism. Alcohol directly potentiates GABAA receptors and activates the mesolimbic dopamine system. Here, we deleted Gabrg2 selectively in dopamine cells of adult mice. The deletion resulted in elevated firing of dopamine neurons and made them less sensitive to drugs acting at GABAA receptors. At the behavioral level, the deletion increased exploratory behavior and augmented both correct and incorrect responding in the go/no-go task, a test often used to assay the response inhibition component of impulsivity. In addition, conditioned place preference to alcohol, but not to cocaine or morphine, was increased. Ethanol-induced locomotor activation was enhanced in the mice lacking Gabrg2 on dopaminergic cells, whereas the sedative effect of alcohol was reduced. Finally, the alcohol drinking, but not the alcohol preference, at a high concentration was increased in the mutant mice. In summary, deletion of Gabrg2 on dopamine cells induced several behavioral traits associated with high risk of developing alcoholism. The findings suggest that mice lacking Gabrg2 on dopaminergic cells could be used as models for individuals at high risk for developing alcoholism and that GABAA receptors on dopamine cells are protective against the development of excessive alcohol drinking.

    更新日期:2018-02-06
  • Positive regulation of raphe serotonin neurons by serotonin 2B receptors
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-05
    Arnauld Belmer, Emily Quentin, Silvina L. Diaz, Bruno P. Guiard, Sebastian P. Fernandez, Stéphane Doly, Sophie M. Banas, Pothitos M. Pitychoutis, Imane Moutkine, Aude Muzerelle, Anna Tchenio, Anne Roumier, Manuel Mameli, Luc Maroteaux

    Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT2B-receptor stimulation by BW723C86 counteracted 5-HT1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT2B receptor expression in serotonergic neurons. In Htr2b5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2blox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT1A-autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT1A-negative autoreceptor.

    更新日期:2018-02-06
  • Behavioral and neural markers of cigarette-craving regulation in young-adult smokers during abstinence and after smoking
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-05
    Dara G. Ghahremani, Paul Faulkner, Chelsea Cox, Edythe D. London

    Cigarette craving contributes substantially to the maintenance of tobacco use disorder. Behavioral strategies to regulate craving may facilitate smoking cessation but remain underexplored. We adapted an emotion-regulation strategy, using proximal/distal self-positioning, to the context of cigarette craving to examine craving regulation in 42, daily smokers (18–25 years old). After overnight abstinence from smoking, before and after smoking their first cigarette of the day, participants viewed videos of natural scenes presenting young adults who were either smoking cigarettes (“smoke”) or not (“non-smoke”). Before each video, participants were instructed to imagine themselves either immersed in the scene (“close”) or distanced from it (“far”). Task-based fMRI data are presented for a subsample of participants (N = 21). They rated their craving after each video. We found main effects of smoking, instruction, and video type on craving—lower ratings after smoking than before, following the “far” vs. “close” instructions, and when viewing non-smoke vs. smoke videos. Before smoking, “smoke” vs. “non-smoke” videos elicited activation in, orbitofrontal cortex, anterior cingulate, lateral parietal cortex, mid-occipital cortex, ventral striatum, dorsal caudate, and midbrain. Smoking reduced activation in anterior cingulate, left inferior frontal gyrus, and bilateral temporal poles. Activation was reduced in the ventral striatum and medial prefrontal cortex after the “far” vs. the “close” instruction, suggesting less engagement with the stimuli during distancing. The results indicate that proximal/distal regulation strategies impact cue-elicited craving, potentially via downregulation of the ventral striatum and medial prefrontal cortex, and that smoking during abstinence may increase cognitive control capacity during craving regulation.

    更新日期:2018-02-06
  • Role of the mesolimbic dopamine system in relief learning
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-02-05
    Dana Mayer, Evelyn Kahl, Taygun C. Uzuneser, Markus Fendt

    The relief from an aversive event is rewarding. Since organisms are able to learn which environmental cues can cease an aversive event, relief learning helps to better cope with future aversive events. Literature data suggest that relief learning is affected in various psychopathological conditions, such as anxiety disorders. Here, we investigated the role of the mesolimbic dopamine system in relief learning. Using a relief learning procedure in Sprague Dawley rats, we applied a combination of behavioral experiments with anatomical tracing, c-Fos immunohistochemistry, and local chemogenetic and pharmacological interventions to broadly characterize the role of the mesolimbic dopamine system. The present study shows that a specific part of the mesolimbic dopamine system, the projection from the posterior medial ventral tegmental area (pmVTA) to the nucleus accumbens shell (AcbSh), is activated by aversive electric stimuli. 6-OHDA lesions of the pmVTA blocked relief learning but fear learning and safety learning were not affected. Chemogenetic silencing of the pmVTA-AcbSh projection using the DREADD approach, as well as intra-AcbSh injections of the dopamine D2/3 receptor antagonist raclopride inhibited relief learning. Taken together, the present data demonstrate that the dopaminergic pmVTA-AcbSh projection is critical for relief learning but not for similar learning phenomena. This novel finding may have clinical implications since the processing of signals predicting relief and safety is often impaired in patients suffering from anxiety disorders. Furthermore, it may help to better understand psychological conditions like non-suicidal self-injury, which are associated with pain offset relief.

    更新日期:2018-02-06
  • Reversing Cocaine-Induced Adaptations and Reducing Relapse: An Opportunity for Repurposing Riluzole
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-01-17
    Joseph J Ziminski, Eisuke Koya

    Reversing Cocaine-Induced Adaptations and Reducing Relapse: An Opportunity for Repurposing Riluzole Reversing Cocaine-Induced Adaptations and Reducing Relapse: An Opportunity for Repurposing Riluzole, Published online: 17 January 2018; doi:10.1038/npp.2017.300 Reversing Cocaine-Induced Adaptations and Reducing Relapse: An Opportunity for Repurposing Riluzole

    更新日期:2018-01-17
  • Reduced Density of DISC1 Expressing Astrocytes in the Dentate Gyrus but not in the Subventricular Zone in Schizophrenia
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-01-12
    Hans-Gert Bernstein, Henrik Dobrowolny, Gerburg Keilhoff, Bernhard Bogerts, Johann Steiner

    Reduced Density of DISC1 Expressing Astrocytes in the Dentate Gyrus but not in the Subventricular Zone in Schizophrenia Reduced Density of DISC1 Expressing Astrocytes in the Dentate Gyrus but not in the Subventricular Zone in Schizophrenia, Published online: 12 January 2018; doi:10.1038/npp.2017.242 Reduced Density of DISC1 Expressing Astrocytes in the Dentate Gyrus but not in the Subventricular Zone in Schizophrenia

    更新日期:2018-01-12
  • Memory Retention Involves the Ventrolateral Orbitofrontal Cortex: Comparison with the Basolateral Amygdala
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-01-12
    Kelsey S Zimmermann, Chen-chen Li, Donald G Rainnie, Kerry J Ressler, Shanmon L Gourley

    Memory Retention Involves the Ventrolateral Orbitofrontal Cortex: Comparison with the Basolateral Amygdala Memory Retention Involves the Ventrolateral Orbitofrontal Cortex: Comparison with the Basolateral Amygdala, Published online: 12 January 2018; doi:10.1038/npp.2017.219 Memory Retention Involves the Ventrolateral Orbitofrontal Cortex: Comparison with the Basolateral Amygdala

    更新日期:2018-01-12
  • Yue Chen
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-01-12
    Deborah L Levy, Terry A Bragg

    Yue Chen Yue Chen, Published online: 12 January 2018; doi:10.1038/npp.2017.271 Yue Chen

    更新日期:2018-01-12
  • A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-01-10
    Mary M Torregrossa

    A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression, Published online: 10 January 2018; doi:10.1038/npp.2017.286 A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression

    更新日期:2018-01-10
  • CNO Evil? Considerations for the Use of DREADDs in Behavioral Neuroscience
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-01-05
    Stephen V Mahler, Gary Aston-Jones

    CNO Evil? Considerations for the Use of DREADDs in Behavioral Neuroscience CNO Evil? Considerations for the Use of DREADDs in Behavioral Neuroscience, Published online: 05 January 2018; doi:10.1038/npp.2017.299 CNO Evil? Considerations for the Use of DREADDs in Behavioral Neuroscience

    更新日期:2018-01-05
  • The Protective Action Encoding of Serotonin Transients in the Human Brain
    Neuropsychopharmacology (IF 6.403) Pub Date : 2018-01-03
    Rosalyn J Moran, Kenneth T Kishida, Terry Lohrenz, Ignacio Saez, Adrian W Laxton, Mark R Witcher, Stephen B Tatter, Thomas L Ellis, Paul EM Phillips, Peter Dayan, P Read Montague

    The role of serotonin in human brain function remains elusive due, at least in part, to our inability to measure rapidly the local concentration of this neurotransmitter. We used fast-scan cyclic voltammetry to infer serotonergic signaling from the striatum of fourteen brains of human patients with Parkinson’s disease. Here we report these novel measurements and show that they correlate with outcomes and decisions in a sequential investment game. We find that serotonergic concentrations transiently increase as a whole following negative reward prediction errors, while reversing when counterfactual losses predominate. This provides initial evidence that the serotonergic system acts as an opponent to dopamine signaling, as anticipated by theoretical models. Serotonin transients on one trial were also associated with actions on the next trial in a manner that correlated with decreased exposure to poor outcomes. Thus, the fluctuations observed for serotonin appear to correlate with the inhibition of over-reactions and promote persistence of ongoing strategies in the face of short-term environmental changes. Together these findings elucidate a role for serotonin in the striatum, suggesting it encodes a protective action strategy that mitigates risk and modulates choice selection particularly following negative environmental events.

    更新日期:2018-01-03
  • Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-21
    Maria Morena, Andrea Berardi, Paola Colucci, Maura Palmery, Viviana Trezza, Matthew N Hill, Patrizia Campolongo

    Exposure to a traumatic event may result in the development of Post-Traumatic Stress Disorder (PTSD). Endocannabinoids are crucial modulators of the stress response, interfere with excessive retrieval and facilitate the extinction of traumatic memories. Exposure therapy, combined with pharmacotherapy, represents a promising tool for PTSD treatment. We investigated whether pharmacological manipulations of the endocannabinoid system during extinction learning ameliorates the behavioral changes induced by trauma exposure. Rats were exposed to inescapable footshocks paired with social isolation, a risk factor for PTSD. One week after trauma, rats were subjected to three spaced extinction sessions, mimicking human exposure therapy. The anandamide hydrolysis inhibitor URB597, the 2-arachidonoylglycerol hydrolysis inhibitor JZL184 or the cannabinoid agonist WIN55,212-2 were administered before or after the extinction sessions. Rats were tested for extinction retention 16 or 36 days after trauma and 24-h later for social interaction. Extinction training alone reduced fear of the trauma-associated context but did not restore normal social interaction. Traumatized animals not exposed to extinction sessions exhibited reductions in hippocampal anandamide content with respect to home-cage controls. Noteworthy, all drugs exerted beneficial effects, but URB597 (0.1 mg/kg) induced the best improvements by enhancing extinction consolidation and restoring normal social behavior in traumatized rats through indirect activation of CB1 receptors. The ameliorating effects remained stable long after treatment and trauma exposure. Our findings suggest that drugs potentiating endocannabinoid neurotransmission may represent promising tools when combined to exposure-based psychotherapies in the treatment of PTSD.

    更新日期:2017-12-21
  • A Novel Role for Oligodendrocyte Precursor Cells (OPCs) and Sox10 in Mediating Cellular and Behavioral Responses to Heroin
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-20
    Jennifer A Martin, Aaron Caccamise, Craig T Werner, Rathipriya Viswanathan, Jessie J Polanco, Andrew F Stewart, Shruthi A Thomas, Fraser J Sim, David M Dietz

    Opiate abuse and addiction have become a worldwide epidemic with great societal and financial burdens, highlighting a critical need to understand the neurobiology of opiate addiction. While several studies have focused on drug-dependent changes in neurons, the role of glia in opiate addiction remains largely unstudied. RNA sequencing pathway analysis from the prefrontal cortex of male rats revealed changes in several genes associated with oligodendrocyte differentiation and maturation following heroin self-administration. Among these genes changed was Sox10, which is regulated, in part, by the chromatin remodeler BRG1/SMARCA4. To directly test the functional role of Sox10 in mediating heroin-induced behavioral plasticity, we selectively overexpressed Sox10 and BRG1 in the prefrontal cortex. Overexpression of either Sox10 or BRG1 decreased the motivation to obtain heroin infusions in a progressive ratio test without altering the acquisition or maintenance of heroin self-administration. These data demonstrate a critical, and perhaps compensatory, role of Sox10 and BRG1 in oligodendrocytes in regulating the motivation for heroin.

    更新日期:2017-12-20
  • Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-18
    Laura B Ferguson, Angela R Ozburn, Igor Ponomarev, Pamela Metten, Matthew Reilly, John C Crabbe, R Adron Harris, R Dayne Mayfield

    Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice, Published online: 18 December 2017; doi:10.1038/npp.2017.301 Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice

    更新日期:2017-12-18
  • Dopamine Receptor-Specific Contributions to the Computation of Value
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-18
    Christopher J Burke, Alexander Soutschek, Susanna Weber, Anjali R Beharelle, Ernst Fehr, Helene Haker, Philippe N Tobler

    Dopamine Receptor-Specific Contributions to the Computation of Value Dopamine Receptor-Specific Contributions to the Computation of Value, Published online: 18 December 2017; doi:10.1038/npp.2017.302 Dopamine Receptor-Specific Contributions to the Computation of Value

    更新日期:2017-12-18
  • Carmen Keith Conners
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-12
    Bernard J Carroll

    Carmen Keith Conners Carmen Keith Conners, Published online: 12 December 2017; doi:10.1038/npp.2017.240 Carmen Keith Conners

    更新日期:2017-12-15
  • Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 a and AP-2 b in Frontal Cortex of Rats Treated with Lithium for 6 Weeks
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-12
    Jagadeesh S Rao, Stanley I Rapoport, Francesca Bosetti

    Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 a and AP-2 b in Frontal Cortex of Rats Treated with Lithium for 6 Weeks Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 a and AP-2 b in Frontal Cortex of Rats Treated with Lithium for 6 Weeks, Published online: 12 December 2017; doi:10.1038/npp.2017.237 Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 a and AP-2 b in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

    更新日期:2017-12-15
  • Telomere Length and Bipolar Disorder
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-12
    Timothy R Powell, Danai Dima, Sophia Frangou, Gerome Breen

    Telomere Length and Bipolar Disorder Telomere Length and Bipolar Disorder, Published online: 12 December 2017; doi:10.1038/npp.2017.239 Telomere Length and Bipolar Disorder

    更新日期:2017-12-15
  • Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-05
    Ada Eban-Rothschild, Lior Appelbaum, Luis de Lecea

    Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive, Published online: 05 December 2017; doi:10.1038/npp.2017.294 Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive

    更新日期:2017-12-15
  • mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-05
    Elyza Kelly, Samantha M Schaeffer, Sameer C Dhamne, Jonathan O Lipton, Lothar Lindemann, Michael Honer, Georg Jaeschke, Chloe E Super, Stephen HT Lammers, Meera E Modi, Jill L Silverman, John R Dreier, David J Kwiatkowski, Alexander Rotenberg, Mustafa Sahin

    mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex, Published online: 05 December 2017; doi:10.1038/npp.2017.295 mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex

    更新日期:2017-12-15
  • Cognitive Signaling in Cerebellar Granule Cells
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-01
    Mark J Wagner

    Cognitive Signaling in Cerebellar Granule Cells Cognitive Signaling in Cerebellar Granule Cells, Published online: 01 December 2017; doi:10.1038/npp.2017.186 Cognitive Signaling in Cerebellar Granule Cells

    更新日期:2017-12-15
  • The Promise of Genome Editing for Modeling Psychiatric Disorders
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-01
    Stephanie PB Caligiuri, Paul J Kenny

    The Promise of Genome Editing for Modeling Psychiatric Disorders The Promise of Genome Editing for Modeling Psychiatric Disorders, Published online: 01 December 2017; doi:10.1038/npp.2017.197 The Promise of Genome Editing for Modeling Psychiatric Disorders

    更新日期:2017-12-15
  • Selective Adenylyl Cyclase Type 1 Inhibitors as Potential Opioid Alternatives For Chronic Pain
    Neuropsychopharmacology (IF 6.403) Pub Date : 2017-12-01
    Val J Watts

    Selective Adenylyl Cyclase Type 1 Inhibitors as Potential Opioid Alternatives For Chronic Pain Selective Adenylyl Cyclase Type 1 Inhibitors as Potential Opioid Alternatives For Chronic Pain, Published online: 01 December 2017; doi:10.1038/npp.2017.190 Selective Adenylyl Cyclase Type 1 Inhibitors as Potential Opioid Alternatives For Chronic Pain

    更新日期:2017-12-15
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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