Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-24 Oliver Vranjkovic, Garrett Winkler, Danny G. Winder
Forced abstinence from chronic two bottle-choice ethanol drinking produces the development of negative affective states in female C57BL/6J mice. We previously reported that this disrupted behavior is acutely reversed by administration of ketamine 30 min-prior to testing. Here we assessed whether ketamine can be used as an inoculant against the development of abstinence- dependent affective disturbances. In parallel, we examined the impact of ketamine administration on long-term potentiation (LTP) in the bed nucleus of the stria terminalis (BNST), a region implicated in affective disturbances. We administered ketamine (3 mg/kg i.p.) to female C57BL/6J mice with a history of chronic ethanol drinking at either the onset, two, or 6 days- post-abstinence and observed its impact on affective behavior in the elevated plus maze (EPM), the Novelty Suppressed Feeding Test (NSFT), and the Forced Swim Test (FST). In addition, we assessed BNST synaptic plasticity with field potential electrophysiology two to 3 weeks into abstinence. We found that early abstinence was associated with disrupted behavior on the EPM. Ketamine administered at the onset of forced abstinence prevented both the deficit in early EPM behavior, and the delayed deficits in NSFT and FST. However, ketamine administered either two or 6 days post-abstinence failed to prevent the abstinence-induced affective disturbances. To begin to explore potential alterations in neural circuit activity that accompanies these actions of ketamine, we assessed the impact of ketamine administration at the onset of forced abstinence and measured LTP induction in the BNST. We find that early ketamine administration persistently increased the capacity for LTP within the BNST. These findings suggest a critical period at the onset of forced abstinence in which ketamine inoculation can prevent the development of affective disturbances, in part by enhancing plasticity within the BNST.
Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ΔFosB Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-24 Joram D. Mul, Marion Soto, Michael E. Cahill, Rebecca E. Ryan, Hirokazu Takahashi, Kawai So, Jia Zheng, Denise E. Croote, Michael F. Hirshman, Susanne E. la Fleur, Eric J. Nestler, Laurie J. Goodyear
Elucidating mechanisms by which physical exercise promotes resilience, the brain’s ability to cope with prolonged stress exposure while maintaining normal psychological functioning, is a major research challenge given the high prevalence of stress-related mental disorders, including major depressive disorder. Chronic voluntary wheel running (VWR), a rodent model that mimics aspects of aerobic physical exercise, induces the transcription factor ΔFosB in the nucleus accumbens (NAc), a key reward-related brain area. ΔFosB expression in NAc modulates stress susceptibility. Here, we explored whether VWR induction of NAc ΔFosB promotes resilience to chronic social defeat stress (CSDS). Male young-adult C57BL/6J mice were single housed for up to 21 d with or without running wheels and then subjected to 10 d of CSDS. Stress-exposed sedentary mice developed a depressive-like state, characterized by anhedonia and social avoidance, whereas stress-exposed mice that had been wheel running showed resilience. Functional inhibition of NAc ΔFosB during VWR, by viral-mediated overexpression of a transcriptionally inactive JunD mutant, reinstated susceptibility to CSDS. Within the NAc, VWR induction of ΔFosB was CREB-dependent, associated with altered dendritic morphology, and medium spiny neuron (MSN) subtype specific in the NAc core and shell subregions. Finally, when mice performed VWR following the onset of CSDS-induced social avoidance, VWR normalized such behavior. These data indicate that VWR promoted resilience to CSDS, and suggest that sustained induction of ΔFosB in the NAc underlies, at least in part, the stress resilience mediated by VWR. These findings provide a potential framework for the development of treatments for stress-associated mental illnesses based on physical exercise.
Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-22 Ji-Woon Kim, Kwanghoon Park, Ri Jin Kang, Edson Luck T. Gonzales, Do Gyeong Kim, Hyun Ah Oh, Hana Seung, Mee Jung Ko, Kyoung Ja Kwon, Ki Chan Kim, Sung Hoon Lee, ChiHye Chung, Chan Young Shin
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, featuring social communication deficit and repetitive/restricted behaviors as common symptoms. Its prevalence has continuously increased, but, till now, there are no therapeutic approaches to relieve the core symptoms, particularly social deficit. In previous studies, abnormal function of the glutamatergic neural system has been proposed as a critical mediator and therapeutic target of ASD-associated symptoms. Here, we investigated the possible roles of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in autism symptoms using two well-known autistic animal models, Cntnap2 knockout (KO) mice and in utero valproic acid-exposed ICR (VPA) mice. We found that Cntnap2 KO mice displayed decreased glutamate receptor expression and transmission. Contrarily, VPA mice exhibited increased glutamate receptor expression and transmission. Next, we investigated whether AMPAR modulators (positive-allosteric-modulator for Cntnap2 KO mice and antagonist for VPA mice) can improve autistic symptoms by normalizing the aberrant excitatory transmission in the respective animal models. Interestingly, the AMPAR modulation specifically ameliorated social deficits in both animal models. These results indicated that AMPAR-derived excitatory neural transmission changes can affect normal social behavior. To validate this, we injected an AMPAR agonist or antagonist in control ICR mice and, interestingly, these treatments impaired only the social behavior, without affecting the repetitive and hyperactive behaviors. Collectively, these results provide insight into the role of AMPARs in the underlying pathophysiological mechanisms of ASD, and demonstrate that modulation of AMPAR can be a potential target for the treatment of social behavior deficits associated with ASD.
Involvement of dopamine, but not norepinephrine, in the sex-specific regulation of juvenile socially rewarding behavior by vasopressin Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-22 Remco Bredewold, Nara F. Nascimento, Grace S. Ro, Shannon E. Cieslewski, Christina J. Reppucci, Alexa H. Veenema
Social play is a highly rewarding behavior displayed mostly during the juvenile period. We recently showed that vasopressin V1a receptor (V1aR) blockade in the lateral septum (LS) enhances social play in male juvenile rats, but reduces it in females. Here, we determined whether the LS-AVP system modulates dopamine (DA) and/or norepinephrine (NE) neurotransmission in the LS to regulate social play behavior in sex-specific ways. Using microdialysis combined with retrodialysis, we demonstrated that both LS-AVP administration and social play exposure increased extracellular LS-DA release in females, but not in males. Pharmacological blockade of LS-DA receptors reduced social play in both sexes, but required a higher dose in females. This suggests that baseline LS-DA release is sufficient for social play in males, while increased LS-DA release is necessary for social play in females. Administration of a V1aR antagonist into the LS inhibited the social play-induced increase in extracellular LS-DA release in females. Furthermore, co-administration of the DA agonist apomorphine prevented the LS-V1aR blockade-induced decrease in social play in females. This suggests that LS-V1aR blockade reduces social play in females by dampening the rise in LS-DA release. Extracellular LS-NE release was enhanced in response to pharmacological manipulations of the LS-AVP system and to social play in males and/or females, but pharmacological blockade or stimulation of LS-NE receptors did not alter social play in either sex. Overall, we define a mechanism by which the LS-AVP system alters LS-DA neurotransmission differently in males than females resulting in the sex-specific regulation of juvenile social play behavior.
Effects of alcohol dependence on discrete choice between alcohol and saccharin Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-22 Melissa Russo, Douglas Funk, Andrew Loughlin, Kathleen Coen, A. D. Lê
Dependence on drugs has enduring effects on drug intake and relapse. The role of choice in enhanced susceptibility to drug use in drug dependence has been little studied. Here we determine the effects of alcohol dependence on the choice between alcohol and a non-drug reward, saccharin, using the discrete choice model in food-restricted male rats. We trained rats to self-administer alcohol (12% w/v) and saccharin (0.05, 0.1%), tested their choice of alcohol vs. saccharin, and determined the effects of deprivation and intertrial interval (ITI) duration on choice. We then determined the effects of alcohol dependence, induced by repeated intermittent exposure to alcohol vapor on choice of alcohol vs. saccharin (0.1%) in discrete choice trials as well as on the effects of adulteration of alcohol with quinine on choice. We trained another group of rats to self-administer intravenous (i.v.) nicotine (0.03 mg/kg/infusion) and oral saccharin (0.1%), determined their choice, and examined the roles of ITI duration and concurrent access on choice. Rats chose equivalent amounts of 0.05% saccharin and 12% alcohol, showed a stronger choice for 0.1% saccharin, and alcohol and saccharin choice were modestly decreased and increased, respectively, by deprivation. Alcohol dependence led to profound increases in the choice of alcohol over saccharin while adulteration of alcohol with quinine did not affect choice in non-dependent or dependent rats. Rats showed marked choice for 0.1% saccharin over i.v. nicotine. The strong effect that dependence had on alcohol choice is an important validation of the discrete choice procedure.
Chemogenetic activation of ventral tegmental area GABA neurons, but not mesoaccumbal GABA terminals, disrupts responding to reward-predictive cues Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-22 Ken T. Wakabayashi, Malte Feja, Ajay N. Baindur, Michael J. Bruno, Rohan V. Bhimani, Jinwoo Park, Kathryn Hausknecht, Roh-Yu Shen, Samir Haj-Dahmane, Caroline E. Bass
Cues predicting rewards can gain motivational properties and initiate reward-seeking behaviors. Dopamine projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) are critical in regulating cue-motivated responding. Although, approximately one third of mesoaccumbal projection neurons are GABAergic, it is unclear how this population influences motivational processes and cue processing. This is largely due to our inability to pharmacologically probe circuit level contributions of VTA-GABA, which arises from diverse sources, including multiple GABA afferents, interneurons, and projection neurons. Here we used a combinatorial viral vector approach to restrict activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to GABA neurons in the VTA of wild-type rats trained to respond during a distinct audiovisual cue for sucrose. We measured different aspects of motivation for the cue or primary reinforcer, while chemogenetically activating either the VTA-GABA neurons or their projections to the NAc. Activation of VTA-GABA neurons decreased cue-induced responding and accuracy, while increasing latencies to respond to the cue and obtain the reward. Perseverative and spontaneous responses decreased, yet the rats persisted in entering the reward cup when the cue and reward were absent. However, activation of the VTA-GABA terminals in the accumbens had no effect on any of these behaviors. Together, we demonstrate that VTA-GABA neuron activity preferentially attenuates the ability of cues to trigger reward-seeking, while some aspects of the motivation for the reward itself are preserved. Additionally, the dense VTA-GABA projections to the NAc do not influence the motivational salience of the cue.
Exposure to conditions of uncertainty promotes the pursuit of amphetamine Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-22 Paola Mascia, Nichole M Neugebauer, Jason Brown, Nancy Bubula, Kathryn M Nesbitt, Robert T Kennedy, Paul Vezina
Prior exposure to abused drugs leads to long-lasting neuroadaptations culminating in excessive drug intake. Given the comorbidity between substance use and gambling disorders, surprisingly little is known about the effects of exposure to reinforcement contingencies experienced during games of chance. As it is a central feature of these games, we characterized the effects of exposure to uncertainty on biochemical and behavioral effects normally observed in rats exposed to amphetamine. Rats in different groups were trained to nose-poke for saccharin under certain [fixed-ratio (FR)] or uncertain conditions [variable-ratio (VR)] for 55 1-h sessions. Ratios were escalated on successive sessions and rats maintained on the last ratio (FR/VR 20) for 20–25 days. Two to three weeks later, rats were tested for their locomotor or nucleus accumbens dopamine (NAcc DA) response to amphetamine or self-administration of the drug using a lever press operant. NAcc DA overflow was also assessed in additional rats during the saccharin sessions. Rats exposed to uncertainty subsequently showed a higher locomotor and NAcc DA response to amphetamine and self-administered more drug infusions relative to rats exposed to predictable reinforcement. NAcc DA levels during the saccharin sessions tracked the variance of the scheduled ratios (a measure of uncertainty). VR rats showed escalating DA overflow with increasing ratios. Exposure to uncertainty triggered neuroadaptations similar to those produced by exposure to abused drugs. As these were produced in drug naive rats both during and after exposure to uncertainty, they provide a novel common pathway to drug and behavioral addictions.
Does human language limit translatability of clinical and preclinical addiction research? Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-17 Harriet de Wit, David H. Epstein, Kenzie L. Preston
Does human language limit translatability of clinical and preclinical addiction research? Does human language limit translatability of clinical and preclinical addiction research?, Published online: 17 May 2018; doi:10.1038/s41386-018-0095-8 Does human language limit translatability of clinical and preclinical addiction research?
Response to therapeutic sleep deprivation: a naturalistic study of clinical and genetic factors and post-treatment depressive symptom trajectory Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-17 Nina Trautmann, Jerome C. Foo, Josef Frank, Stephanie H. Witt, Fabian Streit, Jens Treutlein, Steffen Conrad von Heydendorff, Maria Gilles, Andreas J. Forstner, Ulrich Ebner-Priemer, Markus M. Nöthen, Michael Deuschle, Marcella Rietschel
Research has shown that therapeutic sleep deprivation (SD) has rapid antidepressant effects in the majority of depressed patients. Investigation of factors preceding and accompanying these effects may facilitate the identification of the underlying biological mechanisms. This exploratory study aimed to examine clinical and genetic factors predicting response to SD and determine the impact of SD on illness course. Mood during SD was also assessed via visual analogue scale. Depressed inpatients (n = 78) and healthy controls (n = 15) underwent ~36 h of SD. Response to SD was defined as a score of ≤ 2 on the Clinical Global Impression Scale for Global Improvement. Depressive symptom trajectories were evaluated for up to a month using self/expert ratings. Impact of genetic burden was calculated using polygenic risk scores for major depressive disorder. In total, 72% of patients responded to SD. Responders and non-responders did not differ in baseline self/expert depression symptom ratings, but mood differed. Response was associated with lower age (p = 0.007) and later age at life-time disease onset (p = 0.003). Higher genetic burden of depression was observed in non-responders than healthy controls. Up to a month post SD, depressive symptoms decreased in both patients groups, but more in responders, in whom effects were sustained. The present findings suggest that re-examining SD with a greater focus on biological mechanisms will lead to better understanding of mechanisms of depression.
Reduced GABAergic cortical inhibition in aging and depression Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-17 Jennifer I. Lissemore, Apoorva Bhandari, Benoit H. Mulsant, Eric J. Lenze, Charles F. Reynolds, Jordan F. Karp, Tarek K. Rajji, Yoshihiro Noda, Reza Zomorrodi, Etienne Sibille, Zafiris J. Daskalakis, Daniel M. Blumberger
The neurobiology underlying depression in older adults is less extensively evaluated than in younger adults, despite the putative influence of aging on depression neuropathology. Studies using transcranial magnetic stimulation (TMS), a neurophysiological tool capable of probing inhibitory and excitatory cortical neurotransmission, have identified dysfunctional GABAergic inhibitory activity in younger adults with depression. However, GABAergic and glutamatergic cortical neurotransmission have not yet been studied in late-life depression (LLD). Here, we used single- and paired-pulse TMS to measure cortical inhibition and excitation in 92 LLD patients and 41 age-matched healthy controls. To differentiate the influence of age and depression, we also compared these TMS indices to those of 30 younger depressed adults and 30 age- and sex-matched younger healthy adults. LLD patients, older healthy adults, and younger depressed adults demonstrated significantly lower GABAA receptor-mediated cortical inhibition than younger healthy controls. By contrast, no significant differences in cortical inhibition were observed between older adults with and without depression. No significant differences in GABAB receptor-mediated inhibition or cortical excitation were found between the groups. Altogether, these findings suggest that reduced cortical inhibition may be associated with both advancing age and depression, which (i) supports the model of depression as a disease of accelerated aging, and (ii) prompts future investigation into diminished GABAergic neurotransmission in late-life as a biological predisposing factor to the development of depression. Given that cortical neurophysiology was similar in depressed and healthy older adults, future prospective studies need to establish the relative influence of age and depression on cortical inhibition deficits.
Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-16 L Holper, D Ben-Shachar, JJ Mann
Complex I (NADH dehydrogenase, NDU) and complex IV (cytochrome-c-oxidase, COX) of the mitochondrial electron transport chain have been implicated in the pathophysiology of major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), as well as in neurodegenerative disorders, such as Alzheimer disease (AD) and Parkinson disease (PD). We conducted meta-analyses comparing complex I and IV in each disorder MDD, BD, SZ, AD, and PD, as well as in normal aging. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar, were searched for studies published between 1980 and 2018. Of 2049 screened studies, 125 articles were eligible for the meta-analyses. Complex I and IV were assessed in peripheral blood, muscle biopsy, or postmortem brain at the level of enzyme activity or subunits. Separate meta-analyses of mood disorder studies, MDD and BD, revealed moderate effect sizes for similar abnormality patterns in the expression of complex I with SZ in frontal cortex, cerebellum and striatum, whereas evidence for complex IV alterations was low. By contrast, the neurodegenerative disorders, AD and PD, showed strong effect sizes for shared deficits in complex I and IV, such as in peripheral blood, frontal cortex, cerebellum, and substantia nigra. Beyond the diseased state, there was an age-related robust decline in both complexes I and IV. In summary, the strongest support for a role for complex I and/or IV deficits, is in the pathophysiology of PD and AD, and evidence is less robust for MDD, BD, or SZ.
Metaplasticity contributes to memory formation in the hippocampus Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-16 Ana P. Crestani, Jamie N. Krueger, Eden V. Barragan, Yuki Nakazawa, Sonya E. Nemes, Jorge A. Quillfeldt, John A. Gray, Brian J. Wiltgen
Prior learning can modify the plasticity mechanisms that are used to encode new information. For example, NMDA receptor (NMDAR) activation is typically required for new spatial and contextual learning in the hippocampus. However, once animals have acquired this information, they can learn new tasks even if NMDARs are blocked. This finding suggests that behavioral training alters cellular plasticity mechanisms such that NMDARs are not required for subsequent learning. The mechanisms that mediate this change are currently unknown. To address this issue, we tested the idea that changes in intrinsic excitability (induced by learning) facilitate the encoding of new memories via metabotropic glutamate receptor (mGluR) activation. Consistent with this hypothesis, hippocampal neurons exhibited increases in intrinsic excitability after learning that lasted for several days. This increase was selective and only observed in neurons that were activated by the learning event. When animals were trained on a new task during this period, excitable neurons were reactivated and memory formation required the activation of mGluRs instead of NMDARs. These data suggest that increases in intrinsic excitability may serve as a metaplastic mechanism for memory formation.
NPTX2 is a key component in the regulation of anxiety Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-11 Simon Chang, Philane Bok, Ching-Yen Tsai, Cheng-Pu Sun, Hsuan Liu, Jan M. Deussing, Guo-Jen Huang
Anxiety disorders significantly impair quality of life. However, limited knowledge of the underlying mechanisms impedes the development of effective therapeutics. Previous studies have suggested that the expression of the Nptx2 gene is associated with anxiety, but the neurobiological processes underlying this association remain unclear. We generated multiple mouse models with knockout or overexpression of Nptx2 in specific brain regions and during different developmental stages to assess anxiety, adult neurogenesis, and glucocorticoid-related gene expression. Our results provide evidence that Nptx2 expression in the adult hippocampus regulates anxiety in mice. Eliminating Nptx2 expression in either the developing mouse brain or in adulthood leads to increased anxiety levels. The increase in anxiety was evident in hippocampus-specific Nptx2 knockout mice, but not in an amygdala specific knockouts. Gene expression analysis revealed increased expression of glucocorticoid receptor target genes in Nptx2 knockout mice after acute stress. Overexpression of Nptx2 in the hippocampus alleviates stress-induced anxious behaviors and reverses the changes in expression of glucocorticoid receptor related genes. In conclusion, we demonstrate that Nptx2 in the hippocampus performs a critical role in modulating anxiety, hippocampal cell proliferation, and glucocorticoid receptor related gene expression. Our results suggest Nptx2 may be a potential target for anxiolytic therapeutics.
Cerebral white matter sex dimorphism in alcoholism: a diffusion tensor imaging study Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-09 Kayle S. Sawyer, Nasim Maleki, George Papadimitriou, Nikos Makris, Marlene Oscar-Berman, Gordon J. Harris
Excessive alcohol consumption is associated with brain aberrations, including abnormalities in frontal and limbic brain regions. In a prior diffusion tensor magnetic resonance imaging (dMRI) study of neuronal circuitry connecting the frontal lobes and limbic system structures, we demonstrated decreases in white matter fractional anisotropy in abstinent alcoholic men. In the present study, we examined sex differences in alcoholism-related abnormalities of white matter connectivity and their association with alcoholism history. The dMRI scans were acquired from 49 abstinent alcoholic individuals (26 women) and 41 nonalcoholic controls (22 women). Tract-based spatial statistical tools were used to estimate regional FA of white matter tracts and to determine sex differences and their relation to measures of alcoholism history. Sex-related differences in white matter connectivity were observed in association with alcoholism: Compared to nonalcoholic men, alcoholic men had diminished FA in portions of the corpus callosum, the superior longitudinal fasciculi II and III, and the arcuate fasciculus and extreme capsule. In contrast, alcoholic women had higher FA in these regions. Sex differences also were observed for correlations between corpus callosum FA and length of sobriety. Our results suggest that sexual dimorphism in white matter microstructure in abstinent alcoholics may implicate underlying differences in the neurobehavioral liabilities for developing alcohol abuse disorders, or for sequelae following abuse.
Differences in the subjective and motivational properties of alcohol across alcohol use severity: application of a novel translational human laboratory paradigm Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-08 Spencer Bujarski, J. David Jentsch, Daniel J. O. Roche, Vijay A. Ramchandani, Karen Miotto, Lara A. Ray
The Allostatic Model proposes that Alcohol Use Disorder (AUD) is associated with a transition in the motivational structure of alcohol drinking: from positive reinforcement in early-stage drinking to negative reinforcement in late-stage dependence. However, direct empirical support for this preclinical model from human experiments is limited. This study tests predictions derived from the Allostatic Model in humans. Specifically, this study tested whether alcohol use severity (1) independently predicts subjective responses to alcohol (SR; comprised of stimulation/hedonia, negative affect, sedation and craving domains), and alcohol self-administration and 2) moderates associations between domains of SR and alcohol self-administration. Heavy drinking participants ranging in severity of alcohol use and problems (N = 67) completed an intravenous alcohol administration paradigm combining an alcohol challenge (target BrAC = 60 mg%), with progressive ratio self-administration. Alcohol use severity was associated with greater baseline negative affect, sedation, and craving but did not predict changes in any SR domain during the alcohol challenge. Alcohol use severity also predicted greater self-administration. Craving during the alcohol challenge strongly predicted self-administration and sedation predicted lower self-administration. Neither stimulation, nor negative affect predicted self-administration. This study represents a novel approach to translating preclinical neuroscientific theories to the human laboratory. As expected, craving predicted self-administration and sedation was protective. Contrary to the predictions of the Allostatic Model, however, these results were inconsistent with a transition from positively to negatively reinforced alcohol consumption in severe AUD. Future studies that assess negative reinforcement in the context of an acute stressor are warranted.
Burst activation of dopamine neurons produces prolonged post-burst availability of actively released dopamine Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-07 Sweyta Lohani, Adria K. Martig, Suzanne M. Underhill, Alicia DeFrancesco, Melanie J. Roberts, Linda Rinaman, Susan Amara, Bita Moghaddam
Both phasic and tonic modes of neurotransmission are implicated in critical functions assigned to dopamine. In learning, for example, sub-second phasic responses of ventral tegmental area (VTA) dopamine neurons to salient events serve as teaching signals, but learning is also interrupted by dopamine antagonists administered minutes after training. Our findings bridge the multiple timescales of dopamine neurotransmission by demonstrating that burst stimulation of VTA dopamine neurons produces a prolonged post-burst increase (>20 min) of extracellular dopamine in nucleus accumbens and prefrontal cortex. This elevation is not due to spillover from the stimulation surge, but depends on impulse flow-mediated dopamine release. We identified Rho-mediated internalization of dopamine transporter as a mechanism responsible for prolonged availability of actively released dopamine. Thus, a critical consequence of burst activity of dopamine neurons may be post-burst sustained elevation of extracellular dopamine in terminal regions via an intracellular mechanism that promotes dopamine transporter internalization. These results demonstrate that phasic and tonic dopamine neurotransmission can be a continuum and may explain why both modes of signaling are critical for motivational and cognitive functions associated with dopamine.
Ventral striatal response during decision making involving risk and reward is associated with future binge drinking in adolescents Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-07 Angelica M. Morales, Scott A. Jones, Alissa Ehlers, Jessye B. Lavine, Bonnie J. Nagel
Beginning to engage in heavy alcohol use during adolescence, as opposed to later in life, is associated with elevated risk for a variety of negative consequences, including the development of an alcohol use disorder. Behavioral studies suggest that poor decision making predicts alcohol use during adolescence; however, more research is needed to determine the neurobiological risk factors that underlie this association. Using functional magnetic resonance imaging, brain activation during decision making involving risk and reward was assessed in 47 adolescents (14–15 years old) with no significant history or alcohol or drug use. After baseline assessment, the participants completed follow-up interviews every 3 months to assess the duration to onset of binge drinking. Adolescents who made a greater number of risky selections and had greater activation in the nucleus accumbens, precuneus, and occipital cortex during decision making involving greater potential for risk and reward began binge drinking sooner. Findings suggest that heightened activation of reward circuitry during decision making under risk is a neurobiological risk factor for earlier onset of binge drinking. Furthermore, brain activation was a significant predictor of onset to binge drinking, even after controlling for decision-making behavior, suggesting that neurobiological markers may provide additional predictive validity over behavioral assessments. Interventions designed to modify these behavioral and neurobiological risk factors may be useful for curbing heavy alcohol use during adolescence.
Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-04 A Versace, CD Ladouceur, S Graur, HE Acuff, LK Bonar, K Monk, A McCaffrey, A Yendiki, A Leemans, MJ Travis, VA Diwadkar, SK Holland, JL Sunshine, RA Kowatch, SM Horwitz, TW Frazier, LE Arnold, MA Fristad, EA Youngstrom, RL Findling, BI Goldstein, T Goldstein, D Axelson, B Birmaher, ML Phillips
Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.
Influence of alcoholism and cholesterol on TSPO binding in brain: PET [11C]PBR28 studies in humans and rodents Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-03 Sung Won Kim, Corinde E. Wiers, Ryan Tyler, Ehsan Shokri-Kojori, Yeon Joo Jang, Amna Zehra, Clara Freeman, Veronica Ramirez, Elsa Lindgren, Gregg Miller, Elizabeth A. Cabrera, Tyler Stodden, Min Guo, Şükrü B. Demiral, Nancy Diazgranados, Luke Park, Jeih-San Liow, Victor Pike, Cheryl Morse, Leandro F. Vendruscolo, Robert B. Innis, George F. Koob, Dardo Tomasi, Gene-Jack Wang, Nora D. Volkow
Neuroinflammation appears to contribute to neurotoxicity observed with heavy alcohol consumption. To assess whether chronic alcohol results in neuroinflammation we used PET and [11C]PBR28, a ligand that binds to the 18-kDa translocator protein (TSPO), to compare participants with an alcohol use disorder (AUD: n = 19) with healthy controls (HC: n = 17), and alcohol-dependent (n = 9) with -nondependent rats (n = 10). Because TSPO is implicated in cholesterol’s transport for steroidogenesis, we investigated whether plasma cholesterol levels influenced [11C]PBR28 binding. [11C]PBR28 binding did not differ between AUD and HC. However, when separating by TSPO genotype rs6971, we showed that medium-affinity binders AUD participants showed lower [11C]PBR28 binding than HC in regions of interest (whole brain, gray and white matter, hippocampus, and thalamus), but no group differences were observed in high-affinity binders. Cholesterol levels inversely correlated with brain [11C]PBR28 binding in combined groups, due to a correlation in AUD participants. In rodents, we observed no differences in brain [11C]PBR28 uptake between alcohol-dependent and -nondependent rats. These findings, which are consistent with two previous [11C]PBR28 PET studies, may indicate lower activation of microglia in AUD, whereas failure to observe alcohol effects in the rodent model indicate that species differences do not explain the discrepancy with prior rodent autoradiographic studies reporting increases in TSPO binding with chronic alcohol. However, reduced binding in AUD participants could also reflect competition from endogenous TSPO ligands such as cholesterol; and since the rs6971 polymorphism affects the cholesterol-binding domain of TSPO this could explain why differences were observed only in medium-affinity binders.
(2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-03 Jun-ichi Yamaguchi, Hidetoh Toki, Youge Qu, Chun Yang, Hiroyuki Koike, Kenji Hashimoto, Akiko Mizuno-Yasuhira, Shigeyuki Chaki
(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the antidepressant actions of (R)-ketamine. Antidepressant effects were evaluated using the forced swimming test in the lipopolysaccharide (LPS)-induced inflammation model of mice and the tail suspension test in naive mice. To prevent the metabolism of (R)-ketamine to (2 R,6 R)-HNK, mice were pretreated with cytochrome P450 (CYP) inhibitors. The concentrations of (R)-ketamine, (R)-norketamine, and (2 R,6 R)-HNK in plasma, brain, and cerebrospinal fluid (CSF) samples were determined using enantioselective liquid chromatography-tandem mass spectrometry. The concentrations of (R)-norketamine and (2 R,6 R)-HNK in plasma, brain, and CSF samples after administration of (R)-norketamine (10 mg/kg) and (2 R,6 R)-HNK (10 mg/kg), respectively, were higher than those generated after administration of (R)-ketamine (10 mg/kg). Nonetheless, while (R)-ketamine attenuated, neither (R)-norketamine nor (2 R,6 R)-HNK significantly altered immobility times of LPS-treated mice. Treatment with CYP inhibitors prior to administration of (R)-ketamine increased the plasma levels of (R)-ketamine, while generation of (2 R,6 R)-HNK was almost completely blocked. (R)-Ketamine exerted the antidepressant effects at a lower dose in the presence of CYP inhibitors than in their absence, which is consistent with exposure levels of (R)-ketamine but not (2 R,6 R)-HNK. These results indicate that metabolism to (2 R,6 R)-HNK is not necessary for the antidepressant effects of (R)-ketamine and that unmetabolized (R)-ketamine itself may be responsible for its antidepressant actions.
Disrupting reconsolidation: memory erasure or blunting of emotional/motivational value? Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-03 Elizabeth S. Cogan, Mark A. Shapses, Terry E. Robinson, Natalie C. Tronson
When memories are retrieved they become labile, and subject to alteration by a process known as reconsolidation. Disruption of memory reconsolidation decreases the performance of learned responses, which is often attributed to erasure of the memory; in the case of Pavlovian learning, to a loss of the association between a conditioned stimulus (CS) and unconditioned stimulus (US). However, an alternative interpretation is that disrupting reconsolidation does not erase memories, but blunts their emotional/motivational impact. It is difficult to parse the predictive vs. emotional/motivational value of CSs in non-human animals, but studies on variation in the form of conditioned responses (CRs) in a Pavlovian conditioned approach task suggest a way to do this. In this task a lever-CS paired with a food reward (US) acquires predictive value in all rats, but is attributed with emotional/motivational value to a greater extent in some rats (sign-trackers) than others (goal-trackers). We report that the post-retrieval administration of propranolol selectively attenuates a sign-tracking CR, and the associated neural activation of brain “motive circuits”, while having no effect on conditioned orienting behavior in sign-trackers, or on goal-tracking CRs evoked by either a lever-CS or a tone-CS. We conclude that the disruption of reconsolidation by post-retrieval propranolol degrades the emotional/motivational impact of the CS, required for sign-tracking, but leaves the CS–US association intact. The possibility that post-retrieval interventions can reduce the emotional/motivational aspects of memories, without actually erasing them, has important implications for treating maladaptive memories that contribute to some psychiatric disorders.
The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-03 Nii A. Addy, Eric J. Nunes, Shannon M. Hughley, Keri M. Small, Sarah J. Baracz, Joshua L. Haight, Anjali M. Rajadhyaksha
Previous preclinical and clinical investigations have focused on the L-type calcium channel (LTCC) as a potential therapeutic target for substance abuse. While some clinical studies have examined the ability of LTCC blockers to alter cocaine’s subjective effects, very few LTCC studies have examined cocaine relapse. Here, we examined whether ventral tegmental area (VTA)-specific or systemic administration of the LTCC inhibitor, isradipine, altered cocaine-seeking behavior in a rat model. Male Sprague-Dawley rats first received 10 days of cocaine self-administration training (2 h sessions), where active lever depression resulted in delivery of a ∼0.5 mg/kg cocaine infusion paired with a tone + light cue. Rats then underwent 10 days of forced abstinence, without access to cocaine or cocaine cues. Rats were then returned to the opertant chamber for the cue-induced cocaine-seeking test, where active lever depression in the original training context resulted in tone + light cue presentation. We found VTA specific or systemic isradipine administration robustly attenuated cocaine-seeking, without altering cocaine-taking nor natural reward seeking. Dopamine (DA) signaling in the nucleus accumbens (NAc) core is necessary and sufficient for cue-induced drug-seeking. Surprisingly in our study, isradipine enhanced tonic and phasic DA signaling in cocaine abstinent rats, with no change in sucrose abstinent nor naïve rats. Strikingly, isradipine’s behavioral effects were dependent upon NAc core DA receptor activation. Together, our findings reveal a novel mechanism by which the FDA-approved drug, isradipine, could act to decrease cocaine relapse.
Aberrant working memory processing in major depression: evidence from multivoxel pattern classification Neuropsychopharmacology (IF 6.403) Pub Date : 2018-05-02 Matti Gärtner, M. Elisabetta Ghisu, Milan Scheidegger, Luisa Bönke, Yan Fan, Anna Stippl, Ana-Lucia Herrera-Melendez, Sophie Metz, Emilia Winnebeck, Maria Fissler, Anke Henning, Malek Bajbouj, Karsten Borgwardt, Thorsten Barnhofer, Simone Grimm
Major depressive disorder (MDD) is often accompanied by severe impairments in working memory (WM). Neuroimaging studies investigating the mechanisms underlying these impairments have produced conflicting results. It remains unclear whether MDD patients show hyper- or hypoactivity in WM-related brain regions and how potential aberrations in WM processing may contribute to the characteristic dysregulation of cognition–emotion interactions implicated in the maintenance of the disorder. In order to shed light on these questions and to overcome limitations of previous studies, we applied a multivoxel pattern classification approach to investigate brain activity in large samples of MDD patients (N = 57) and matched healthy controls (N = 61) during a WM task that incorporated positive, negative, and neutral stimuli. Results showed that patients can be distinguished from healthy controls with good classification accuracy based on functional activation patterns. ROI analyses based on the classification weight maps showed that during WM, patients had higher activity in the left DLPFC and the dorsal ACC. Furthermore, regions of the default-mode network (DMN) were less deactivated in patients. As no performance differences were observed, we conclude that patients required more effort, indexed by more activity in WM-related regions, to successfully perform the task. This increased effort might be related to difficulties in suppressing task-irrelevant information reflected by reduced deactivation of regions within the DMN. Effects were most pronounced for negative and neutral stimuli, thus pointing toward important implications of aberrations in WM processes in cognition–emotion interactions in MDD.
Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-27 Xiaoyan Li, Zhenwu Luo, Chunjie Gu, Lynsey S. Hall, Andrew M. McIntosh, Yanni Zeng, David J Porteous, Caroline Hayward, Ming Li, Yong-Gang Yao, Chen Zhang, Xiong-Jian Luo
Accumulating evidence suggests that genetic factors have a role in major depressive disorder (MDD). However, only limited MDD risk loci have been identified so far. Here we perform a meta-analysis (a total of 90,150 MDD cases and 246,603 controls) through combing three genome-wide association studies of MDD, including 23andMe (cases were self-reported with a clinical diagnosis or treatment of depression), CONVERGE (cases were diagnosed using the Composite International Diagnostic Interview) and PGC (cases were diagnosed using direct structured diagnostic interview (by trained interviewers) or clinician-administered DSM-IV checklists). Genetic variants from two previously unreported loci (rs10457592 on 6q16.2 and rs2004910 on 12q24.31) showed significant associations with MDD (P < 5 × 10−8) in a total of 336,753 subjects. SNPs (a total of 171) with a P < 1 × 10−7 in the meta-analysis were further replicated in an independent sample (GS:SFHS, 2,659 MDD cases (diagnosed with DSM-IV) and 17,237 controls) and one additional risk locus (rs3785234 on 16p13.3, P = 1.57 × 10−8) was identified in the combined samples (a total of 92,809 cases and 263,840 controls). Risk variants on the identified risk loci were associated with gene expression in human brain tissues and mRNA expression analysis showed that FBXL4 and RSRC1 were significantly upregulated in brains of MDD cases compared with controls, suggesting that genetic variants may confer risk of MDD through regulating the expression of these two genes. Our study identified three novel risk loci (6q16.2, 12q24.31, and 16p13.3) for MDD and suggested that FBXL4 and RSRC1 may play a role in MDD. Further functional characterization of the identified risk genes may provide new insights for MDD pathogenesis.
Letter to editor–Reponse to Send et al. telomere length in newborns is related to maternal stress during pregnancy Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-27 Kyle C. Esteves, Christopher W. Jones, Stacy S. Drury
Letter to editor–Reponse to Send et al. telomere length in newborns is related to maternal stress during pregnancy Letter to editor–Reponse to Send et al. telomere length in newborns is related to maternal stress during pregnancy, Published online: 27 April 2018; doi:10.1038/s41386-018-0077-x Letter to editor–Reponse to Send et al. telomere length in newborns is related to maternal stress during pregnancy
Motivational changes that develop in a mouse model of inflammation-induced depression are independent of indoleamine 2,3 dioxygenase Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-27 Elisabeth G. Vichaya, Geoffroy Laumet, Diana L. Christian, Aaron J. Grossberg, Darlene J. Estrada, Cobi J. Heijnen, Annemieke Kavelaars, Robert Dantzer
Despite years of research, our understanding of the mechanisms by which inflammation induces depression is still limited. As clinical data points to a strong association between depression and motivational alterations, we sought to (1) characterize the motivational changes that are associated with inflammation in mice, and (2) determine if they depend on inflammation-induced activation of indoleamine 2,3 dioxygenase-1 (IDO1). Lipopolysaccharide (LPS)-treated or spared nerve injured (SNI) wild type (WT) and Ido1−/− mice underwent behavioral tests of antidepressant activity (e.g., forced swim test) and motivated behavior, including assessment of (1) reward expectancy using a food-related anticipatory activity task, (2) willingness to work for reward using a progressive ratio schedule of food reinforcement, (3) effort allocation using a concurrent choice task, and (4) ability to associate environmental cues with reward using conditioned place preference. LPS- and SNI-induced deficits in behavioral tests of antidepressant activity in WT but not Ido1−/− mice. Further, LPS decreased food related-anticipatory activity, reduced performance in the progressive ratio task, and shifted effort toward the preferred reward in the concurrent choice task. These effects were observed in both WT and Ido1−/− mice. Finally, SNI mice developed a conditioned place preference based on relief from pain in an IDO1-independent manner. These findings demonstrate that the motivational effects of inflammation do not require IDO1. Further, they indicate that the motivational component of inflammation-induced depression is mechanistically distinct from that measured by behavioral tests of antidepressant activity.
Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-27 Inés Ibarra-Lecue, Irene Mollinedo-Gajate, J Javier Meana, Luis F Callado, Rebeca Díez-Alarcia, Leyre Urigüen
Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ9tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.
Deficient inhibition in alcohol-dependence: let’s consider the role of the motor system! Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-26 Caroline Quoilin, Emmanuelle Wilhelm, Pierre Maurage, Philippe de Timary, Julie Duque
Impaired inhibitory control contributes to the development, maintenance, and relapse of alcohol-dependence, but the neural correlates of this deficit are still unclear. Because inhibitory control has been labeled as an executive function, most studies have focused on prefrontal areas, overlooking the contribution of more “primary” structures, such as the motor system. Yet, appropriate neural inhibition of the motor output pathway has emerged as a central aspect of healthy behavior. Here, we tested the hypothesis that this motor inhibition is altered in alcohol-dependence. Neural inhibitory measures of motor activity were obtained in 20 detoxified alcohol-dependent (AD) patients and 20 matched healthy subjects, using a standard transcranial magnetic stimulation procedure whereby motor-evoked potentials (MEPs) are elicited in a choice reaction time task. Moreover, behavioral inhibition and trait impulsivity were evaluated in all participants. Finally, the relapse status of patients was assessed 1 year after the experiment. As expected, AD patients displayed poorer behavioral inhibition and higher trait impulsivity than controls. More importantly, the MEP data revealed a considerable shortage of neural motor inhibition in AD patients. Interestingly, this neural defect was strongest in the patients who ended up relapsing during the year following the experiment. Our data suggest a strong motor component in the neural correlates of altered inhibitory control in AD patients. They also highlight an intriguing relationship with relapse and the perspective of a new biomarker to follow strategies aiming at reducing relapse in AD patients.
Response to the letter by Esteves et al. Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-25 T. Send, M. Gilles, V. Codd, I. A. C. Wolf, S. Bardtke, F. Streit, J. Strohmaier, J. Frank, D. Schendel, M. W. Sütterlin, M. Denniff, M. Laucht, N. J. Samani, M. Deuschle, M. Rietschel, S. H. Witt
Response to the letter by Esteves et al. Response to the letter by Esteves et al., Published online: 25 April 2018; doi:10.1038/s41386-018-0079-8 Response to the letter by Esteves et al.
Glutamatergic and gabaergic ventral BNST neurons differ in their physiological properties and responsiveness to noradrenaline Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-20 Nur Zeynep Gungor, Ryo Yamamoto, Denis Pare
The bed nucleus of the stria terminalis (BNST) regulates defensive responses to threats and its anteroventral portion (BNST-AV) is involved. BNST-AV contains a minority of glutamatergic neurons scattered among a dominant population of GABAergic cells. There is evidence that these two cell types might exert opposite influences, the former promoting and the latter reducing anxiety. Although GABAergic cells greatly outnumber glutamatergic neurons in BNST-AV, in some circumstances the influence of glutamatergic cells appears to predominate. Related to this, BNST-AV receives a very strong noradrenaline (NA) input and negative emotional states are associated with a marked rise of NA concentration in BNST-AV. However, it is currently unclear whether NA differentially alters the excitability of glutamatergic and GABAergic BNST-AV neurons. Thus, to shed light on how BNST-AV regulates negative emotional states, the present study compared the physiological properties and NA responsiveness of glutamatergic and GABAergic BNST-AV neurons using whole-cell recordings in transgenic mice that express a fluorescent reporter in either cell group. We found that glutamatergic cells had a slightly more complex morphology than the GABAergic cells, a higher intrinsic excitability, and a different responsiveness to NA. Indeed, while NA inhibited EPSPs in both cell types through α1 and α2 adrenoreceptors, the EPSP reduction seen in glutamatergic cells had a lower amplitude and a shorter duration than in GABAergic cells. These differences were due to the presence of a β-receptor-mediated EPSP enhancement in the glutamatergic cells. Together, our results suggest that multiple properties contribute to the disproportionate influence of glutamatergic BNST-AV neurons.
Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-20 Luisa L. Scott, James J. Sahn, Antonio Ferragud, Rachel C. Yen, Praveen N. Satarasinghe, Michael D. Wood, Timothy R. Hodges, Ted Shi, Brooke A. Prakash, Kaitlyn M. Friese, Angela Shen, Valentina Sabino, Jonathan T. Pierce, Stephen F. Martin
Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.
Cognitive deficit In methamphetamine users relative to childhood academic performance: Link to cortical thickness Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-20 Andy C. Dean, Angelica M. Morales, Gerhard Hellemann, Edythe D. London
Individuals with cognitive problems may be predisposed to develop substance use disorders; therefore, differences in cognitive function between methamphetamine users and control participants may be attributable to premorbid factors rather than methamphetamine use. The goal of this study was to clarify the extent to which this is the case. Childhood academic transcripts were obtained for 37 methamphetamine-dependent adults and 41 control participants of similar educational level and premorbid IQ. Each participant completed a comprehensive cognitive battery and received a structural magnetic resonance imaging scan. Data from control participants and linear regression were used to develop a normative model to describe the relationship between childhood academic performance and scores on the cognitive battery. Using this model, cognitive performance of methamphetamine users was predicted from their premorbid academic scores. Results indicated that methamphetamine users’ childhood grade point average was significantly lower than that of the control group (p < 0.05). Further, methamphetamine users’ overall cognitive performance was lower than was predicted from their grade point average prior to methamphetamine use (p = 0.001), with specific deficits in attention/concentration and memory (ps < 0.01). Memory deficits were associated with lower whole-brain cortical thickness (p < 0.05). Thus, in addition to having an apparent premorbid weakness in cognition, methamphetamine users exhibit subsequent cognitive function that is significantly lower than premorbid estimates would predict. The results support the view that chronic methamphetamine use causes a decline in cognition and/or a failure to develop normative cognitive abilities, although aside from methamphetamine use per se, other drug use and unidentified factors likely contribute to the observed effects.
α7 Nicotinic receptor-modulating agents reverse the hyperdopaminergic tone in the MAM model of schizophrenia Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-19 Gilda A Neves, Anthony A Grace
Recent evidence has emerged supporting a role for the cholinergic system in schizophrenia, including the potential of α7 modulators as a treatment strategy. However, preclinical studies to date have relied on studies in normal systems rather than on a validated developmental model of schizophrenia. Furthermore, there have been only few studies on whether orthosteric and allosteric modulators have differential impacts in such models. We investigated the effects of α7 agonists and positive allosteric modulators (PAMs) on dopamine (DA) neuron activity in the ventral tegmental area (VTA) in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. Four different drugs were evaluated: PNU282987 (full agonist), SSR180711 (partial agonist) NS1738 (PAM type I) and PNU120596 (PAM type II). PNU120596 increased the number of spontaneously active VTA DA neurons in normal rats. In contrast, PNU282987 and SSR180711 reduced the hyperdopaminergic tone in MAM rats. This appeared to be due to effects on DA afferent regulation, in that PNU282987 or SSR180711 infusion into the ventral hippocampus of MAM rats replicated the decrease in the number of spontaneously active VTA DA neurons. In contrast, infusion of the same drugs into the basolateral amygdala increased the number of spontaneously active VTA DA neurons in normal rats without impacting MAM rats. These data suggest that α7 receptors may represent a promising target in the development of new pharmacological therapies for schizophrenia.
Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-19 Kaijie Ma, Luye Qin, Emmanuel Matas, Lara J. Duffney, Aiyi Liu, Zhen Yan
Autism is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors. Genetic screening has identified synaptic, transcriptional, and chromatin genes disrupted in autistic patients. Haploinsufficiency of Shank3, which encodes a scaffold protein at glutamatergic synapses, is causally linked to autism. Using a Shank3-deficient mouse model that exhibits prominent autism-like phenotypes, we have found that histone acetylation in the prefrontal cortex (PFC) is abnormally low, which can be reversed by MS-275, a class I histone deacetylase (HDAC) inhibitor that is selectively potent in PFC. A brief (3-day) treatment with MS-275 (i.p.) led to the sustained (11 days) rescue of autistic social preference deficits in Shank3-deficient mice, without altering locomotion, motor coordination, anxiety, or the increased grooming. MS-275 treatment also rescued the diminished NMDAR surface expression and NMDAR function induced by Shank3 deficiency. Moreover, F-actin at synapses was restored and the transcription of actin regulators was elevated by MS-275 treatment of Shank3-deficient mice, which may contribute to the recovery of actin-based NMDAR synaptic delivery. Taken together, these results suggest that MS-275 treatment could normalize the aberrant epigenetic regulation of genes, leading to the amelioration of synaptic and social deficits associated with autism.
Nicotine normalizes cortico-striatal connectivity in non-smoking individuals with major depressive disorder Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-19 Amy C. Janes, Maya Zegel, Kyoko Ohashi, Jennifer Betts, Elena Molokotos, David Olson, Lauren Moran, Diego A. Pizzagalli
Nicotine dependence and major depressive disorder (MDD) are highly comorbid, yet causal links between these prevalent disorders are unclear. One possible mechanism is that nicotine ameliorates MDD-related neurobiological dysfunction in specific networks. For instance, cortico-striatal circuitry is enhanced by nicotine, and such paths are disrupted in individuals with MDD. Specifically, MDD has been associated with reduced connectivity between the nucleus accumbens (NAc) and rostral anterior cingulate cortex (rACC) but enhanced connectivity between the dorsal striatum (DS) and dorsolateral prefrontal cortex (DLPFC). Determining whether nicotine normalizes these circuits in non-smokers with MDD may elucidate mechanisms underlying links between disorders. This was tested by administering placebo and a 2-mg dose of nicotine to unmedicated non-smokers with and without MDD prior to collecting resting-state functional magnetic imaging data using a cross-over design. On placebo, individuals with MDD showed significantly reduced NAc–rACC and a trend for enhanced DS–DLPFC functional connectivity relative to healthy controls. In MDD, acute nicotine administration normalized both pathways to the level of healthy controls, while having no impact on healthy controls. Nicotine’s effects on NAc–rACC connectivity was influenced by anhedonia, consistent with the role of this network in reward and nicotine’s ability to enhance reward deficiencies in MDD. These results indicate that nicotine normalizes dysfunctional cortico-striatal communication in unmedicated non-smokers with MDD. Nicotine’s influence on these circuitries highlights a possible mechanism whereby individuals with MDD are more vulnerable to develop nicotine dependence. Findings suggest that nicotinic agents may have therapeutic effects on disrupted cortico-striatal connectivity.
Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-19 Amy R. Johnson, Matthew L. Banks, Dana E. Selley, S. Stevens Negus
Amphetamine maintenance is effective clinically to reduce the consumption of the monoamine uptake inhibitor cocaine but not of the monoamine releaser methamphetamine, and its effectiveness in treating the abuse of other psychostimulants is not known. The mechanisms for differential amphetamine-maintenance effectiveness to treat different types of psychostimulant abuse are also not known. Accordingly, the present study compared the effects of amphetamine maintenance on abuse-related behavioral and neurochemical effects of cocaine, methamphetamine, and the “bath salts” constituent 3,4-methylenedioxypyrovalerone (MDPV) in rats. In behavioral studies, rats were trained to lever press for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. In neurochemical studies, nucleus accumbens (NAc) levels of dopamine (DA) and serotonin (5-HT) were monitored by in vivo microdialysis. Cocaine, methamphetamine, and MDPV each produced dose-dependent ICSS facilitation and increases in NAc DA; cocaine and methamphetamine also increased NAc 5-HT. Amphetamine maintenance (0.32 mg/kg/h × 7 days) produced (1) sustained increases in basal ICSS and NAc DA with no change in NAc 5-HT, (2) blockade of cocaine but not methamphetamine effects on ICSS and NAc DA, and (3) no blockade of cocaine- or methamphetamine-induced increases in NAc 5-HT. Amphetamine maintenance blocked the increases in NAc DA produced by the selective DA uptake inhibitor MDPV, but it did not block MDPV-induced ICSS facilitation. These results show different effects of amphetamine maintenance on behavioral and neurochemical effects of different psychostimulants. The selective effectiveness of amphetamine maintenance to treat cocaine abuse may reflect attenuation of cocaine-induced increases in NAc DA while preserving cocaine-induced increases in NAc 5-HT.
The Relationship Between Dopamine Synthesis Capacity and Release: Implications for Psychosis Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-19 Matthew M Nour, Robert McCutcheon, Oliver D Howes
The Relationship Between Dopamine Synthesis Capacity and Release: Implications for Psychosis The Relationship Between Dopamine Synthesis Capacity and Release: Implications for Psychosis, Published online: 19 April 2018; doi:10.1038/npp.2017.293 The Relationship Between Dopamine Synthesis Capacity and Release: Implications for Psychosis
Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-18 Joshua Chiappelli, Laura M. Rowland, Francesca M. Notarangelo, S. Andrea Wijtenburg, Marian A. R. Thomas, Ana Pocivavsek, Aaron Jones, Krista Wisner, Peter Kochunov, Robert Schwarcz, L. Elliot Hong
Frontal glutamatergic synapses are thought to be critical for adaptive, long-term stress responses. Prefrontal cortices, including the anterior cingulate cortex (ACC) contribute to stress perception and regulation, and are involved in top-down regulation of peripheral glucocorticoid and inflammatory responses to stress. Levels of kynurenic acid (KYNA) in saliva increase in response to psychological stress, and this stress-induced effect may be abnormal in people with schizophrenia. Here we test the hypothesis that ACC glutamatergic functioning may contribute to the stress-induced salivary KYNA response in schizophrenia. In 56 patients with schizophrenia and 58 healthy controls, our results confirm that levels of KYNA in saliva increase following psychological stress. The magnitude of the effect correlated negatively with proton magnetic resonance spectroscopy (MRS) glutamate + glutamine (r = −.31, p = .017) and glutamate (r = −0.27, p = .047) levels in the ACC in patients but not in the controls (all p ≥ .45). Although, a causal relationship cannot be ascertained in this cross-sectional study, these findings suggest a potentially meaningful link between central glutamate levels and kynurenine pathway response to stress in individuals with schizophrenia.
Opiate-associated contextual memory formation and retrieval are differentially modulated by dopamine D1 and D2 signaling in hippocampal–prefrontal connectivity Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-17 Yunpeng Wang, Hongying Zhang, Jingjing Cui, Jing Zhang, Fangyuan Yin, Hao Guo, Jianghua Lai, Bo Xing
Contextual memory driven by abused drugs such as opiates has a central role in maintenance and relapse of drug-taking behaviors. Although dopamine (DA) signaling favors memory storage and retrieval via regulation of hippocampal–prefrontal connectivity, its role in modulating opiate-associated contextual memory is largely unknown. Here, we report roles of DA signaling within the hippocampal–prefrontal circuit for opiate-related memories. Combining-conditioned place preference (CPP) with molecular analyses, we investigated the DA D1 receptor (D1R) and extracellular signal-regulated kinase (ERK)-cAMP-response element binding protein (CREB) signaling, as well as DA D2 receptor (D2R) and protein kinase B (PKB or Akt)/glycogen synthase kinase 3 (GSK3) signaling in the ventral hippocampus (vHip) and medial prefrontal cortex (mPFC) during the formation of opiate-related associative memories. Morphine-CPP acquisition increased the activity of the D1R–ERK–CREB pathway in both the vHip and mPFC. Morphine-CPP reinstatement was associated with the D2R-mediated hyperactive GSK3 via Akt inhibition in the vHip and PFC. Furthermore, integrated D1R–ERK–CREB and D2R–Akt–GSK3 pathways in the vHip–mPFC circuit are required for the acquisition and retrieval of the morphine contextual memory, respectively. Moreover, blockage of D1R or D2R signaling could alleviate normal Hip-dependent spatial memory. These results suggest that D1R and D2R signaling are differentially involved in the acquisition and retrieval of morphine contextual memory, and DA signaling in the vHip–mPFC connection contributes to morphine-associated and normal memory, largely depending on opiate exposure states.
Can anti-obesity drugs be repurposed to treat cocaine addiction? Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-17 David J. Reiner, Jennifer M. Bossert
Can anti-obesity drugs be repurposed to treat cocaine addiction? Can anti-obesity drugs be repurposed to treat cocaine addiction?, Published online: 17 April 2018; doi:10.1038/s41386-018-0035-7 Can anti-obesity drugs be repurposed to treat cocaine addiction?
Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2 Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-17 Sabrina Francesca Lisboa, Anzela Niraula, Leonardo Barbosa Resstel, Francisco Silveira Guimaraes, Jonathan P. Godbout, John F. Sheridan
Psychosocial stress contributes to the development of psychiatric disorders. Repeated social defeat (RSD) is a murine stressor that causes a release of inflammatory monocytes into circulation. Moreover, RSD-induced anxiety-like behavior is dependent on the recruitment of these monocytes to the brain. Activation of the endocannabinoid (ECB) system may modulate both neuroendocrine and inflammatory responses mediated by stress. Therefore, we hypothesized that a cannabinoid receptor agonist would attenuate RSD-induced inflammation, anxiety, and stress sensitization. To test this hypothesis, mice received an injection of the synthetic cannabinoid1/2 receptor agonist, WIN55,212-2 (WIN; 1 mg/kg, intraperitoneally) daily for six consecutive days, 30 min before each exposure to RSD. Anxiety-like behavior, immune activation, neuroinflammation, and microglial reactivity were determined 14 h after RSD. RSD-induced anxiety-like behavior in the open field and in the EPM was reversed by WIN55,212-2. Moreover, WIN55,212-2 reduced the accumulation of inflammatory monocytes in circulation and brain after RSD and attenuated RSD-induced interleukin-1β (IL-1β) messenger RNA (mRNA) expression in microglia/macrophages. Increased ex vivo reactivity of microglia/monocytes to lipopolysaccharides (LPS) after RSD was also attenuated by WIN55,212-2. Next, fear expression, extinction, and recall were evaluated 24 and 48 h, respectively, after contextual fear conditioning, which took place 7 days after RSD. Here, RSD caused prolonged fear expression and impaired fear extinction recall, which was associated with increased IL-1β mRNA in the brain. Moreover, these stress-induced effects were reversed by WIN55,212-2. In conclusion, activation of cannabinoid receptors limited the immune and neuroinflammatory responses to RSD and reversed the short-term and long-term behavioral deficits associated with RSD.
Interaction between TSPO—a neuroimmune marker—and redox status in clinical high risk for psychosis: a PET–MRS study Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-13 Sina Hafizi, Tania Da Silva, Jeffrey H. Meyer, Michael Kiang, Sylvain Houle, Gary Remington, Ivana Prce, Alan A. Wilson, Pablo M. Rusjan, Napapon Sailasuta, Romina Mizrahi
Altered neuroimmune response and oxidative stress have both been implicated in the pathophysiology of schizophrenia. While preclinical studies have proposed several pathways regarding potential interactions between oxidative stress and neuroimmune imbalance in the development of psychosis, the molecular mechanisms underlying this interaction are not yet understood. To date, no study has investigated this link in vivo in the human brain. We conducted the first in vivo study linking translocator protein 18 kDa (TSPO) expression and glutathione (a major brain antioxidant and a marker for redox status) in the medial prefrontal cortex (mPFC) of a relatively large sample of participants (N = 48) including 27 antipsychotic-naïve individuals at clinical high risk for psychosis and 21 matched healthy volunteers using high-resolution PET TSPO radioligand, [18F]FEPPA, and 3T proton magnetic resonance spectroscopy (1H MRS). The omnibus model (including TSPO genotype as covariate) was significant (F(4, 43) = 10.01, p < .001), with a significant group interaction (t = −2.10, p = 0.04), suggesting a different relation between [18F]FEPPA VT and glutathione in each clinical group. In healthy volunteers, but not in individuals at clinical high risk for psychosis, we found a significant negative association between glutathione levels and [18F]FEPPA VT (r = −0.60, p = 0.006). We observed no significant group differences with respect to [18F]FEPPA VT or glutathione levels. These findings suggest an abnormal interaction between TSPO expression and redox status in the clinical high risk states for psychosis.
Oxytocin reduces a chemosensory-induced stress bias in social perception Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-12 Ayline Maier, Dirk Scheele, Franny B. Spengler, Tugba Menba, Franziska Mohr, Onur Güntürkün, Birgit Stoffel-Wagner, Thomas M. Kinfe, Wolfgang Maier, Sahib S. Khalsa, René Hurlemann
Social transmission of fear is not restricted to visual or auditory cues, but extends to the phylogenetically more ancient olfactory domain. Anxious individuals exhibit heightened sensitivity towards chemosensory stress signals in sweat, but it is still unknown whether endogenous neuromodulators such as the peptide hormone oxytocin (OXT) influence the chemosensory communication of stress. Here, we investigated whether OXT selectively diminishes behavioral and neural responses to social chemosensory stress cues utilizing a randomized, double-blind, placebo (PLC)-controlled, within-subject functional MRI study design. Axillary sweat was obtained from 30 healthy male donors undergoing the Trier Social Stress Test (stress) and bicycle ergometer training (sport). Subsequently, 58 healthy participants (30 females) completed a forced-choice emotional face recognition task with stimuli of varying intensities (neutral to fearful) while they were exposed to both sweat stimuli and a non-social control odor following intranasal OXT or PLC administration, respectively. OXT diminished stress-induced recognition accuracy and response time biases towards fear. On the neural level, OXT reduced stress-evoked responses in the amygdala in both sexes, the anterior cingulate cortex (ACC) in females, and the hippocampus in males. Furthermore, OXT reinstated the functional connectivity between the ACC and the fusiform face area that was disrupted by stress odors under PLC. Our findings reveal a new role for OXT signaling in the modulation of chemosensory communication of stress in humans. Mechanistically, this effect appears to be rooted in a downregulation of stress-induced limbic activations and concomitant strengthening of top-down control descending from the ACC to the fusiform face area.
Cortico-thalamic hypo- and hyperconnectivity extend consistently to basal ganglia in schizophrenia Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-12 Mihai Avram, Felix Brandl, Josef Bäuml, Christian Sorg
Schizophrenia is characterized by hypoconnectivity or decreased intrinsic functional connectivity (iFC) between prefrontal-limbic cortices and thalamic nuclei, as well as hyperconnectivity or increased iFC between primary-sensorimotor cortices and thalamic nuclei. However, cortico-thalamic iFC overlaps with larger, structurally defined cortico-striato-pallido-thalamo-cortical (CSPTC) circuits. If such an overlap is relevant for intrinsic hypo-/hyperconnectivity, it suggests (i) that patterns of cortico-subcortical hypo-/hyperconnectivity extend consistently from thalamus to basal ganglia nuclei; and (ii) such consistent hypo-/hyperconnectivity might link distinctively but consonant with different symptom dimensions, namely cognitive and psychotic impairments.To test this hypothesis, 57 patients with schizophrenia and 61 healthy controls were assessed by resting-state functional magnetic resonance imaging (fMRI) and clinical–behavioral testing. IFC from intrinsic cortical networks into thalamus, striatum, and pallidum was estimated by partial correlations between fMRI time courses. In patients, the salience network covering prefrontal-limbic cortices was hypoconnected with the mediodorsal thalamus and ventral parts of striatum and pallidum; these iFC-hypoconnectivity patterns were correlated both among each other and specifically with patients’ impaired cognition. In contrast, the auditory-sensorimotor network covering primary-sensorimotor cortices was hyperconnected with the anterior ventral nucleus of the thalamus and dorsal parts of striatum and pallidum; these iFC-hyperconnectivity patterns were likewise correlated among each other and specifically with patients’ psychotic symptoms. The results demonstrate that prefrontal-limbic hypoconnectivity and primary-sensorimotor hyperconnectivity extend consistently across subcortical nuclei and specifically across distinct symptom dimensions. Data support the model of consistent cortico-subcortical hypo-/hyperconnectivity within CSPTC circuits in schizophrenia.
Previous cocaine self-administration disrupts reward expectancy encoding in ventral striatum Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-10 Amanda C. Burton, Gregory B. Bissonette, Daniela Vazquez, Elyse M. Blume, Maria Donnelly, Kendall C. Heatley, Abhishek Hinduja, Matthew R. Roesch
The nucleus accumbens core (NAc) is important for integrating and providing information to downstream areas about the timing and value of anticipated reward. Although NAc is one of the first brain regions to be affected by drugs of abuse, we still do not know how neural correlates related to reward expectancy are affected by previous cocaine self-administration. To address this issue, we recorded from single neurons in the NAc of rats that had previously self-administered cocaine or sucrose (control). Neural recordings were then taken while rats performed an odor-guided decision-making task in which we independently manipulated value of expected reward by changing the delay to or size of reward across a series of trial blocks. We found that previous cocaine self-administration made rats more impulsive, biasing choice behavior toward more immediate reward. Further, compared to controls, cocaine-exposed rats showed significantly fewer neurons in the NAc that were responsive during odor cues and reward delivery, and in the reward-responsive neurons that remained, diminished directional and value encoding was observed. Lastly, we found that after cocaine exposure, reward-related firing during longer delays was reduced compared to controls. These results demonstrate that prior cocaine self-administration alters reward-expectancy encoding in NAc, which could contribute to poor decision making observed after chronic cocaine use.
Neural cell adhesion molecule peptide mimetics modulate emotionality: pharmacokinetic and behavioral studies in rats and non-human primates Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-09 Cortney A. Turner, David M. Lyons, Christine L. Buckmaster, Elyse L. Aurbach, Stanley J. Watson, Alan F. Schatzberg, Huda Akil
Recent evidence highlights the fibroblast growth factor (FGF) family in emotion modulation. Although ligands that activate FGF receptors have antidepressant and anxiolytic effects in animal models, FGF ligands have a broad range of actions both in the brain and the periphery. Therefore, identifying molecular partners that may function as allosteric modulators could offer new avenues for drug development. Since neural cell adhesion molecule (NCAM) activates FGF receptors, we asked whether peripherally administered NCAM peptide mimetics penetrate the brain and alter the behavior of standardized tests that have predictive validity for drug treatments of anxiety or depression. The NCAM peptide mimetic, plannexin, acutely increased and chronically decreased anxiety, but did not have antidepressant effects in rats. Another NCAM peptide mimetic, FGLL, had acute anxiogenic effects and chronic antidepressant effects in rats. A related NCAM peptide mimetic, FGLS, had antidepressant effects without modulating anxiety-like behavior, and these antidepressant effects were blocked by an AMPA receptor antagonist. Cisternal cerebrospinal fluid (CSF) levels of FGLs correlated with blood plasma levels in rats and non-human primates, and CSF-to-blood ratios of FGLS were comparable in both species. Results indicate that NCAM peptide mimetics penetrate the brain and support the suggestion that FGLS may be a candidate for further development as a novel treatment for major depressive disorder in humans.
Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-06 Brooke E. Schmeichel, Alessandra Matzeu, Pascale Koebel, Leandro F. Vendruscolo, Harpreet Sidhu, Roxana Shahryari, Brigitte L. Kieffer, George F. Koob, Rémi Martin-Fardon, Candice Contet
The hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug-seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. Chronic Hcrt silencing did not impact cocaine self-administration under short-access conditions, but robustly attenuated cocaine intake under extended access conditions, a model that mimics key features of compulsive cocaine taking. In addition, Hcrt silencing decreased motivation for both cocaine and a highly palatable food reward (i.e., sweetened condensed milk; SCM) under a progressive ratio schedule of reinforcement, but did not alter responding for SCM under a fixed ratio schedule. Importantly, Hcrt silencing did not affect food or water consumption, and had no consequence for general measures of arousal and stress reactivity. At the molecular level, chronic Hcrt knockdown reduced the number of neurons expressing dynorphin (DYN), and to a smaller extent melanin-concentrating hormone (MCH), in the dorsal hypothalamus. These original findings support the hypothesis that HCRT neurotransmission promotes operant responding for both drug and non-drug rewards, preferentially under conditions requiring a high degree of motivation. Furthermore, the current study provides compelling evidence for the involvement of the HCRT system in cocaine self-administration also under low-effort conditions in rats allowed extended access, possibly via functional interactions with DYN and MCH signaling.
An unsuspected role for organic cation transporter 3 in the actions of amphetamine Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-06 Felix P. Mayer, Diethart Schmid, W. Anthony Owens, Georgianna G. Gould, Mia Apuschkin, Oliver Kudlacek, Isabella Salzer, Stefan Boehm, Peter Chiba, Piper H. Williams, Hsiao-Huei Wu, Ulrik Gether, Wouter Koek, Lynette C. Daws, Harald H. Sitte
Amphetamine abuse is a major public health concern for which there is currently no effective treatment. To develop effective treatments, the mechanisms by which amphetamine produces its abuse-related effects need to be fully understood. It is well known that amphetamine exerts its actions by targeting high-affinity transporters for monoamines, in particular the cocaine-sensitive dopamine transporter. Organic cation transporter 3 (OCT3) has recently been found to play an important role in regulating monoamine signaling. However, whether OCT3 contributes to the actions of amphetamine is unclear. We found that OCT3 is expressed in dopamine neurons. Then, applying a combination of in vivo, ex vivo, and in vitro approaches, we revealed that a substantial component of amphetamine’s actions is OCT3-dependent and cocaine insensitive. Our findings support OCT3 as a new player in the actions of amphetamine and encourage investigation of this transporter as a potential new target for the treatment of psychostimulant abuse.
Abnormal reward prediction-error signalling in antipsychotic naive individuals with first-episode psychosis or clinical risk for psychosis Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-05 Anna O. Ermakova, Franziska Knolle, Azucena Justicia, Edward T. Bullmore, Peter B. Jones, Trevor W. Robbins, Paul C. Fletcher, Graham K. Murray
Ongoing research suggests preliminary, though not entirely consistent, evidence of neural abnormalities in signalling prediction errors in schizophrenia. Supporting theories suggest mechanistic links between the disruption of these processes and the generation of psychotic symptoms. However, it is unknown at what stage in psychosis these impairments in prediction-error signalling develop. One major confound in prior studies is the use of medicated patients with strongly varying disease durations. Our study aims to investigate the involvement of the meso-cortico-striatal circuitry during reward prediction-error signalling in earliest stages of psychosis. We studied patients with first-episode psychosis (FEP) and help-seeking individuals at-risk for psychosis due to sub-threshold prodromal psychotic symptoms. Patients with either FEP (n = 14), or at-risk for developing psychosis (n = 30), and healthy volunteers (n = 39) performed a reinforcement learning task during fMRI scanning. ANOVA revealed significant (p < 0.05 family-wise error corrected) prediction-error signalling differences between groups in the dopaminergic midbrain and right middle frontal gyrus (dorsolateral prefrontal cortex, DLPFC). FEP patients showed disrupted reward prediction-error signalling compared to controls in both regions. At-risk patients showed intermediate activation in the midbrain that significantly differed from controls and from FEP patients, but DLPFC activation that did not differ from controls. Our study confirms that FEP patients have abnormal meso-cortical signalling of reward-prediction errors, whereas reward-prediction-error dysfunction in the at-risk patients appears to show a more nuanced pattern of activation with a degree of midbrain impairment but preserved cortical function.
7T 1H-MRS in major depressive disorder: a Ketamine Treatment Study Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-05 Jennifer W. Evans, Níall Lally, Li An, Ningzhi Li, Allison C. Nugent, Banerjee Dipavo, Sam L. Snider, Jun Shen, Jonathan P. Roiser, Carlos A. Zarate Jr
The glutamatergic modulator ketamine has striking and rapid antidepressant effects in major depressive disorder (MDD), but its mechanism of action remains unknown. Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive method able to directly measure glutamate levels in vivo; in particular, glutamate and glutamine metabolite concentrations are separable by 1H-MRS at 7T. This double-blind, placebo-controlled, crossover study that included 1H-MRS scans at baseline and at 24 h post ketamine and post-placebo infusions sought to determine glutamate levels in the pregenual anterior cingulate (pgACC) of 20 medication-free MDD subjects and 17 healthy volunteers (HVs) 24 h post ketamine administration, and to evaluate any other measured metabolite changes, correlates, or predictors of antidepressant response. Metabolite levels were compared at three scan times (baseline, post-ketamine, and post-placebo) in HVs and MDD subjects at 7T using a 1H-MRS sequence specifically optimized for glutamate. No significant between-group differences in 1H-MRS-measured metabolites were observed at baseline. Antidepressant response was not predicted by baseline glutamate levels. Our results suggest that any infusion-induced increases in glutamate at the 24-h post ketamine time point were below the sensitivity of the current technique; that these increases may occur in different brain regions than the pgACC; or that subgroups of MDD subjects may exist that have a differential glutamate response to ketamine.
Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-05 Antonia Serrano, Francisco J. Pavon, Matthew W. Buczynski, Joel Schlosburg, Luis A. Natividad, Ilham Y. Polis, David G. Stouffer, Eric P. Zorrilla, Marisa Roberto, Benjamin F. Cravatt, Rémi Martin-Fardon, Fernando Rodriguez de Fonseca, Loren H. Parsons
Negative emotional states that are associated with excessive alcohol intake, particularly anxiety-like states, have been linked to opponent processes in the central nucleus of the amygdala (CeA), affecting stress-related transmitters and monoamines. This study extends these observations to include endocannabinoid signaling in alcohol-dependent animals. Rats and mice were exposed to chronic intermittent alcohol with vapor inhalation or liquid diet to induce dependence. In vivo microdialysis was used to estimate interstitial concentrations of endocannabinoids [N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG)] and amino acids (glutamate and GABA) in rat CeA. Additionally, we evaluated the inhibition of endocannabinoids clearance enzymes [monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase] on anxiety-like behavior and alcohol consumption in alcohol-dependent rats and mice. Results revealed that alcohol dependence produced decreases in baseline 2-AG dialysate levels and increases in baseline levels of glutamate and GABA. Acute alcohol abstinence induced an enhancement of these dependence-induced effects and the levels of 2-AG and GABA were restored upon alcohol re-exposure. Additional studies showed that the increased CeA 2-AG levels induced by restraint stress and alcohol self-administration were blunted in alcohol-dependent rats. Pharmacological studies in rats and mice showed that anxiety-like behavior and alcohol consumption were increased in alcohol-dependent animals, and these behavioral effects were attenuated mainly by MAGL inhibitors [MJN110 (10 and 20 mg/kg) in rats and JZL184 (1 and 3 mg/kg) in mice]. The present results suggest a key role for endocannabinoid signaling in motivational neuroadaptations during alcohol dependence, in which a deficiency in CeA 2-AG signaling in alcohol-dependent animals is linked to stress and excessive alcohol consumption.
Opportunities and needs in digital phenotyping Neuropsychopharmacology (IF 6.403) Pub Date : 2018-04-03 Lisa A. Marsch, Andrew G. Wallace
Opportunities and needs in digital phenotyping Opportunities and needs in digital phenotyping, Published online: 03 April 2018; doi:10.1038/s41386-018-0051-7 Opportunities and needs in digital phenotyping
Neurocognitive effects of umami: association with eating behavior and food choice Neuropsychopharmacology (IF 6.403) Pub Date : 2018-03-30 Greta Magerowski, Gabrielle Giacona, Laura Patriarca, Konstantinos Papadopoulos, Paola Garza-Naveda, Joanna Radziejowska, Miguel Alonso-Alonso
Free glutamate, a key substance underlying the umami taste of foods, fulfills a number of physiological functions related to energy balance. Previous experimental studies have shown that intake of a broth or soup supplemented with monosodium glutamate (MSG) prior to a meal can decrease appetite and food intake, particularly in women with propensity to overeat and gain weight. In this study, we examined potential neurocognitive mechanisms underlying this effect. We evaluated changes after intake of a chicken broth with or without MSG added (MSG+/MSG−) in a sample of healthy young women. Subjects were assessed with a food-modified computerized inhibitory control task, a buffet meal test with eye-tracking, and brain responses during a food choice paradigm evaluated with functional neuroimaging. We found evidence for improvement in key parameters related to inhibitory control following intake of the MSG+ broth, particularly in subjects with high levels of eating disinhibition, who also showed lower intake of saturated fat during the meal. Additionally, consumption of the MSG+ broth led to a reduction of the rate of fixation switches between plates at the meal, and increased engagement of a brain region in the left dorsolateral prefrontal cortex previously associated with successful self-control during dietary decisions. Altogether, these results, while preliminary, suggest potential facilitating effects of glutamate (MSG) on cognitive executive processes that are relevant for the support of healthy eating behaviors and food choice.
Prophylactic ketamine alters nucleotide and neurotransmitter metabolism in brain and plasma following stress Neuropsychopharmacology (IF 6.403) Pub Date : 2018-03-29 Josephine C. McGowan, Collin Hill, Alessia Mastrodonato, Christina T. LaGamma, Alexander Kitayev, Rebecca A. Brachman, Niven R. Narain, Michael A. Kiebish, Christine A. Denny
Recently, we have shown that ketamine given prior to stress exposure protects against the development of depressive-like behavior in mice. These data suggest that it may be possible to prevent the induction of affective disorders before they develop by administering prophylactic pharmaceuticals, a relatively nascent and unexplored strategy for psychiatry. Here, we performed metabolomics analysis of brain and plasma following prophylactic ketamine treatment in order to identify markers of stress resilience enhancement. We administered prophylactic ketamine in mice to buffer against fear expression. Following behavioral analyses, untargeted metabolomic profiling was performed on both hemispheres of the prefrontal cortex (PFC) and the hippocampus (HPC), and plasma. We found that prophylactic ketamine attenuated learned fear. Eight metabolites were changed in the PFC and HPC upon ketamine treatment. Purine and pyrimidine metabolism were most significantly changed in the HPC, PFC, and, interestingly, plasma of mice two weeks after prophylactic administration. Moreover, most precursors to inhibitory neurotransmitters were increased whereas precursors to excitatory neurotransmitters were decreased. Strikingly, these long-term metabolomic changes were not observed when no stressor was administered. Our results suggest that prophylactic treatment differentially affects purine and pyrimidine metabolism and neurotransmission in brain and plasma following stress, which may underlie the long-lasting resilience to stress induced by a single injection of ketamine. These data may provide novel targets for prophylactic development, and indicate an interaction effect of prophylactic ketamine and stress. To our knowledge, this is the first study that identifies metabolomic alterations and biomarker candidates for prophylactic ketamine efficacy in mice.
mGlu1 and mGlu5 modulate distinct excitatory inputs to the nucleus accumbens shell Neuropsychopharmacology (IF 6.403) Pub Date : 2018-03-27 Brandon D. Turner, Jerri M. Rook, Craig W. Lindsley, P. Jeffrey Conn, Brad A. Grueter
Glutamatergic transmission in the nucleus accumbens shell (NAcSh) is a substrate for reward learning and motivation. Metabotropic glutamate (mGlu) receptors regulate NAcSh synaptic strength by inducing long-term depression (LTD). Inputs from prefrontal cortex (PFC) and medio-dorsal thalamus (MDT) drive opposing motivated behaviors yet mGlu receptor regulation of these synapses is unexplored. We examined Group I mGlu receptor regulation of PFC and MDT glutamatergic synapses onto specific populations of NAc medium spiny neurons (MSNs) using D1tdTom BAC transgenic mice and optogenetics. Synaptically evoked long-term depression (LTD) at MDT-NAcSh synapses required mGlu5 but not mGlu1 and was specific for D1(+) MSNs, whereas PFC LTD was expressed at both D1(+) and D1(−) MSNs and required mGlu1 but not mGlu5. Two weeks after five daily non-contingent cocaine exposures (15 mg/kg), LTD was attenuated at MDT-D1(+) synapses but was rescued by a mGlu5-positive allosteric modulator (PAM), VU0409551. These results highlight unique plasticity mechanisms regulating specific NAcSh synapses.
Behavioral and neurobiological mechanisms of punishment: implications for psychiatric disorders Neuropsychopharmacology (IF 6.403) Pub Date : 2018-03-27 Philip Jean-Richard-Dit-Bressel, Simon Killcross, Gavan P. McNally
Punishment involves learning about the relationship between behavior and its adverse consequences. Punishment is fundamental to reinforcement learning, decision-making and choice, and is disrupted in psychiatric disorders such as addiction, depression, and psychopathy. However, little is known about the brain mechanisms of punishment and much of what is known is derived from study of superficially similar, but fundamentally distinct, forms of aversive learning such as fear conditioning and avoidance learning. Here we outline the unique conditions that support punishment, the contents of its learning, and its behavioral consequences. We consider evidence implicating GABA and monoamine neurotransmitter systems, as well as corticostriatal, amygdala, and dopamine circuits in punishment. We show how maladaptive punishment processes are implicated in addictions, impulse control disorders, psychopathy, anxiety, and depression and argue that a better understanding of the cellular, circuit, and cognitive mechanisms of punishment will make important contributions to next generation therapeutic approaches.
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