显示样式:     当前期刊: Neuropsychopharmacology    加入关注       排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Prefrontal-amygdala plasticity enabled by observational fear
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-13
    Wataru Ito, Alexei Morozov

    Observing fear in others (OF) is a form of social stress. In mice, it enhances inhibitory avoidance learning and causes the formation of silent synapses in the prefrontal-amygdala pathway. Here, we report that OF made that pathway prone to facilitation both ex vivo and in vivo. Ex vivo, OF enabled induction of long-term potentiation (LTP), expressed mostly postsynaptically and occluded by inhibitory avoidance training. In vivo, OF enabled facilitation of the dmPFC-BLA pathway by inhibitory avoidance training. The facilitation persisted during the first 4 h after the training when the prefrontal cortex and amygdala are involved in memory consolidation. Thus, the OF-generated silent synapses likely enable plasticity that may enhance the consolidation of inhibitory avoidance memories.

    更新日期:2019-02-14
  • Anxiety, the chicken or the egg of addiction: targeting G9a for the treatment of comorbid anxiety and cocaine addiction
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-13
    Charlotte C. Bavley, Anjali M. Rajadhyaksha

    Treating cocaine addiction is a major challenge and currently no FDA approved pharmacotherapies exist. One complicating factor is a high rate of comorbidity between cocaine and neuropsychiatric conditions such as anxiety. The relationship between anxiety symptoms and cocaine addiction is complicated; anxiety can be both a predisposing factor and a consequence of cocaine use as anxiety symptoms often emerge during drug use and withdrawal. Identifying and understanding the shared biological mechanisms that lead to comorbid anxiety and cocaine addiction, irrespective of which comes first, is critical for the identification of new treatments.

    更新日期:2019-02-14
  • Neurobiology of maternal regulation of infant fear: the role of mesolimbic dopamine and its disruption by maltreatment
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-13
    Maya Opendak, Patrese Robinson-Drummer, Anna Blomkvist, Roseanna M. Zanca, Kira Wood, Lily Jacobs, Stephanie Chan, Stephen Tan, Joyce Woo, Gayatri Venkataraman, Emma Kirschner, Johan N. Lundström, Donald A. Wilson, Peter A. Serrano, Regina M. Sullivan

    Child development research highlights caregiver regulation of infant physiology and behavior as a key feature of early life attachment, although mechanisms for maternal control of infant neural circuits remain elusive. Here we explored the neurobiology of maternal regulation of infant fear using neural network and molecular levels of analysis in a rodent model. Previous research has shown maternal suppression of amygdala-dependent fear learning during a sensitive period. Here we characterize changes in neural networks engaged during maternal regulation and the transition to infant self-regulation. Metabolic mapping of 2-deoxyglucose uptake during odor-shock conditioning in postnatal day (PN)14 rat pups showed that maternal presence blocked fear learning, disengaged mesolimbic circuitry, basolateral amygdala (BLA), and plasticity-related AMPA receptor subunit trafficking. At PN18, when maternal presence only socially buffers threat learning (similar to social modulation in adults), maternal presence failed to disengage the mesolimbic dopaminergic system, and failed to disengage both the BLA and plasticity-related AMPA receptor subunit trafficking. Further, maternal presence failed to block threat learning at PN14 pups following abuse, and mesolimbic dopamine engagement and AMPA were not significantly altered by maternal presence—analogous to compromised maternal regulation of children in abusive relationships. Our results highlight three key features of maternal regulation: (1) maternal presence blocks fear learning and amygdala plasticity through age-dependent suppression of amygdala AMPA receptor subunit trafficking, (2) maternal presence suppresses engagement of brain regions within the mesolimbic dopamine circuit, and (3) early-life abuse compromises network and molecular biomarkers of maternal regulation, suggesting reduced social scaffolding of the brain.

    更新日期:2019-02-14
  • TrkB-dependent disinhibition of the nucleus accumbens is enhanced by ethanol
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-13
    Mary H. Patton, Katherine E. Padgett, Paige N. McKeon, Houman Qadir, Michael S. Patton, Chaoqi Mu, Bradley M. Roberts, Brian N. Mathur

    The nucleus accumbens is a critical integration center for reward-related circuitry and is comprised primarily of medium spiny projection neurons. The dynamic balance of excitation and inhibition onto medium spiny neurons determines the output of this structure. While nucleus accumbens excitatory synaptic plasticity is well-characterized, inhibitory synaptic plasticity mechanisms and their potential relevance to shaping motivated behaviors is poorly understood. Here we report the discovery of long-term depression of inhibitory synaptic transmission in the mouse nucleus accumbens core. This long-term depression is postsynaptically expressed, tropomyosin kinase B (TrkB) receptor-mediated, and augmented in the presence of ethanol. Our findings support the emerging view that TrkB signaling regulates inhibitory synaptic plasticity and suggest this mechanism in the nucleus accumbens as a target for ethanol modulation of reward.

    更新日期:2019-02-14
  • Baseline and follow-up activity and functional connectivity in reward neural circuitries in offspring at risk for bipolar disorder
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-13
    Heather E. Acuff, Amelia Versace, Michele A. Bertocci, Cecile D. Ladouceur, Lindsay C. Hanford, Anna Manelis, Kelly Monk, Lisa Bonar, Alicia McCaffrey, Benjamin I. Goldstein, Tina R. Goldstein, Dara Sakolsky, David Axelson, Boris Birmaher, Mary L. Phillips

    Bipolar disorder (BD) is a serious psychiatric illness with demonstrated abnormalities in reward processing circuitry. Examining this circuitry in youth at familial risk for BD may provide further insight into the underlying mechanisms of BD development. In this study, we compared offspring of bipolar parents (OBP, n = 32), offspring of comparison parents with non-BD psychopathology (OCP, n = 36), and offspring of healthy parents (OHP, n = 39) during a functional magnetic resonance imaging reward processing task. Elastic net regression analyses identified 26 activity, functional connectivity (FC), and demographic variables that explained 34.24% of the variance in group (λ = 0.224). ANOVA and post-hoc analyses revealed that OBP had significantly lower right ventral striatum–left caudal anterior cingulate FC to loss (OBP versus OCP: p = 0.028, OBP versus OHP: p = 0.015) and greater right pars orbitalis-left (OBP versus OCP: p = 0.003, OBP versus OHP: p = 0.036) and -right (OBP versus OCP: p = 0.001, OBP versus OHP: p = 0.038) orbitofrontal cortex FC to reward versus OCP and OHP, respectively. These findings were not affected by non-BD psychopathology, psychotropic medication use, or symptomatology. There were no changes in, or relationships between, neuroimaging or symptom measures at follow-up (mean(SD) = 2.70(1.22) year inter-scan interval) in a subset of youth with follow-up data (OBP, n = 14; OCP, n = 8; OHP, n = 19). These findings suggest that lower right ventral striatum–left caudal anterior cingulate FC to loss and greater right pars orbitalis–orbitofrontal cortex FC to reward may be trait-level neural markers that may reflect risk for BD in at-risk youth. These findings comprise important steps toward identifying neural markers of BD risk, which may enhance early identification and guide interventions for youth at familial risk for BD.

    更新日期:2019-02-13
  • Testing the 10 most wanted: a preclinical algorithm to screen candidate opioid use disorder medications
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-09
    Matthew L. Banks, E. Andrew Townsend, S. Stevens Negus

    Perspective

    更新日期:2019-02-11
  • Context and topography determine the role of basolateral amygdala metabotropic glutamate receptor 5 in appetitive Pavlovian responding
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-08
    Shaun Yon-Seng Khoo, Mandy Rita LeCocq, Ghislaine E. Deyab, Nadia Chaudhri

    Preclinical data have shown that the excitatory metabotropic Gαq-coupled glutamate receptor, mGluR5, has a role in substance abuse and relapse. However, little is known about the contribution of mGluR5 to the expression of conditioned responding elicited by appetitive Pavlovian cues. We investigated this question in rats that were trained to associate a discrete, auditory conditioned stimulus (CS) with a fructose-glucose solution (5.5% fructose/4.5% glucose; “sugar”). In subsequent tests for the expression of conditioned responding without sugar delivery, CS-elicited fluid port entries were elevated in a context associated with sugar, relative to an equally familiar, neutral context. Inhibiting mGluR5 via systemic injections of a negative allosteric modulator (MTEP; 5 mg/kg) reduced CS port entries in both the sugar context and neutral context. Targeting MTEP microinjections (3 µg/side; 0.3 µl/min) to the nucleus accumbens (Acb) core had no effect on CS port entries at test, whereas the same manipulation in the basolateral amygdala (BLA) produced effects that were topographically dependent. Specifically, microinjecting MTEP in the posterior BLA had no effect on behavior, whereas inhibiting mGluR5 in the anterior BLA enhanced the contextual discrimination of CS port entries. These data are the first to show a role of mGluR5 in the context-dependent expression of appetitive Pavlovian conditioned responding, with a topographically defined arrangement of mGluR5 in the BLA being particularly important for context-based responding to a discrete, appetitive cue.

    更新日期:2019-02-11
  • β1-adrenergic receptors mediate plasma acyl-ghrelin elevation and depressive-like behavior induced by chronic psychosocial stress
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-08
    Deepali Gupta, Jen-Chieh Chuang, Bharath K. Mani, Kripa Shankar, Juan A. Rodriguez, Sherri Osborne-Lawrence, Nathan P. Metzger, Jeffrey M. Zigman

    The ghrelin system is a key component of the mood and metabolic responses to chronic psychosocial stress. For example, circulating acyl-ghrelin rises in several rodent and human stress models, administered acyl-ghrelin induces antidepressant-like behavioral responses in mice, and mice with deleted ghrelin receptors (GHSRs) exhibit exaggerated depressive-like behaviors, changed eating behaviors, and altered metabolism in response to chronic stress. However, the mechanisms mediating stress-induced rises in ghrelin are unknown and ghrelin’s antidepressant-like efficacy in the setting of chronic stress is incompletely characterized. Here, we used a pharmacological approach in combination with a 10-day chronic social defeat stress (CSDS) model in male mice to investigate whether the sympathoadrenal system is involved in the ghrelin response to stress. We also examined the antidepressant-like efficacy of administered ghrelin and the synthetic GHSR agonist GHRP-2 during and/or after CSDS. We found that administration of the β1-adrenergic receptor (β1AR) blocker atenolol during CSDS blunts the elevation of plasma acyl-ghrelin and exaggerates depressive-like behavior. Neither acute injection of acyl-ghrelin directly following CSDS nor its chronic administration during or after CSDS nor chronic delivery of GHRP-2 during and after CSDS improved stress-induced depressive-like behavior. Thus, β1ARs drive the acyl-ghrelin response to CSDS, but supplementing the natural increases in acyl-ghrelin with exogenous acyl-ghrelin or GHSR agonist does not further enhance the antidepressant-like actions of the endogenous ghrelin system in the setting of CSDS.

    更新日期:2019-02-08
  • Alcohol intake enhances glutamatergic transmission from D2 receptor-expressing afferents onto D1 receptor-expressing medium spiny neurons in the dorsomedial striatum
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-07
    Jiayi Lu, Yifeng Cheng, Xuehua Wang, Kayla Woodson, Craig Kemper, Emily Disney, Jun Wang

    Dopaminergic modulation of corticostriatal transmission is critically involved in reward-driven behaviors. This modulation is mainly mediated by dopamine D1 receptors (D1Rs) and D2Rs, which are highly expressed in medium spiny neurons (MSNs) of the dorsomedial striatum (DMS), a brain region essential for goal-directed behaviors and addiction. D1Rs and D2Rs are also present at presynaptic cortical terminals within the DMS. However, it is not known how addictive substances alter the glutamatergic strength of striatal synapses expressing presynaptic dopamine receptors. Using cell type-specific Cre mice in combination with optogenetic techniques, we measured glutamatergic transmission at D1R or D2R-expressing afferents to DMS MSNs. We found larger excitatory postsynaptic currents at the synapses between the extra-striatal D2R-expressing afferents and D1R-expressing MSNs (D2→D1), as compared with those observed at the other tested synapses (D1→D1, D1→D2, and D2→D2). Additionally, excessive alcohol consumption induced a long-lasting potentiation of glutamatergic transmission at the corticostriatal D2→D1 synapse. Furthermore, we demonstrated that activation of postsynaptic, but not presynaptic, D2Rs inhibited corticostriatal transmission in an endocannabinoid-dependent manner. Taken together, these data provide detailed information on the mechanisms underlying dopamine receptor-mediated modulation of brain reward circuitry.

    更新日期:2019-02-07
  • Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-06
    Charlotte Marie Pretzsch, Jan Freyberg, Bogdan Voinescu, David Lythgoe, Jamie Horder, Maria Andreina Mendez, Robert Wichers, Laura Ajram, Glynis Ivin, Martin Heasman, Richard A. E. Edden, Steven Williams, Declan G. M. Murphy, Eileen Daly, Gráinne M. McAlonan

    There is increasing interest in the use of cannabis and its major non-intoxicating component cannabidiol (CBD) as a treatment for mental health and neurodevelopmental disorders, such as autism spectrum disorder (ASD). However, before launching large-scale clinical trials, better understanding of the effects of CBD on brain would be desirable. Preclinical evidence suggests that one aspect of the polypharmacy of CBD is that it modulates brain excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels, including in brain regions linked to ASD, such as the basal ganglia (BG) and the dorsomedial prefrontal cortex (DMPFC). However, differences in glutamate and GABA pathways in ASD mean that the response to CBD in people with and without ASD may be not be the same. To test whether CBD ‘shifts’ glutamate and GABA levels; and examine differences in ASD, we used magnetic resonance spectroscopy (MRS) to measure glutamate (Glx = glutamate + glutamine) and GABA+ (GABA + macromolecules) levels in 34 healthy men (17 neurotypicals, 17 ASD). Data acquisition commenced 2 h (peak plasma levels) after a single oral dose of 600 mg CBD or placebo. Test sessions were at least 13 days apart. Across groups, CBD increased subcortical, but decreased cortical, Glx. Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant. Thus, CBD modulates glutamate-GABA systems, but prefrontal-GABA systems respond differently in ASD. Our results do not speak to the efficacy of CBD. Future studies should examine the effects of chronic administration on brain and behaviour, and whether acute brain changes predict longer-term response.

    更新日期:2019-02-07
  • Impact of adult attention deficit hyperactivity disorder and medication status on sleep/wake behavior and molecular circadian rhythms
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-06
    A. N. Coogan, M. Schenk, D. Palm, A. Uzoni, J. Grube, A. H. Tsang, I. Kolbe, N. M. McGowan, R. Wandschneider, M. Colla, H. Oster, J. Thome, F. Faltraco

    Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition that has been strongly associated with changes in sleep and circadian rhythms. Circadian rhythms are near 24-h cycles that are primarily generated by an endogenous circadian timekeeping system, encoded at the molecular level by a panel of clock genes. Stimulant and non-stimulant medication used in the management of ADHD has been shown to potentially impact on circadian processes and their behavioral outputs. In the current study, we have analyzed circadian rhythms in daily activity and sleep, and the circadian gene expression in a cohort of healthy controls (N = 22), ADHD participants not using ADHD-medication (N = 17), and participants with ADHD and current use of ADHD medication (N = 17). Rhythms of sleep/wake behavior were assessed via wrist-worn actigraphy, whilst rhythms of circadian gene expression were assessed ex-vivo in primary human-derived dermal fibroblast cultures. Behavioral data indicate that patients with ADHD using ADHD-medication have lower relative amplitudes of diurnal activity rhythms, lower sleep efficiency, more nocturnal activity but not more nocturnal wakenings than both controls and ADHD participants without medication. At the molecular level, there were alterations in the expression of PER2 and CRY1 between ADHD individuals with no medication compared to medicated ADHD patients or controls, whilst CLOCK expression was altered in patients with ADHD and medication. Analysis of fibroblasts transfected with a BMAL1:luc reporter showed changes in the timing of the peak expression across the three groups. Taken together, these data support the contention that both ADHD and medication status impact on circadian processes.

    更新日期:2019-02-06
  • Reduced auditory evoked gamma-band response and schizophrenia-like clinical symptoms under subanesthetic ketamine
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-06
    Curic Stjepan, Leicht Gregor, Thiebes Stephanie, Andreou Christina, Polomac Nenad, Eichler Iris-Carola, Eichler Lars, Zöllner Christian, Gallinat Jürgen, Steinmann Saskia, Mulert Christoph

    Abnormal gamma-band oscillations (GBO) have been frequently associated with the pathophysiology of schizophrenia. GBO are modulated by glutamate, a neurotransmitter, which is continuously discussed to shape the complex symptom spectrum in schizophrenia. The current study examined the effects of ketamine, a glutamate N-methyl-d-aspartate receptor (NMDAR) antagonist, on the auditory-evoked gamma-band response (aeGBR) and psychopathological outcomes in healthy volunteers to investigate neuronal mechanisms of psychotic behavior. In a placebo-controlled, randomized crossover design, the aeGBR power, phase-locking factor (PLF) during a choice reaction task, the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale were assessed in 25 healthy subjects. Ketamine was applied in a subanaesthetic dose. Low-resolution brain electromagnetic tomography was used for EEG source localization. Significant reductions of the aeGBR power and PLF were identified under ketamine administration compared to placebo (p < 0.01). Source-space analysis of aeGBR generators revealed significantly reduced current source density (CSD) within the anterior cingulate cortex during ketamine administration. Ketamine induced an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01) and increased response times (p < 0.001) and error rates (p < 0.01). Only negative symptoms were significantly associated with an aeGBR power decrease (p = 0.033) as revealed by multiple linear regression. These findings argue for a substantial role of the glutamate system in the mediation of dysfunctional gamma band responses and negative symptomatology of schizophrenia and are compatible with the NMDAR hypofunction hypothesis of schizophrenia.

    更新日期:2019-02-06
  • Herbert D. Kleber
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-02-04
    Frances R. Levin, Jeffrey A. Lieberman, Herbert Pardes
    更新日期:2019-02-05
  • Early life alcohol exposure primes hypothalamic microglia to later-life hypersensitivity to immune stress: possible epigenetic mechanism
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-30
    Lucy G. Chastain, Tina Franklin, Omkaram Gangisetty, Miguel A. Cabrera, Sayani Mukherjee, Pallavi Shrivastava, Shaima Jabbar, Dipak K. Sarkar

    Growing evidence has shown that developmental alcohol exposure induces central nervous system inflammation and microglia activation, which may contribute to long-term health conditions, such as fetal alcohol spectrum disorders. These studies sought to investigate whether neonatal alcohol exposure during postnatal days (PND) 2–6 in rats (third trimester human equivalent) leads to long-term disruption of the neuroimmune response by microglia. Exposure to neonatal alcohol resulted in acute increases in activation and inflammatory gene expression in hypothalamic microglia including tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Adults with neonatal alcohol pre-exposure (alcohol fed; AF) animals showed an exaggerated peripheral stress hormonal response to an immune challenge (lipopolysaccharides; LPS). In addition, there were significantly more microglia present in the hypothalamus of adult AF animals, and their hypothalamic microglia showed more cluster of differentiation molecule 11b (Cd11b) activation, TNF-α expression, and IL-6 expression in response to LPS. Interestingly, blocking microglia activation with minocycline treatment during PND 2–6 alcohol exposure ameliorated the hormonal and microglial hypersensitivity to LPS in AF adult animals. Investigation of possible epigenetic programming mechanisms by alcohol revealed neonatal alcohol decreased several repressive regulators of transcription in hypothalamic microglia, while concomitantly increasing histone H3 acetyl lysine 9 (H3K9ac) enrichment at TNF-α and IL-6 promoter regions. Importantly, adult hypothalamic microglia from AF animals showed enduring increases in H3K9ac enrichment of TNF-α and IL-6 promoters both at baseline and after LPS exposure, suggesting a possible epigenetic mechanism for the long-term immune disruption due to hypothalamic microglial priming.

    更新日期:2019-01-30
  • Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-26
    Martin K. Madsen, Patrick M. Fisher, Daniel Burmester, Agnete Dyssegaard, Dea S. Stenbæk, Sara Kristiansen, Sys S. Johansen, Sczabolz Lehel, Kristian Linnet, Claus Svarer, David Erritzoe, Brice Ozenne, Gitte M. Knudsen

    The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3–30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modeled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.

    更新日期:2019-01-28
  • Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-27
    Jonathan M. Hailwood, Christopher J. Heath, Benjamin U. Phillips, Trevor W. Robbins, Lisa M. Saksida, Timothy J. Bussey
    更新日期:2019-01-26
  • Social anhedonia in major depressive disorder: a symptom-specific neuroimaging approach
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-27
    Verena Enneking, Pia Krüssel, Dario Zaremba, Katharina Dohm, Dominik Grotegerd, Katharina Förster, Susanne Meinert, Christian Bürger, Fanni Dzvonyar, Elisabeth J. Leehr, Joscha Böhnlein, Jonathan Repple, Nils Opel, Nils R. Winter, Tim Hahn, Ronny Redlich, Udo Dannlowski
    更新日期:2019-01-26
  • Correction: Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-28
    Tung-Ping Su, Mu-Hong Chen, Cheng-Ta Li, Wei-Chen Lin, Chen-Jee Hong, Ralitza Gueorguieva, Pei-Chi Tu, Ya-Mei Bai, Chih-Ming Cheng, John H. Krystal
    更新日期:2019-01-26
  • Occupancy of dopamine D 2 and D 3 receptors by a novel D3 partial agonist BP1.4979: a [ 11 C]-(+)-PHNO PET study in humans
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-30
    Patricia Di Ciano, Esmaeil Mansouri, Junchao Tong, Alan A. Wilson, Sylvain Houle, Isabelle Boileau, Thierry Duvauchelle, Philippe Robert, Jean Charles Schwartz, Bernard Le Foll
    更新日期:2019-01-26
  • Methylphenidate’s effects on thalamic metabolism and functional connectivity in cannabis abusers and healthy controls
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-01
    Şükrü Barış Demiral, Dardo Tomasi, Corinde E. Wiers, Peter Manza, Ehsan Shokri-Kojori, Yana Studentsova, Gene-Jack Wang, Nora D. Volkow
    更新日期:2019-01-26
  • D1 receptor hypersensitivity in mice with low striatal D2 receptors facilitates select cocaine behaviors
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-01
    Lauren K. Dobbs, Alanna R. Kaplan, Roland Bock, Khanhky Phamluong, J. Hoon Shin, Miriam E. Bocarsly, Lindsay Eberhart, Dorit Ron, Veronica A. Alvarez
    更新日期:2019-01-26
  • 更新日期:2019-01-26
  • Synaptic adaptations in the central amygdala and hypothalamic paraventricular nucleus associated with protracted ethanol abstinence in male rhesus monkeys
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-05
    V. A. Jimenez, M. A. Herman, V. C. Cuzon Carlson, N. A. Walter, K. A. Grant, M. Roberto
    更新日期:2019-01-26
  • ACNP 57 th Annual Meeting: Poster Session I
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-06

    Sponsorship Statement: Publication of this supplement is sponsored by the ACNP. Individual contributor disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting.

    更新日期:2019-01-26
  • ACNP 57 th Annual Meeting: Poster Session III
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-06

    Sponsorship Statement: Publication of this supplement is sponsored by the ACNP. Individual contributor disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting.

    更新日期:2019-01-26
  • ACNP 57 th Annual Meeting: Panels, Mini-Panels and Study Groups
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-06

    Sponsorship Statement: Publication of this supplement is sponsored by the ACNP. Individual contributor disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting.

    更新日期:2019-01-26
  • ACNP 57 th Annual Meeting: Poster Session II
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-06

    Sponsorship Statement: Publication of this supplement is sponsored by the ACNP. Individual contributor disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting.

    更新日期:2019-01-26
  • Dynorphin-kappa opioid receptor activity in the central amygdala modulates binge-like alcohol drinking in mice
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-11
    Rachel I. Anderson, Marcelo F. Lopez, William C. Griffin, Harold L. Haun, Daniel W. Bloodgood, Dipanwita Pati, Kristen M. Boyt, Thomas L. Kash, Howard C. Becker
    更新日期:2019-01-26
  • TSPO upregulation in bipolar disorder and concomitant downregulation of mitophagic proteins and NLRP3 inflammasome activation
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-11
    Giselli Scaini, Tatiana Barichello, Gabriel R. Fries, Elizabeth A. Kennon, Taylor Andrews, Bobby R. Nix, Giovana Zunta-Soares, Samira S. Valvassori, Jair C. Soares, João Quevedo
    更新日期:2019-01-26
  • A diet enriched with curcumin promotes resilience to chronic social defeat stress
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-12
    Antonio V. Aubry, Hameda Khandaker, Rebecca Ravenelle, Itamar S. Grunfeld, Valentina Bonnefil, Kenny L. Chan, Flurin Cathomas, Jia Liu, Glenn E. Schafe, Nesha S. Burghardt
    更新日期:2019-01-26
  • A novel role for E2F3b in regulating cocaine action in the prefrontal cortex
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-14
    Hannah M. Cates, Rosemary C. Bagot, Elizabeth A. Heller, Immanuel Purushothaman, Casey K. Lardner, Deena M. Walker, Catherine J. Peña, Rachael L. Neve, Li Shen, Eric J. Nestler
    更新日期:2019-01-26
  • The polygenic nature of telomere length and the anti-ageing properties of lithium
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-18
    Fiona Coutts, Alish B. Palmos, Rodrigo R. R. Duarte, Simone de Jong, Cathryn M. Lewis, Danai Dima, Timothy R. Powell
    更新日期:2019-01-26
  • Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-19
    Cristina Sánchez-Mora, María Soler Artigas, Iris Garcia-Martínez, Mireia Pagerols, Paula Rovira, Vanesa Richarte, Montse Corrales, Christian Fadeuilhe, Natàlia Padilla, Xavier de la Cruz, Barbara Franke, Alejandro Arias-Vásquez, Miguel Casas, Josep-Antoni Ramos-Quiroga, Marta Ribasés
    更新日期:2019-01-26
  • The role of prediction error and memory destabilization in extinction of cued-fear within the reconsolidation window
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-20
    Emma N. Cahill, Melissa A. Wood, Barry J. Everitt, Amy L. Milton
    更新日期:2019-01-26
  • Brain structure, cognition, and brain age in schizophrenia, bipolar disorder, and healthy controls
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-20
    Saba Shahab, Benoit H. Mulsant, Melissa L. Levesque, Navona Calarco, Arash Nazeri, Anne L. Wheeler, George Foussias, Tarek K. Rajji, Aristotle N. Voineskos
    更新日期:2019-01-26
  • Serotonin transporter inhibition and 5-HT 2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-21
    Adele Stewart, Gwynne L. Davis, Paul J. Gresch, Rania M. Katamish, Rodeania Peart, Maximilian J. Rabil, Raajaram Gowrishankar, F. Ivy Carroll, Maureen K. Hahn, Randy D. Blakely
    更新日期:2019-01-26
  • T-448, a specific inhibitor of LSD1 enzyme activity, improves learning function without causing thrombocytopenia in mice
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-22
    Satoru Matsuda, Rina Baba, Hideyuki Oki, Shinji Morimoto, Masashi Toyofuku, Shigeru Igaki, Yusuke Kamada, Shinji Iwasaki, Kota Matsumiya, Ryosuke Hibino, Hiroko Kamada, Takeshi Hirakawa, Misa Iwatani, Ken Tsuchida, Ryujiro Hara, Mitsuhiro Ito, Haruhide Kimura
    更新日期:2019-01-26
  • Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-26
    Ethan M. Anderson, Haosheng Sun, Daniel Guzman, Makoto Taniguchi, Christopher W. Cowan, Ian Maze, Eric J. Nestler, David W. Self
    更新日期:2019-01-26
  • Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-26
    Claudia Delgado-Acevedo, Sebastián F. Estay, Anna R. Radke, Ayesha Sengupta, Angélica P. Escobar, Francisca Henríquez-Belmar, Cristopher A. Reyes, Valentina Haro-Acuña, Elías Utreras, Ramón Sotomayor-Zárate, Andrew Cho, Jens R. Wendland, Ashok B. Kulkarni, Andrew Holmes, Dennis L. Murphy, Andrés E. Chávez, Pablo R. Moya
    更新日期:2019-01-26
  • Impaired instrumental reversal learning is associated with increased medial prefrontal cortex activity in Sapap3 knockout mouse model of compulsive behavior
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-26
    Elizabeth E. Manning, Alexandre Y. Dombrovski, Mary M. Torregrossa, Susanne E. Ahmari

    Convergent functional neuroimaging findings implicate hyperactivity across the prefrontal cortex (PFC) and striatum in the neuropathology of obsessive compulsive disorder (OCD). The impact of cortico-striatal circuit hyperactivity on executive functions subserved by these circuits is unclear, because impaired recruitment of PFC has also been observed in OCD patients during paradigms assessing cognitive flexibility. To investigate the relationship between cortico-striatal circuit disturbances and cognitive functioning relevant to OCD, Sapap3 knockout mice (KOs) and littermate controls were tested in an instrumental reversal-learning paradigm to assess cognitive flexibility. Cortical and striatal activation associated with reversal learning was assessed via quantitative analysis of expression of the immediate early gene cFos and generalized linear mixed-effects models. Sapap3-KOs displayed heterogeneous reversal-learning performance, with almost half (n = 13/28) failing to acquire the reversed contingency, while the other 15/28 had similar acquisition as controls. Notably, reversal impairments were not correlated with compulsive grooming severity. cFos analysis revealed that reversal performance declined as medial PFC (mPFC) activity increased in Sapap3-KOs. No such relationship was observed in controls. Our studies are among the first to describe cognitive impairments in a transgenic OCD-relevant model, and demonstrate pronounced heterogeneity among Sapap3-KOs. These findings suggest that increased neural activity in mPFC is associated with impaired reversal learning in Sapap3-KOs, providing a likely neural basis for this observed heterogeneity. The Sapap3-KO model is thus a useful tool for future mechanistic studies to determine how mPFC hyperactivity contributes to OCD-relevant cognitive dysfunction.

    更新日期:2019-01-26
  • Prevalence and phenomenology of violent ideation and behavior among 200 young people at clinical high-risk for psychosis: an emerging model of violence and psychotic illness
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-12-27
    Gary Brucato, Paul S. Appelbaum, Michael D. Masucci, Stephanie Rolin, Melanie M. Wall, Mark Levin, Rebecca Altschuler, Michael B. First, Jeffrey A. Lieberman, Ragy R. Girgis
    更新日期:2019-01-26
  • DeepSqueak: a deep learning-based system for detection and analysis of ultrasonic vocalizations
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-04
    Kevin R. Coffey, Russell G. Marx, John F. Neumaier
    更新日期:2019-01-26
  • Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-05
    Verginia C. Cuzon Carlson, Matthew M. Ford, Timothy L. Carlson, Alejandro Lomniczi, Kathleen A. Grant, Betsy Ferguson, Rita P. Cervera-Juanes

    Alcohol use disorder (AUD) is a chronic condition with devastating health and socioeconomic effects. Still, pharmacotherapies to treat AUD are scarce. In a prior study aimed at identifying novel AUD therapeutic targets, we investigated the DNA methylome of the nucleus accumbens core (NAcc) of rhesus macaques after chronic alcohol use. The G-protein coupled receptor 39 (GPR39) gene was hypermethylated and its expression downregulated in heavy alcohol drinking macaques. GPR39 encodes a Zn2+-binding metabotropic receptor known to modulate excitatory and inhibitory neurotransmission, the balance of which is altered in AUD. These prior findings suggest that a GPR39 agonist would reduce alcohol intake. First, using a drinking-in-the-dark two bottle choice (DID-2BC) model we showed that an acute 7.5 mg/kg dose of the GPR39 agonist, TC-G 1008, reduced ethanol intake in mice without affecting total fluid intake, locomotor activity or saccharin preference. Furthermore, repeated doses of the agonist prevented ethanol escalation in an intermittent access 2BC paradigm (IA-2BC). This effect was reversible, as ethanol escalation occurred following agonist “washout”. As observed during the DID-2BC study, a subsequent acute agonist challenge during the IA-2BC procedure reduced ethanol intake by ~47%. Finally, Gpr39 activation was associated with changes in Gpr39 and Bdnf expression, and in glutamate release in the NAcc. Together, our findings suggest that Gpr39 is a promising target for the prevention and treatment of AUD.

    更新日期:2019-01-26
  • 更新日期:2019-01-26
  • A novel GPR55-mediated satiety signal in the oval Bed Nucleus of the Stria Terminalis
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-07
    E. R. Hawken, C. P. Normandeau, J. Gardner Gregory, B. Cécyre, J.-F. Bouchard, K. Mackie, É. C. Dumont
    更新日期:2019-01-26
  • Insulin modulates the strong reinforcing effects of nicotine and changes in insulin biomarkers in a rodent model of diabetes
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-07
    Bryan Cruz, Rodolfo J. Flores, Kevin P. Uribe, Evangelina J. Espinoza, Charles T. Spencer, Katherine M. Serafine, Arbi Nazarian, Laura E. O’Dell
    更新日期:2019-01-26
  • Medial prefrontal cortex neuropeptide Y modulates binge-like ethanol consumption in C57BL/6J mice
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-07
    Stacey L. Robinson, Isabel M. Marrero, Carlos A. Perez-Heydrich, Marian T. Sepulveda-Orengo, Kathryn J. Reissner, Todd E. Thiele
    更新日期:2019-01-26
  • Acute and long-term effects of electroconvulsive therapy on human dentate gyrus
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-08
    Akihiro Takamiya, Eric Plitman, Jun Ku Chung, Mallar Chakravarty, Ariel Graff-Guerrero, Masaru Mimura, Taishiro Kishimoto
    更新日期:2019-01-26
  • Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-08
    Nabil Karnib, Rim El-Ghandour, Lauretta El Hayek, Patrick Nasrallah, Mohamad Khalifeh, Nour Barmo, Vanessa Jabre, Pascale Ibrahim, Maria Bilen, Joseph S. Stephan, Edward B. Holson, Rajiv R. Ratan, Sama F. Sleiman
    更新日期:2019-01-26
  • Oxytocin modulates hippocampal perfusion in people at clinical high risk for psychosis
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-09
    Cathy Davies, Yannis Paloyelis, Grazia Rutigliano, Marco Cappucciati, Andrea De Micheli, Valentina Ramella-Cravaro, Umberto Provenzani, Mathilde Antoniades, Gemma Modinos, Dominic Oliver, Daniel Stahl, Silvia Murguia, Fernando Zelaya, Paul Allen, Sukhi Shergill, Paul Morrison, Steve Williams, David Taylor, Philip McGuire, Paolo Fusar-Poli

    Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that can include social withdrawal and have a 20–35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22–28 and at 30–36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.

    更新日期:2019-01-26
  • 更新日期:2019-01-26
  • Altered frontostriatal white matter microstructure is associated with familial alcoholism and future binge-drinking in adolescence
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-12
    Scott A. Jones, Bonnie J. Nagel

    Adolescence is a time of significant neurobiological development, including changes in white matter microstructure. Familial alcoholism and adolescent binge-drinking have both been associated with altered white matter microstructure; however, the temporal nature of these effects, and their interaction, is unclear. Using diffusion-weighted imaging and voxel-wise multilevel modeling, the effects of familial alcoholism and future binge-drinking on white matter microstructural development were assessed in 45 adolescents, who went on to binge-drink (but were alcohol-naive at baseline), and 68 adolescents, who remained largely alcohol-naive, all with varying degrees of familial alcoholism. Both future binge-drinking and familial alcoholism were associated with altered frontostriatal white matter microstructure early in adolescence, prior to alcohol use. While several binge-drinking-related effects persisted throughout adolescence (in the posterior limb of the internal capsule, superior corona radiata, and cerebellar peduncles), the association between familial alcoholism and altered white matter microstructure dissipated across adolescence in all regions. There were no white matter regions identified where future binge-drinking or familial alcoholism were significantly associated with emergent or exacerbated alterations in white matter microstructure. Altogether, these findings suggest that alterations in frontostiatal white matter microstructure, some of which are associated with familial alcoholism, may be used to predict which adolescents are more likely to go on and engage in alcohol use. Meanwhile, a reduction in family history-related associations with altered white matter microstructure by late-adolescence is encouraging for future prevention work targeted at at-risk youth.

    更新日期:2019-01-26
  • Transcriptomic predictors of inflammation-induced depressed mood
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-14
    Joshua Hyong-Jin Cho, Michael R. Irwin, Naomi I. Eisenberger, Donald M. Lamkin, Steve W. Cole

    Inflammation plays a significant role in the pathophysiology of depression. However, not all individuals exposed to inflammatory challenge develop depression, and identifying those at risk is necessary to develop targeted monitoring, prevention, and treatment strategies. Within a randomized double-blind placebo-controlled study (n = 115), we examined whether leukocyte transcriptome profiles predicted inflammation-induced depressed mood in volunteers who received low-dose intravenous endotoxin (n = 58; aged 18–50). At baseline, transcription factor (TF) activities were assessed using genome-wide transcriptional profiling of peripheral blood mononuclear cells and promoter-based bioinformatic analyses. Then, participants were administered endotoxin. Self-reported depressed mood was assessed using the Profile of Mood States. Based on extant studies linking transcriptional profiles to depressive disorder, we examined whether post-endotoxin depressed mood is predicted by baseline activity of TFs related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR). Twenty-one participants (36%) experienced an increase in depressed mood from baseline to 2 h post endotoxin, when depressive response peaks. Bioinformatics analyses controlling for age, sex, ethnicity, body mass index, and physical sickness response revealed that post-endotoxin depressed mood was predicted by increased baseline activity of TFs related to inflammation (NF-kB) and beta-adrenergic signaling (CREB) and by decreased activity of GR-related TFs (P’s < 0.001). Inflammation-induced depressed mood is predicted by peripheral transcriptome profiles related to immune activation, sympathetic activation, and glucocorticoid insensitivity. With further replication, these stress-related molecular profiles could be used for a novel genomic approach for identifying individuals at high-risk for the inflammatory phenotype of depression.

    更新日期:2019-01-26
  • Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-17
    Samuel T. Wilkinson, Cristan Farmer, Elizabeth Ballard, Sanjay J. Mathew, Michael F. Grunebaum, James W. Murrough, Peter Sos, Gang Wang, Ralitza Gueorguieva, Carlos A. Zarate

    The goal of this study was to infer the effectiveness of midazolam as a comparator in preserving the blind in ketamine studies for mood disorders through patient-level analyses of efficacy trial outcomes. In this integrative data analysis (k = 9, N = 367 patients with mood disorders), clinical outcomes were compared across four groups: ketamine (midazolam-controlled), ketamine (saline-controlled), midazolam, and saline. Ketamine doses ranged from 0.5 to 0.54 mg/kg and midazolam doses ranged from 0.02 to 0.045 mg/kg. The baseline-to-Day 1 effect size was d = 0.7 (95% CI: 0.4–0.9) for ketamine (midazolam) versus midazolam and d = 1.8 (95% CI: 1.4–2.2) for ketamine (saline) versus saline. The effect of ketamine relative to control was larger in saline-controlled studies than in midazolam-controlled studies (t(276) = 2.32, p = 0.02). This was driven by a comparatively larger effect under midazolam than saline (t(111) = 5.40, p < 0.0001), whereas there was no difference between ketamine (midazolam) versus ketamine (saline) (t(177) = 0.65, p = 0.51). Model-estimated rates of response (with 95% CI) yielded similar results: ketamine (midazolam), 45% (34–56%); ketamine (saline), 46% (34–58%); midazolam, 18% (6–30%); saline, 1% (0–11%). The response rate for ketamine was higher than the control condition for both saline (t(353) = 7.41, p < 0.0001) and midazolam (t(353) = 4.59, p < 0.0001). Studies that used midazolam as a comparator yielded smaller effects of ketamine than those which used saline, which was accounted for by greater improvement following midazolam compared to saline.

    更新日期:2019-01-26
  • Chronic adolescent stress sex-specifically alters the hippocampal transcriptome in adulthood
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-23
    Sydney A. Rowson, Mandakh Bekhbat, Sean D. Kelly, Elisabeth B. Binder, Molly M. Hyer, Gladys Shaw, Maria Alexis Bent, Georgia Hodes, Gregory Tharp, David Weinshenker, Zhouhui Qin, Gretchen N. Neigh

    Chronic adolescent stress alters behavior in a sex-specific manner at the end of adolescence and in adulthood. Although prolonged behavioral repercussions of chronic adolescent stress have been documented, the potential underlying mechanisms are incompletely understood. In this study we demonstrate that a history of chronic adolescent stress modified the adult stress response, as measured by corticosterone concentration, such that a history of chronic adolescent stress resulted in a blunted response to a novel acute stressor. In order to begin to address potential mechanistic underpinnings, we assessed the extent to which chronic adolescent stress impacted global DNA methylation. Reduced global hippocampal methylation was evident in females with a history of chronic adolescent stress; thus, it was possible that chronic adolescent stress altered global transcription in the whole hippocampi of adult male and female rats. In addition, because acute stress can stimulate a genomic response, we assessed the transcriptome following exposure to an acute novel stressor to determine the extent to which a history of chronic adolescent stress modifies the adult transcriptional response to an acute stressor in males and females. In addition to the reduction in global methylation, chronic adolescent stress resulted in distinct patterns of gene expression in the adult hippocampus that differentiated by sex. Furthermore, both sex and a history of chronic adolescent stress influenced the transcriptional response to an acute novel stressor in adulthood, suggesting both latent and functional effects of chronic adolescent stress at the level of gene transcription. Pathway analysis indicated that ESR1 and IFN-α may be particularly influential transcription factors mediating these transcriptional differences and suggest candidate mechanisms for future studies. Collectively, these studies demonstrate sex-specific and enduring effects of adolescent stress exposure that are more pronounced in females than in males.

    更新日期:2019-01-26
  • An amylin analogue attenuates alcohol-related behaviours in various animal models of alcohol use disorder
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-23
    Aimilia Lydia Kalafateli, Daniel Vallöf, Giancarlo Colombo, Irene Lorrai, Paola Maccioni, Elisabet Jerlhag

    Recent findings have identified salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, as a potential regulator of alcohol-induced activation of the mesolimbic dopamine system and alcohol consumption. Providing that the role of amylin signalling in alcohol-related behaviours remains unknown, the present experiments investigate the effect of sCT on these behaviours and the mechanisms involved. We showed that repeated sCT administration decreased alcohol and food intake in outbred rats. Moreover, single administration of the potent amylin receptor antagonist, AC187, increased short-term alcohol intake in outbred alcohol-consuming rats, but did not affect food intake. Acute administration of sCT prevented relapse-like drinking in the “alcohol deprivation effect” model in outbred alcohol-experienced rats. Additionally, acute sCT administration reduced operant oral alcohol self-administration (under the fixed ratio 4 schedule of reinforcement) in selectively bred Sardinian alcohol-preferring rats, while it did not alter operant self-administration (under the progressive ratio schedule of reinforcement) of a highly palatable chocolate-flavoured beverage in outbred rats. Lastly, we identified differential amylin receptor expression in high compared to low alcohol-consuming rats, as reflected by decreased calcitonin receptor and increased receptor activity modifying protein 1 expression in the nucleus accumbens (NAc) of high consumers. Collectively, our data suggest that amylin signalling, especially in the NAc, may contribute to reduction of various alcohol-related behaviours.

    更新日期:2019-01-26
  • Cues play a critical role in estrous cycle-dependent enhancement of cocaine reinforcement
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-23
    Amy R. Johnson, Kimberly C. Thibeault, Alberto J. Lopez, Emily G. Peck, L. Paul Sands, Christina M. Sanders, Munir Gunes Kutlu, Erin S. Calipari

    While preclinical work has aimed to outline the neural mechanisms of drug addiction, it has overwhelmingly focused on male subjects. There has been a push in recent years to incorporate females into existing addiction models; however, males and females often have different behavioral strategies, making it important to not only include females, but to develop models that assess the factors that comprise female drug addiction. Traditional self-administration models often include light or tone cues that serve as discriminative stimuli and/or consequent stimuli, making it nearly impossible to disentangle the effects of cue learning, the cues themselves, and acute effects of psychostimulant drugs. To disentangle the interaction between drug-associated cues and the consummatory and appetitive responding driven by cocaine, we have developed a new behavioral procedure that combines Pavlovian-instrumental transfer with behavioral economic analysis. This task can be completed within a single session, allowing for studies looking at estrous cycle stage-dependent effects in intact cycling females, something that has been difficult in the past. In this study, we found no differences in self-administration across the estrous cycle in the absence of cues; however, when cues were introduced, the cues that acquired value during estrus—but not during diestrus or in males—increased motivation. Cues paired during estrus also increased c-fos expression to a greater extent in striatal regions, an effect that may underlie the observed increases in seeking induced by these cues, even weeks later. Together, these data suggest that fundamental differences in the motivational properties of psychostimulant drugs between males and females are complex and are driven primarily by the interaction between drug-associated stimuli and drug effects.

    更新日期:2019-01-26
  • Methylation of the FKBP5 gene in association with FKBP5 genotypes, childhood maltreatment and depression
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-23
    Johanna Klinger-König, Johannes Hertel, Sandra Van der Auwera, Stefan Frenzel, Liliane Pfeiffer, Melanie Waldenberger, Janine Golchert, Alexander Teumer, Matthias Nauck, Georg Homuth, Henry Völzke, Hans J. Grabe

    DNA methylation of the FKBP5 gene is assumed to alter FKBP5 expression and hence the synthesis of the FK506 binding protein 51, a central element of a genomic negative feedback loop for glucocorticoid receptor signaling. The present study aimed to replicate and extend previously reported influences of FKBP5 genotypes, childhood maltreatment and depression on methylation levels of five CpG sites in intron 7 of the FKBP5 gene in a large population-based sample. Besides the single nucleotide polymorphism (SNP) rs1360780, associations of the FKBP5 methylation with 22 other, unlinked FKBP5 SNPs as well as associations between FKBP5 methylation levels and transcription levels were investigated. Using whole-blood methylation of 3965 subjects of the Study of Health in Pomerania (SHIP) reduced methylation levels in TT allele carriers of rs1360780 (OR = 0.975, p = .005) and currently depressed subjects (OR = 0.995, p = 0.005) were found. Further, an impact of two yet undescribed SNPs (rs6910300, rs7771727) on methylation levels was observed. However, main and interactive effects for childhood maltreatment and lifetime major depressive disorder observed in previous studies could not be replicated. Finally, FKBP5 methylation levels were not related to FKBP5 transcription levels in whole blood. Thus, the present study verified the associations of FKBP5 genotypes and state depression on the FKBP5 methylation levels of five CpG sites in intron 7. However, FKBP5 methylation of these five CpG sites could not be validated as a valuable clinical biomarker for biological long-term effects of childhood maltreatment or lifetime depression.

    更新日期:2019-01-26
  • Structural similarity networks predict clinical outcome in early-phase psychosis
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-24
    Philipp Homan, Miklos Argyelan, Pamela DeRosse, Philip Szeszko, Juan A. Gallego, Lauren Hanna, Delbert Robinson, John M. Kane, Todd Lencz, Anil K. Malhotra

    Despite recent advances, there is still a major need for prediction of treatment success in schizophrenia, a condition long considered a disorder of dysconnectivity in the brain. Graph theory provides a means to characterize the connectivity in both healthy and abnormal brains. We calculated structural similarity networks in each participant and hypothesized that the “hubness”, i.e., the number of edges connecting a node to the rest of the network, would be associated with clinical outcome. This prospective controlled study took place at an academic research center and included 82 early-phase psychosis patients (23 females; mean age [SD] = 21.6 [5.5] years and 58 healthy controls). Medications were administered in a double-blind randomized manner, and patients were scanned at baseline prior to treatment with second-generation antipsychotics. Symptoms were assessed with the Brief Psychiatric Rating Scale at baseline and over the course of 12 weeks. Nodal degree of structural similarity networks was computed for each subject and entered as a predictor of individual treatment response into a partial least squares (PLS) regression. The model fit was significant in a permutation test with 1000 permutations (P = 0.006), and the first two PLS regression components explained 29% (95% CI: 27; 30) of the variance in treatment response after cross-validation. Nodes loading strongly on the first PLS component were primarily located in the orbito- and prefrontal cortex, whereas nodes loading strongly on the second PLS component were primarily located in the superior temporal, precentral, and middle cingulate cortex. These data suggest a link between brain network morphology and clinical outcome in early-phase psychosis.

    更新日期:2019-01-26
  • The susceptibility to chronic social defeat stress is related to low hippocampal extrasynaptic NMDA receptor function
    Neuropsychopharmacology (IF 6.544) Pub Date : 2019-01-25
    Yiu Chung Tse, Joëlle Lopez, Alexandre Moquin, Shui-Ming Alice Wong, Dusica Maysinger, Tak Pan Wong

    N-methyl-d-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.

    更新日期:2019-01-26
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
导出
化学 • 材料 期刊列表