Neuropsychopharmacology最新文献

{"title":"Efficacy and safety of JNJ-42165279, a fatty acid amide hydrolase inhibitor, in adolescents and adults with autism spectrum disorder: a randomized, phase 2, placebo-controlled study.","authors":"Matthew E Klein, Abigail Bangerter, Robin J Halter, Kim Cooper, Zuleima Aguilar, Carla M Canuso, Wayne C Drevets, Mark E Schmidt, Gahan Pandina","doi":"10.1038/s41386-024-02001-2","DOIUrl":"https://doi.org/10.1038/s41386-024-02001-2","url":null,"abstract":"<p><p>JNJ-42165279, a highly selective and orally bioavailable fatty acid amide (FAA) hydrolase inhibitor, was evaluated for efficacy and safety in adolescents and adults with autism spectrum disorder (ASD) in this phase 2, double-blind, placebo-controlled, multicenter study (NCT03664232). Participants aged 13-35 years, with a diagnosis of ASD (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; Autism Diagnostic Observation Schedule, 2nd edition) were randomized (1:1) to 12 weeks of treatment with JNJ-42165279 (25 mg, twice-daily) or placebo. Primary endpoints were the change in the Autism Behavior Inventory (ABI) Core Domain (ABI-CD), ABI-Social Communication (ABI-SC), and ABI-Repetitive/Restrictive Behavior (ABI-RB) scores from baseline to day 85. Of the 61 participants (16 female, 45 male) included in the efficacy analyses, 53 (87%) completed the double-blind treatment. At day 85, the JNJ-42165279 group did not show a statistically significant reduction in ASD symptoms versus placebo, as assessed with ABI-CD (p = 0.284), ABI-SC (p = 0.290), and ABI-RB (p = 0.231). However, the following secondary outcomes exhibited small to moderate changes directionally favoring JNJ-42165279: Social Responsiveness Scale 2 (SRS, p = 0.064), Repetitive Behavior Scale-Revised (RBS-R, p = 0.006), Zarit Burden Interview short version (ZBI, p = 0.063), Child Adolescent Symptom Inventory-Anxiety (CASI-Anx, p = 0.048), and Caregiver Global Impression of Severity (p = 0.075). Notably, versus placebo, JNJ-42165279-treated participants showed increased concentrations of FAAs throughout the treatment period, with those achieving elevated concentrations experiencing the greatest reduction in the SRS total score at day 85. JNJ-42165279 demonstrated an acceptable safety profile. Although primary endpoints were not met, JNJ-42165279 may have a therapeutic effect on certain aspects of core ASD symptoms.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific and developmental effects of early life adversity on stress reactivity are rescued by postnatal knockdown of 5-HT_1A autoreceptors.","authors":"Rushell Dixon, Lauren Malave, Rory Thompson, Serena Wu, Yifei Li, Noah Sadik, Christoph Anacker","doi":"10.1038/s41386-024-01999-9","DOIUrl":"10.1038/s41386-024-01999-9","url":null,"abstract":"<p><p>Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT_1A) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but whether 5HT_1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT_1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphé 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT_1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT_1A autoreceptors as potential targets to prevent these enduring effects of ELA.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.","authors":"Manoela V Fogaça, Fernanda Daher, Marina R Picciotto","doi":"10.1038/s41386-024-02002-1","DOIUrl":"10.1038/s41386-024-02002-1","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autism spectrum disorder-like behaviors induced by hyper-glutamatergic NMDA receptor signaling through hypo-serotonergic 5-HT_1A receptor signaling in the prefrontal cortex in mice exposed to prenatal valproic acid.","authors":"Hitomi Kurahashi, Kazuo Kunisawa, Kenji F Tanaka, Hisayoshi Kubota, Masaya Hasegawa, Mai Miyachi, Yuka Moriya, Yoichi Hasegawa, Taku Nagai, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri","doi":"10.1038/s41386-024-02004-z","DOIUrl":"10.1038/s41386-024-02004-z","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and cognitive impairments. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation/inhibition (E/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT_1A receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635-a 5-HT_1A receptor antagonist-antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT_1A receptors in prenatal VPA mice.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating cross-sectional and longitudinal relationships between brain structure and distinct dimensions of externalizing psychopathology in the ABCD sample.","authors":"Hajer Nakua, Lee Propp, Anne-Claude V Bedard, Marcos Sanches, Stephanie H Ameis, Brendan F Andrade","doi":"10.1038/s41386-024-02000-3","DOIUrl":"https://doi.org/10.1038/s41386-024-02000-3","url":null,"abstract":"<p><p>Externalizing psychopathology in childhood is a predictor of poor outcomes across the lifespan. Children exhibiting elevated externalizing symptoms also commonly show emotion dysregulation and callous-unemotional (CU) traits. Examining cross-sectional and longitudinal neural correlates across dimensions linked to externalizing psychopathology during childhood may clarify shared or distinct neurobiological vulnerability for psychopathological impairment later in life. We used tabulated brain structure and behavioural data from baseline, year 1, and year 2 timepoints of the Adolescent Brain Cognitive Development Study (ABCD; baseline n = 10,534). We fit separate linear mixed effect models to examine whether baseline brain structures in frontolimbic and striatal regions (cortical thickness or subcortical volume) were associated with externalizing symptoms, emotion dysregulation, and/or CU traits at baseline and over a two-year period. The most robust relationships found at the cross-sectional level was between cortical thickness in the right rostral middle frontal gyrus and bilateral pars orbitalis was positively associated with CU traits (β = |0.027-0.033|, p_corrected = 0.009-0.03). Over the two-year follow-up period, higher baseline cortical thickness in the left pars triangularis and rostral middle frontal gyrus predicted greater decreases in externalizing symptoms ((F = 6.33-6.94, p_corrected = 0.014). The results of the current study suggest that unique regions within frontolimbic and striatal networks may be more strongly associated with different dimensions of externalizing psychopathology. The longitudinal findings indicate that brain structure in early childhood may provide insight into structural features that influence behaviour over time.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medial prefrontal cortex acetylcholine signaling mediates the ability to learn an active avoidance response following learned helplessness training.","authors":"Zuhair I Abdulla, Yann S Mineur, Richard B Crouse, Ian M Etherington, Hanna Yousuf, Jessica J Na, Marina R Picciotto","doi":"10.1038/s41386-024-02003-0","DOIUrl":"10.1038/s41386-024-02003-0","url":null,"abstract":"<p><p>Increased brain levels of acetylcholine (ACh) have been observed in patients with depression, and increasing ACh levels pharmacologically can precipitate stress-related behaviors in humans and animals. Conversely, optimal ACh levels are required for cognition and memory. We hypothesize that excessive ACh signaling results in strengthening of negative encoding in which memory formation is aberrantly strengthened for stressful events. The medial prefrontal cortex (mPFC) is critical for both top-down control of stress-related circuits, and for encoding of sensory experiences. We therefore evaluated the role of ACh signaling in the mPFC in a learned helplessness task in which mice were exposed to repeated inescapable stressors followed by an active avoidance task. Using fiber photometry with a genetically-encoded ACh sensor, we found that ACh levels in the mPFC during exposure to inescapable stressors were positively correlated with later escape deficits in an active avoidance test in males, but not females. Consistent with these measurements, we found that both pharmacologically- and chemogenetically-induced increases in mPFC ACh levels resulted in escape deficits in both male and female mice, whereas chemogenetic inhibition of ACh neurons projecting to the mPFC improved escape performance in males, but impaired escape performance in females. These results highlight the adaptive role of ACh release in stress response, but also support the idea that sustained elevation of ACh contributes to maladaptive behaviors. Furthermore, mPFC ACh signaling may contribute to stress-based learning differentially in males and females.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A digital intervention for cognitive deficits following COVID-19: a randomized clinical trial.","authors":"Lindsay W Victoria, Lauren E Oberlin, Irena P Ilieva, Abhishek Jaywant, Dora Kanellopoulos, Catherine Mercaldi, Caitlin A Stamatis, Deborah N Farlow, Scott H Kollins, Ochuwa Tisor, Sama Joshi, Raura Doreste-Mendez, Roy H Perlis, Faith M Gunning","doi":"10.1038/s41386-024-01995-z","DOIUrl":"https://doi.org/10.1038/s41386-024-01995-z","url":null,"abstract":"<p><p>Post-COVID-19 cognitive deficits are common, persistent, and disabling. Evidence on effective treatments is limited. The goal of this study was to investigate the efficacy of a digital intervention to reduce cognitive and functional deficits in adults with persistent post-COVID-19 cognitive dysfunction. We used the remotely-delivered intervention in a randomized clinical trial conducted from July 13, 2021 to April 26, 2023. We hypothesized that participants in the intervention group would improve in measures of cognition and daily functioning. Participants were adults with cognitive deficits persisting >4 weeks following acute COVID-19 illness. Of 183 participants screened, 110 were enrolled; 98 participants (78.6% female; mean age = 48.1) completed at least one study visit. Participants were randomized 1:1 to the intervention (AKL-T01) or waitlist control. AKL-T01 is a digital therapeutic using a videogame interface to target attention and executive control. The intervention was delivered remotely for 6 weeks. The primary outcome was change in performance on a sustained attention measure (Digit Symbol Matching Task). The difference in the primary outcome between the intervention (n = 49) and controls (n = 49) was not statistically significant (F [3,261] = 0.12, p = 0.95). Secondary cognitive outcomes of task-switching (F[3,262] = 2.78, p = 0.04) and processing speed (F[3,267] = 4.57, p = 0.004) improved in the intervention relative to control. Secondary measures of functioning also improved in the intervention relative to control, including disability (F[1,82] = 4.02, p = 0.05) and quality of life (F[3,271] = 2.66, p = 0.05). Exploratory analyses showed a greater reduction in total fatigue (F[1,85] = 4.51, p = 0.04), cognitive fatigue (F[1,85] = 7.20, p = 0.009), and anxiety (F[1,87] = 7.42, p = 0.008) in the intervention relative to control. Despite the lack of improvement in sustained attention, select post-COVID-19 cognitive deficits may be ameliorated by targeted cognitive training with AKL-T01, with associated improvements in quality of life and fatigue. If replicated, the scalable nature of this digital intervention may help address substantial need for accessible, effective treatments among individuals with long COVID.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of striatal indirect pathway during second postnatal week leads to long-lasting deficits in motivated behavior.","authors":"Pedro R Olivetti, Arturo Torres-Herraez, Meghan E Gallo, Ricardo Raudales, MaryElena Sumerau, Sinead Moyles, Peter D Balsam, Christoph Kellendonk","doi":"10.1038/s41386-024-01997-x","DOIUrl":"10.1038/s41386-024-01997-x","url":null,"abstract":"<p><p>Schizophrenia is a neuropsychiatric disorder with postulated neurodevelopmental etiology. Genetic and imaging studies have shown enhanced dopamine and D2 receptor occupancy in the striatum of patients with schizophrenia. However, whether alterations in postnatal striatal dopamine can lead to long-lasting changes in brain function and behavior is still unclear. Here, we approximated striatal D2R hyperfunction in mice via designer receptor-mediated activation of inhibitory Gi-protein signaling during a defined postnatal time window. We found that G_i-mediated inhibition of the indirect pathway (IP) during postnatal days 8-15 led to long-lasting decreases in locomotor activity and motivated behavior measured in the adult animal. In vivo photometry further showed that the motivational deficit was associated with an attenuated adaptation of outcome-evoked dopamine levels to changes in effort requirements. These data establish a sensitive time window of D2R-regulated striatal development with long-lasting impacts on neuronal function and behavior.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of intranasal oxytocin on fear extinction learning.","authors":"Mahmoud Rashidi, Joe J Simon, Katja Bertsch, Gerhard Vincent Wegen, Beate Ditzen, Herta Flor, Valery Grinevich, Robert Christian Wolf, Sabine C Herpertz","doi":"10.1038/s41386-024-01996-y","DOIUrl":"10.1038/s41386-024-01996-y","url":null,"abstract":"<p><p>Once a threat no longer exists, extinction of conditioned fear becomes adaptive in order to reduce allotted resources towards cues that no longer predict the threat. In anxiety and stress disorders, fear extinction learning may be affected. Animal findings suggest that the administration of oxytocin (OT) modulates extinction learning in a timepoint-dependent manner, facilitating extinction when administered prior to fear conditioning, but impairing it when administered prior to extinction learning. The aim of the present study was to examine if these findings translate into human research. Using a randomized, double-blind, placebo-controlled, 2-day fear conditioning and extinction learning design, behavioral (self-reported anxiety), physiological (skin conductance response), neuronal (task-based and resting-state functional magnetic resonance imaging), and hormonal (cortisol) data were collected from 124 naturally cycling (taking no hormonal contraceptives) healthy females. When administered prior to conditioning (Day 1), OT, similar to rodent findings, did not affect fear conditioning, but modulated the intrinsic functional connectivity of the anterior insula immediately after fear conditioning. In contrast to animal findings, OT impaired, not facilitated, extinction learning on the next day and increased anterior insula activity. When administered prior to extinction learning (day 2), OT increased the activity in the bilateral middle temporal gyrus, and similar to animal findings, reduced extinction learning. The current findings suggest that intranasal OT impedes fear extinction learning in humans regardless of the timepoint of administration, providing new insights and directions for future translational research and clinical applications.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vasopressin regulates social play behavior in sex-specific ways through glutamate modulation in the lateral septum.","authors":"Remco Bredewold, Catherine Washington, Alexa H Veenema","doi":"10.1038/s41386-024-01987-z","DOIUrl":"10.1038/s41386-024-01987-z","url":null,"abstract":"<p><p>Understanding the neural basis of social play in juvenile rats may ultimately help restore social play deficits in autistic children. We previously found that administration of a vasopressin (AVP) V1a receptor (V1aR) antagonist into the lateral septum (LS) increased social play behavior in male juvenile rats and decreased it in females. Here, we demonstrate that glutamate, but not GABA, is involved in this sex-specific regulation. First, we found a sex difference in extracellular LS glutamate/GABA ratio (lower in females) that was eliminated by V1aR antagonist infusion in the LS that caused an increase in glutamate release in females only. Second, infusion of the glutamate receptor agonist L-glutamic acid into the LS mimicked the V1aR antagonist-induced decrease in female social play while preventing the increase in male social play. Third, infusion of the glutamate receptor antagonists AP-5 and CNQX into the LS prevented the V1aR antagonist-induced decrease in female social play. Fourth, there were no sex differences in extracellular GABA release in the LS upon either V1aR antagonist infusion or in social play expression upon infusion of the GABA-A receptor agonist muscimol into the LS, suggesting that GABA is not involved in the sex-specific regulation of social play by the LS-AVP system. Last, we found no sex differences in the type (GAD1/2, somatostatin, calbindin 1, Sox9) of V1aR-expressing LS cells, suggesting other cellular mechanisms mediating the sex-specific effects on glutamate release in the LS by the LS-AVP system. In conclusion, we demonstrate that the LS-AVP system regulates social play sex-specifically via glutamatergic neurotransmission. These findings have relevance for potential sex-specific effects of AVP-based treatment of social deficits in children.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}