Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology最新文献

{"title":"Cannabidiol mitigates alcohol dependence and withdrawal with neuroprotective effects in the basolateral amygdala and striatum.","authors":"Selen Dirik, Michelle R Doyle, Courtney P Wood, Paola Campo, Angelica R Martinez, McKenzie Fannon, Maria G Balaguer, Spencer Seely, Bryan A Montoya, Gregory M R Cook, Gabrielle M Palermo, Junjie Lin, Madelyn D Sist, Parsa K Naghshineh, Zihang Lan, Sara R M U Rahman, Raymond Suhandynata, Paul Schweitzer, Marsida Kallupi, Giordano de Guglielmo","doi":"10.1038/s41386-025-02164-6","DOIUrl":"https://doi.org/10.1038/s41386-025-02164-6","url":null,"abstract":"<p><p>Alcohol use disorder (AUD) remains a pervasive public health issue with limited effective treatments. Cannabidiol (CBD), a non-psychotropic constituent of cannabis, shows promise in modulating addictive behaviors. This study investigated the effects of chronic CBD administration on alcohol dependence, withdrawal symptoms, and neurodegeneration using two complementary rodent models: chronic intermittent ethanol (CIE) exposure, which models established alcohol dependence, and ethanol vapor self-administration (EVSA), which captures the volitional aspects of alcohol intake. In the CIE model, CBD reduced alcohol self-administration during acute withdrawal without affecting alcohol metabolism or locomotor activity. CBD decreased motivation for alcohol, somatic withdrawal signs, withdrawal-induced anxiety-like behaviors, and mechanical sensitivity. During extinction, CBD attenuated alcohol-seeking behavior and stress-induced reinstatement. Electrophysiological recordings revealed that CBD reversed alcohol-induced decreases in neuronal excitability in the basolateral amygdala, suggesting a mechanism involving normalization of neural function. In the EVSA model, CBD reduced voluntary alcohol intake during the escalation phase, impacting voluntary alcohol intake. This effect was specific to alcohol-related behaviors, as it did not affect saccharin self-administration. Immunohistochemical analyses showed that CBD prevented alcohol-induced neurodegeneration in the nucleus accumbens shell and dorsomedial striatum, regions implicated in the volitional control of alcohol consumption. These findings indicate that chronic CBD administration attenuates both behavioral and neurobiological facets of alcohol dependence by modulating neuronal excitability and preventing neurodegeneration, supporting its therapeutic potential for AUD and providing mechanistic insights for future research.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"M⁶A RNA epitranscriptome dynamics linked to major depressive disorder and suicide risk.","authors":"Bhaskar Roy, Yogesh Dwivedi","doi":"10.1038/s41386-025-02165-5","DOIUrl":"https://doi.org/10.1038/s41386-025-02165-5","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is the most prevalent psychiatric disorder. MDD patients are at substantially increased risk of dying by suicide. The molecular mechanisms associated with MDD and associated suicide are not clearly understood, which impedes the development of novel therapeutics. N6-methyladenosine (m6A) is the most prevalent epitranscriptomic mark on mRNA and plays significant roles in various physiological processes. This study investigated m6A RNA methylation and its potential contributions to MDD pathogenesis and associated suicide risk. High-throughput microarray analysis in the dorsolateral prefrontal cortex (dlPFC) of MDD subjects (n = 49) and non-psychiatric controls (n = 49) identified 1290 significantly hypermethylated and 6842 hypomethylated transcripts, with most m6A sites enriched in coding sequences. Chromosome-wide analysis showed hypermethylation hotspots on chromosomes 1 and 19. In-silico analysis identified enriched AAGA and ACCCA m6A motifs in the MDD group. Expression analysis revealed reduced FTO demethylase and increased METTL3 methyltransferase levels. A majority of M6A hypermethylated genes showed inverse correlation with their expression levels. Functional enrichment of hypermethylated genes highlighted disruptions in molecular pathways relevant to MDD. Comparison of MDD-non-suicide (n = 32) and MDD-suicide (n = 17) identified 6750 transcripts with significant hypermethylation, whereas 6159 transcripts had significant hypomethylation in the MDD-suicide group; of them, 196 hypermethylated genes were explicitly associated with suicide in the MDD group, whereas 38 hypermethylated genes appeared to elevate suicide risk in MDD patients. Also, the MDD-suicide group had distinct neuromolecular pathways associated with these risk genes. Collectively, the findings suggest a critical role for m6A methylation in modulating the molecular networks underlying MDD and suicide susceptibility.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A biological blind spot in addiction research: hormonal contraceptives and adolescent reward seeking.","authors":"Laurel R Seemiller, Nicole A Crowley","doi":"10.1038/s41386-025-02172-6","DOIUrl":"https://doi.org/10.1038/s41386-025-02172-6","url":null,"abstract":"","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia as critical mediators linking perinatal immune stress to mental health trajectories.","authors":"Ravikiran M Raju, Caroline J Smith","doi":"10.1038/s41386-025-02162-8","DOIUrl":"https://doi.org/10.1038/s41386-025-02162-8","url":null,"abstract":"<p><p>Neurodevelopmental and neuropsychiatric disorders that emerge in childhood (such as autism) and adolescence (such as depression and schizophrenia) currently lack broadly effective therapies, underlying an urgent need to better understand their etiology. While each disorder has its own set of complex genetic and environmental risk factors, perinatal exposure to intense immune activation and/or stress has been linked to increased disease risk. Microglia, the resident immune cells of the brain, are impacted in each disorder and exquisitely sensitive to early life experience. Here, we review the literature suggesting microglia-specific changes in response to early life immune activation and/or stress with an emphasis on microglial interactions with neural synapses and circuits. We also review the existing literature linking these findings to microglia-specific changes in the brain in autism, depression, and schizophrenia. Our goal is to bridge the gap between developmental insults and the subsequent pathogenesis of these disorders, highlighting key areas for future mechanistic work.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"nNOS-expressing neurons in the mPFC mediate depression-related behaviors in mice through pPVT-mPFC projections.","authors":"Hai-Ying Liang, Zhi-Bin Zhao, Zhen Liu, James Samsom, Kai-Hong Chen, Ying Chen, Li-Ling Chen, Cheng-Yun Cai, Fang Liu","doi":"10.1038/s41386-025-02163-7","DOIUrl":"https://doi.org/10.1038/s41386-025-02163-7","url":null,"abstract":"<p><p>Depression is one of the most common mental disorders, but its etiology remains poorly understood. Neuronal nitric oxide synthase (nNOS) has been implicated in depression, but the role of nNOS-expressing neurons is still unknown. We used chemogenetic strategies to show that nNOS-expressing neurons in the medial prefrontal cortex (mPFC) are essential for depression-related behaviors. Using electrophysiology, we determined that mPFC nNOS-expressing neurons receive projections from the posterior subregion of the paraventricular thalamic nucleus (pPVT). We show that excitatory projections from the pPVT onto mPFC nNOS-expressing neurons regulate depression-related behaviors. We further explore a mechanism in which activation of mPFC nNOS-expressing neurons leads to the subsequent release of nitric oxide (NO), which enhances the nitrosylation of cyclin-dependent kinase 5 (CDK5). Our data suggest a mechanism for depression involving excitatory pPVT projections onto nNOS-expressing neurons in the mPFC that represents a potential target for future treatments.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental sterol biosynthesis inhibition: are prescription medications as safe as we think?","authors":"Zeljka Korade, Karoly Mirnics","doi":"10.1038/s41386-025-02171-7","DOIUrl":"https://doi.org/10.1038/s41386-025-02171-7","url":null,"abstract":"","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct subpopulations of parvalbumin neurons participating in divergent prefrontal functions.","authors":"Yehong Hu, Xinyang Zhang, Tsz Hei Fong, Tianyu Wang, Jin Zhang, Yujie Zhang, Qiang Zhou","doi":"10.1038/s41386-025-02159-3","DOIUrl":"https://doi.org/10.1038/s41386-025-02159-3","url":null,"abstract":"<p><p>Prefrontal parvalbumin (PV) neurons play crucial roles in various distinct functions, while malfunction of PV-neurons also has critical contributions to various brain diseases, including both psychiatric and neurodegenerative disorders. However, whether the prefrontal cortex (PFC) PV-neurons participating in these functions and malfunctions are distinct subpopulations is not well understood. This question is important for a better understanding of both the basic properties/function of PV-neurons and inhibitory neurons in general, and for potential comorbid occurrence of dysfunctions in disease settings. Here, we analyzed dorsomedial prefrontal cortex (dmPFC) PV-neurons participating in working memory, modulation of conditioned fear memory, and anxiety, regarding their relative localization, electrophysiological properties, and synaptic inputs. In addition, by using activity-dependent tagging method, we examined whether manipulating the dmPFC PV-neurons participating in one function may affect another function as a way to test for potential functional interactions between them. We found that: (1) one single group of dmPFC PV-neurons participating in the two forms of modulation of conditioned fear memory, based on their high overlap in localization and mutual functional interactions with each other. (2) dmPFC PV-neurons participating in fear memory modulation and anxiety are two different subpopulations, with unique electrophysiological properties. (3) dmPFC PV-neurons participating in working memory and fear memory modulation are two different subpopulations, with different synaptic and neuronal properties. These findings provide important insights into the organization of PV-neurons in the PFC and highlight the distinct and non-interacting nature of different PV-subpopulations in the PFC functional diversity.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cocaine self-administration in adult female and male rhesus monkeys: longitudinal comparison with adolescent behavior and role of early life stress.","authors":"Mia I Allen, Erin R Siebert, Alison G P Wakeford, Kendra Jenkins, Jessica Khan, Leonard L Howell, Mar M Sanchez, Michael A Nader","doi":"10.1038/s41386-025-02161-9","DOIUrl":"https://doi.org/10.1038/s41386-025-02161-9","url":null,"abstract":"<p><p>A phenomenon involving cocaine use disorders is the \"incubation of drug craving\" - the drive for the drug increases the longer the abstinence period. The present longitudinal study provided a unique opportunity to test whether an increase in the reinforcing effects of cocaine developed after prolonged abstinence and if early life stress was a risk factor. Fourteen (N = 6 female, 8 male) adult rhesus monkeys, some (N = 7) that were maltreated as infants by their mothers (MALT), had previously self-administered cocaine under a fixed-ratio (FR) schedule of reinforcement as adolescents, but had not been studied for >3 years. In Experiment 1, cocaine self-administration dose-response curves were redetermined in adulthood when responding was maintained under the identical FR 20 schedule used during adolescence. In Experiment 2, the reinforcing strength of cocaine was evaluated (n = 12) under a progressive-ratio (PR) schedule of reinforcement. While there were no statistical differences between male and female monkeys on FR responding in adolescents, when redetermined as adults, MALT monkeys showed higher peak response rates relative to adolescence. No such differences were noted in Control monkeys. Under the PR schedule, peak reinforcing strength was not different between groups or sexes. However, higher total adolescent cocaine intake was significantly associated with higher cocaine breakpoints in adulthood. These findings show that after adolescent cocaine self-administration and a long abstinence period, sensitivity to cocaine reinforcement increased, particularly in monkeys who experienced early life stress. Although early life stress (MALT) did not significantly impact measures of cocaine's reinforcing strength, higher adolescent cocaine intake did.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of early social isolation on social circuits and behavior: relevance to schizophrenia.","authors":"Ayako Kawatake-Kuno, Michael B Leventhal, Hirofumi Morishita","doi":"10.1038/s41386-025-02156-6","DOIUrl":"https://doi.org/10.1038/s41386-025-02156-6","url":null,"abstract":"<p><p>Social deficits are a core feature of many psychiatric disorders. Importantly, aberrant social experiences during childhood and adolescence profoundly influence maturation of the brain function and induce social impairments in adulthood. Social isolation, especially among youth, has been highlighted as a serious risk to mental health. As a result, understanding the consequences of social isolation on a mechanistic level has become increasingly urgent. Recent rodent studies have revealed that social isolation during development induces widespread changes in adult brain structures, particularly in the prefrontal cortical circuits, and causes altered social behavior. These findings led us to develop two models proposing that social isolation may cause deficits through either concurrent (social deprivation model) or subsequent (developmental mismatch model) to social disruption. Building on these two models, this review examines how these models provide complementary perspectives on the influence of social isolation on the progression of schizophrenia, from the prodromal to the psychotic phase, a condition in which genetic and environmental risk factors are closely linked to social isolation. Advancing our understanding of treatment timing and targets for isolation-induced social deficits through the lenses of these models may help identify the optimal developmental timing for effective interventions and prevention strategies for schizophrenia.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"To indulge or enrich: how environmental enrichment affects neurons that promote food seeking.","authors":"Pelle Wilbers, Michel C van den Oever","doi":"10.1038/s41386-025-02166-4","DOIUrl":"https://doi.org/10.1038/s41386-025-02166-4","url":null,"abstract":"","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}