Psychopharmacology最新文献

{"title":"A Mechanistic study assessing difficulty discontinuing chronic hypnotic use.","authors":"Timothy Roehrs, Gail Koshorek, Mohammad Sibai, Aisha Tabor, Luisa Bazan, Thomas Roth","doi":"10.1007/s00213-025-06799-7","DOIUrl":"10.1007/s00213-025-06799-7","url":null,"abstract":"<p><strong>Rationale: </strong>The abuse liability of chronic hypnotic use remains a clinical concern.</p><p><strong>Objectives: </strong>This study assessed 1) whether there would be greater difficulty discontinuing chronic hypnotic use for people with insomnia and hyperarousal vs those with insomnia but without hyperarousal and 2) whether those seeking to discontinue chronic hypnotic use of the receptor non-specific hypnotic eszopiclone would have more difficulty than those discontinuing the receptor specific zolpidem XR.</p><p><strong>Methods: </strong>DSM-V diagnosed insomnia participants, aged 23-61 yrs, (n = 41, 36 females), with no other sleep disorders, unstable medical or psychiatric diseases or drug dependency completed the trial. Following a screening nocturnal polysomnogram (NPSG) participants were randomized to zolpidem XR (12.5 mg), eszopiclone (3 mg), or placebo nightly for 6 months. After 6 months nightly use, over a 2-week discontinuation, they were instructed to discontinue their hypnotic use, but, if necessary, to self-administer before sleep either 1, 2, or 3 capsules, each packaged separately in envelopes labeled 1, 2, and 3, containing their assigned \"blinded\" medication or placebo.</p><p><strong>Results: </strong>Over the 14 nights 21 participants took zero (51%) capsules and among the 20 taking capsules the median total number chosen was 3. Those people with insomnia and hyperarousal vs those with insomnia but not hyperarousal had more difficulty discontinuing chronic hypnotic use (aim 1) as did those using eszopiclone vs zolpidem or placebo (aim 2).</p><p><strong>Conclusions: </strong>Most subjects discontinued hypnotic use and among the few continuing to use their use declined from week one to week two of the discontinuation period.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2303-2311"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depression of intracranial self-stimulation in male and female rats by intraperitoneal lactic acid: effects of morphine, ketoprofen, and interactions with G-protein biased kappa opioid agonists.","authors":"Thomas J Martin, Conner W Martin, Kevin J Frankowski, Bruce E Blough, Jeffrey Aubé, Laura M Bohn, Sara R Jones","doi":"10.1007/s00213-025-06800-3","DOIUrl":"10.1007/s00213-025-06800-3","url":null,"abstract":"<p><strong>Introduction: </strong>Numerous pharmacological classes of compounds have been explored as novel and efficacious alternatives to standard mu opioid agonist analgesics. We and others have described G-protein biased kappa opioid agonists as having potential utility as analgesics due to a lower propensity to produce sedation and dysphoria, which are thought to be mediated in large part through beta-arrestin signaling.</p><p><strong>Methods: </strong>Here we compare two G-protein biased kappa agonists that differ in their basic chemical scaffold, triazole 1.1 (Tr1.1) and isoquinolinone 2.1 (Iso2.1), for alteration of intracranial self-stimulation (ICSS) in male and female rats. Lactic acid (LA) was given i.p. at a concentration sufficient to produce moderate to severe depression of ICSS.</p><p><strong>Results: </strong>Neither Tr1.1 nor Iso2.2 reversed the effects of lactic acid at concentrations that produced significant depression of ICSS in either sex. Neither drug altered ICSS in the absence of lactic acid administration. In both males and females, morphine reversed the effects of i.p. lactic acid on ICSS and co-administration of Tr1.1 did not alter the dose-effect curve for morphine in either sex. Similar effects were observed for ketoprofen. Ketoprofen also reversed the effects of i.p. lactic acid on ICSS in both sexes in a dose-dependent manner, and co-administration of neither Tr1.1 nor Iso2.1 altered the ketoprofen dose-effect curve.</p><p><strong>Conclusions: </strong>These data suggest that these G-protein biased kappa agonists may lack sufficient efficacy or potency to alter the effects of opioids or NSAIDs against moderate to severe antinociceptive stimuli in rats, and development of more potent or efficacious compounds may be required to demonstrate efficacy in rat models of moderate to severe nociception.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2313-2325"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxiracetam ameliorates neurological function after traumatic brain injury through competing endogenous RNA regulatory network.","authors":"Liyi Wang, Han Guo, Weidong Zhao, Jiahao Wang, Xuhua Cao","doi":"10.1007/s00213-025-06797-9","DOIUrl":"10.1007/s00213-025-06797-9","url":null,"abstract":"<p><strong>Rationale: </strong>Oxiracetam (ORC) has been demonstrated to improve neurological function resulting from traumatic brain injury (TBI).</p><p><strong>Objectives: </strong>This study aims to explore the precise molecular mechanism of ORC in the treatment of TBI.</p><p><strong>Methods: </strong>TBI rat model was established and treated with ORC. Modified Garcia score, rotarod test and HE staining were employed to evaluate the neuroprotective effects of ORC. Subsequently, RNA-seq was conducted on the hippocampus of sham, TBI and ORC rats to identify differential expression (DE) lncRNAs and mRNAs. Functional analysis of DE lncRNAs and mRNAs was performed. The real-time quantitative polymerase chain reaction (qRT-PCR) was used to determine the expression of DE lncRNAs and DE mRNAs. Western blot was performed to explore important pathway in ceRNA networks.</p><p><strong>Results: </strong>ORC has been demonstrated to effectively improve neurological function in TBI rats. A total of 10 ORC-treated DE lncRNAs and 61 DE mRNAs were obtained. A co-expression network comprising 79 lncRNA-mRNA pairs associated with the treatment of ORC was constructed. Furthermore, an lncRNA-miRNA-mRNA regulated ceRNA network was constructed, comprising 15 mRNAs, 41 miRNAs and 10 lncRNAs. Functional enrichment, qRT-PCR, and Western blot analysis showed that ORC improve neurological function of TBI rats by regulating multiple signaling pathways, including the JAK-STAT/PI3K-Akt pathway, as well as affecting the expression of key genes Prlr, Cdkn1a, and Cldn1.</p><p><strong>Conclusion: </strong>Our study reveals the mechanism of ORC therapy in TBI rats, which mainly relies on the regulation of the JAK-STAT/PI3K-Akt pathway and the influence on the expression of key genes Prlr, Cdkn1a, and Cldn1.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2275-2291"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senegenin ameliorates diabetic encephalopathy via promoting mitophagy and repressing NLRP3 inflammasome activation.","authors":"Xiao-Dan Yan, Yu Yang, Wan-Ting Zhang, Qing-Quan Kong, Xi-Tong Zheng, Lin-Sen Li, Qing Yu","doi":"10.1007/s00213-025-06796-w","DOIUrl":"10.1007/s00213-025-06796-w","url":null,"abstract":"<p><strong>Rationale: </strong>Diabetic encephalopathy (DE) remains a severe complication of diabetes in central nervous system with limited effective therapy.</p><p><strong>Objectives: </strong>This study investigated the beneficial effect of senegenin on DE and its possible mechanisms.</p><p><strong>Methods: </strong>Type 2 diabetes mellitus mouse model and high-glucose (HG)-stimulated PC-12 cells were used as the in vivo and in vitro DE models. Learning and memory ability was evaluated by MWM test. Pathological changes in the brain tissues were determined by HE staining. Cell viability was detected by CCK-8. Mitochondrial membrane potential was measured by JC-1 probe. Target protein levels were assessed by Western blotting. Nucleotide-binding domain-like receptor protein 3 (NLRP3) expression was observed by immunofluorescent staining.</p><p><strong>Results: </strong>Cognitive impairment and obvious pathological changes were found in DE mice, which were effectively attenuated by senegenin treatment. In addition, senegenin induced mitophagy and maintained homeostasis of mitochondrial dynamics to relieve mitochondrial dysfunction. Moreover, NLRP3 inflammation activation induced by DE was inhibited by senegenin. Finally, inhibition of mitophagy counteracted senegenin-mediated inactivation of NLRP3 inflammation and neuroprotection.</p><p><strong>Conclusions: </strong>Senegenin relieved diabetic encephalopathy via inducing mitophagy to inactivate NLRP3 inflammasome. Senegenin might be an effective therapy for treating DE.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2261-2274"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct subcircuits within the mesolimbic dopamine system encode the salience and valence of social stimuli.","authors":"Erica A Cross, Johnathan M Borland, Emma K Shaughnessy, Susan D Lee, Vivian Vu, Elizabeth A Sambor, Robert L Meisel, Kim L Huhman, H Elliott Albers","doi":"10.1007/s00213-025-06793-z","DOIUrl":"10.1007/s00213-025-06793-z","url":null,"abstract":"<p><strong>Rationale: </strong>The mesolimbic dopamine (DA) system (MDS) is the canonical \"reward\" pathway that has been studied extensively in the context of the rewarding properties of food and drugs of abuse. In contrast, little is known about the role of the MDS in the processing of the rewarding and aversive properties of social stimuli.</p><p><strong>Objective: </strong>Social interactions can be characterized by their salience (i.e., importance) and their rewarding or aversive properties (i.e., valence). Here, we test the novel hypothesis that projections from the medial ventral tegmental area (VTA) to the nucleus accumbens (NAc) core code the salience of social stimuli through phasic release of DA in response to rewarding and aversive social stimuli. In contrast, lateral VTA (lVTA) projections to the NAc shell are proposed to encode social valence, with increased tonic DA signaling rewarding interactions and decreased tonic DA signaling aversive ones.</p><p><strong>Methods: </strong>Using DA amperometry, which monitors DA signaling with a high degree of temporal and anatomical resolution, we measured DA release in the NAc core or shell during rewarding and aversive social interactions. Anatomical and functional studies were conducted utilizing retrograde tracing and immunohistochemistry.</p><p><strong>Results: </strong>These studies support the hypothesis that distinct MDS subcircuits (i.e., mVTA to NAc core and lVTA to NAc shell) signal the salience and valence, respectively, of social stimuli.</p><p><strong>Conclusion: </strong>Together, these data provide a novel conceptualization of how functional and anatomical heterogeneity within the MDS detect and distinguish between social salience, social reward, and social aversion.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2219-2232"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive flexibility of male rats is increased by augmented punishment in a reversal learning task but ketamine has no detectable long-term effects.","authors":"Anthony N Nist, Stephen J Walsh, Timothy A Shahan","doi":"10.1007/s00213-025-06794-y","DOIUrl":"10.1007/s00213-025-06794-y","url":null,"abstract":"<p><strong>Rationale: </strong>The probabilistic reversal learning task (PRL) is sometimes used in the context of major depressive disorder (MDD) to assess impairments in cognitive flexibility and feedback sensitivity because behavior in the task is sensitive to pharmacological interventions. Because traditional antidepressants are limited in their effectiveness, new drugs are needed to combat MDD. Ketamine has recently been investigated in the context of probabilistic reversal learning (PRL), but findings regarding its therapeutic efficacy have been mixed. One reason for this could be that almost all non-human versions of the PRL use signaled reward omission (i.e., timeout) as the punishing stimulus. It has long been known that timeout periods do not always function as punishers, and the inclusion of a known effective punishing stimulus could help to produce results of improved translational value.</p><p><strong>Objective: </strong>The present experiment sought to examine the effects of ketamine in the PRL when electric footshocks accompanied timeout periods or not.</p><p><strong>Methods: </strong>A baseline of PRL performance was established with 40 rats in which typical timeouts followed non-rewarded trials. In Phase 2, half the rats also received probabilistic footshock punishment for non-rewarded trials, while the other half continued under baseline conditions. Finally, a single dose of ketamine was administered to half of the rats (n = 10) in each condition (i.e., shock and no shock).</p><p><strong>Results: </strong>Shock punishment increased behavioral persistence and cognitive flexibility in the PRL, but ketamine had no effect beyond causing acute impairments.</p><p><strong>Conclusion: </strong>These results suggest that the conditions of punishment during the PRL can have a significant impact on performance in the task and corroborate previous findings that ketamine may not impact cognitive flexibility or reward processing in healthy rats.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2233-2248"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic administration of methocinnamox, a mu-opioid receptor antagonist, reduces hedonic response without impacting motivation in mice.","authors":"Misbah Sheikh, Emily Cambre, Cory Langreck, Jonathan A Javitch, Sarah E Canetta","doi":"10.1007/s00213-025-06801-2","DOIUrl":"10.1007/s00213-025-06801-2","url":null,"abstract":"<p><strong>Rationale: </strong>Genetic and pharmacological studies suggest that signaling through the mu opioid receptor (MOR) is essential for motivation to seek, and hedonic response to, both drugs of abuse as well as natural rewards. Given that impairments in hedonic reactivity and motivation are key behavioral features of depression, we wondered whether sustained deficits in endogenous opioid signaling in adulthood could produce these 'depression-related' behavioral phenotypes.</p><p><strong>Objectives: </strong>To investigate the effect of chronic MOR blockade in adulthood on motivation and hedonic response to a food reward, as well as whether these behavioral variables are correlated at the individual animal level.</p><p><strong>Methods: </strong>We chronically administered the pseudo-irreversible MOR antagonist methocinnamox (MCAM) for three weeks prior to assessing motivation and hedonic reactivity for a food reward in the progressive ratio and lickometer tasks, respectively. We then assessed whether motivation and hedonic response to reward were correlated at the individual animal level.</p><p><strong>Results: </strong>Chronic administration of MCAM decreased hedonic response, while leaving goal-directed motivation intact. In addition, there was a weak negative correlation between motivation and hedonic response in individual mice treated with chronic MCAM, but not control mice.</p><p><strong>Conclusions: </strong>Chronic blockade of the MOR decreases hedonic response, without impacting motivation to work for the same reward. Although the different components of reward processing such as motivation and hedonic response may be related, they appear to be dissociable.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2327-2339"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting synaptic plasticity and acetylcholine dysregulation in the medial prefrontal cortex: Rosmarinic acid attenuates Autism-like phenotypes in Shank3B^-/- mice via the CREB/BDNF pathway.","authors":"Jiahui Shi, Mei Chen, Yushu Zhang, Xiaotang Fan, Lian Wang, Huiling Liao","doi":"10.1007/s00213-025-06877-w","DOIUrl":"https://doi.org/10.1007/s00213-025-06877-w","url":null,"abstract":"<p><strong>Rationale: </strong>Autism spectrum disorder (ASD) is characterized by cognitive deficits, repetitive behaviors, and social impairments. The SH3 and multiple ankyrin repeat domains protein 3B-deficient (Shank3B^-/-) mouse model displays ASD-related phenotypes. While rosmarinic acid (RosA) is known for its neuroprotective properties, its role in ASD remains unclear.</p><p><strong>Objective: </strong>This study aimed to investigate the therapeutic effects and potential molecular mechanisms of RosA in alleviating behavioral dysfunction in Shank3B^-/- mice. We assessed core ASD-like behavioral indices, performed bioinformatics predictions, and validated the results through molecular biology experiments.</p><p><strong>Methods: </strong>Social deficits were evaluated using the three-chamber social test and the male-male social interaction test. Repetitive behaviors were assessed through the self-grooming and marble-burying tests. Cognitive and memory functions were measured using novel object recognition, the Y-maze, and nesting behavior tests. The open field test was employed to evaluate motor functions and exploratory activities. High-throughput RNA sequencing (RNA-seq) was used to identify key genes in the medial prefrontal cortex (mPFC) of the different groups of mice. Neurotransmitter levels of acetylcholine (ACh) and γ-aminobutyric acid (GABA) were analyzed via ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and high-performance liquid chromatography (HPLC), respectively. Additionally, synaptic function and plasticity in the mPFC were assessed by measuring Postsynaptic Density Protein 95 (PSD95) expression and the activation of the p-CREB/BDNF signaling pathway.</p><p><strong>Results: </strong>RosA significantly improved repetitive behaviors, as well as cognitive and memory abilities, in Shank3B^-/- mice. It also enhanced motor functions and exploratory activities. However, RosA did not show significant therapeutic effects on social deficits. RNA-seq analysis revealed that RosA notably regulated synaptic proteins. Molecular biology experiments indicated that RosA upregulated PSD95 expression and activated the p-CREB/BDNF signaling pathway in the mPFC, enhancing synaptic plasticity. RosA also increased ACh levels without affecting GABA, indicating a cholinergic mechanism. No significant effects were observed in wild-type (WT) mice, suggesting specificity to ASD-related deficits.</p><p><strong>Conclusion: </strong>RosA alleviates cognitive deficits and repetitive behaviors in Shank3B^-/- mice through CREB/BDNF-mediated synaptic and cholinergic regulation in the mPFC. However, its lack of effect on social deficits suggests distinct mechanisms underlying ASD symptoms. These findings highlight the potential of RosA as a targeted ASD therapy.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of MMP8 inhibitors on chronic unpredictable mild stress-induced neuroinflammation and depressive-like behavior：exploring the underlying molecular mechanisms.","authors":"Yan Ren, Weikang Chen, Jinhui Wang, Shasha Wu, Ting Linghu, Jinyin Ge, Ruiping Zhang","doi":"10.1007/s00213-025-06898-5","DOIUrl":"https://doi.org/10.1007/s00213-025-06898-5","url":null,"abstract":"<p><strong>Objective: </strong>Studies have demonstrated a close association between alterations in the immune system and major depressive disorder (MDD), with MDD potentially inducing neuroinflammation, hippocampal atrophy, and depression-like behaviors. Matrix metalloproteinase-8 (MMP8) contributes to the onset of depression, but it has not been studier yet. This study aims to investigate the mechanistic role of the MMP8 inhibitor (M8I) in alleviating depression induced by chronic unpredictable mild stress (CUMS) in rats. The objectives include evaluating the ameliorative effects of M8I on CUMS-induced depression-like behaviors and exploring its impacts on the TNF-α/TNFR1/NF-κB signaling pathway, NLRP3 inflammasome activation, expression levels of GFAP and IBA-1, oxidative stress pathways, apoptosis, regulation other neurotransmitters, and acetylcholinesterase(AChE) expression.</p><p><strong>Methods: </strong>The CUMS model was employed to induce depressive-like behaviors in rats, followed by a one-week treatment with M8I. Behavioral tests were performed to assess depressive-like behaviors. Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, immunohistochemistry, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and near-infrared II (NIR-II) imaging were utilized to evaluate the expression levels of proteins involved in the TNF-α/TNFR1/NF-κB signaling pathway, NLRP3 inflammasome, GFAP and IBA-1 expression in astrocytes and microglia, oxidative stress markers (SOD, GSH, PI3K/AKT), apoptosis-related proteins (Bax, Bcl-2), as well as brain neurotransmitters regulation and AChE activity.</p><p><strong>Results: </strong>CUMS induced depressive-like behaviors in rats, upregulated the expression of TNF-α and its associated proteins (TNFR1, NF-κB), NLRP3 inflammasome-related proteins (p-P38, caspase-1), GFAP, and IBA-1 in the hippocampal tissue, and downregulated the expression of SOD, GSH, and PI3K/AKT. Additionally, it disrupted the balance of apoptosis-related proteins (Bax, Bcl-2), brain neurotransmitters regulation, and AChE activity. Treatment with M8I reversed these alterations; however, certain neurotransmitters, such as norepinephrine and dopamine, did not fully return to normal levels.</p><p><strong>Conclusion: </strong>M8I effectively alleviates CUMS-induced depressive-like behaviors by modulating the TNF-α/TNFR1/NF-κB signaling pathway, inhibiting the NLRP3 inflammasome activation, and suppressing astrocytes and microglia activation, thereby attenuating inflammatory responses, oxidative stress pathways, and apoptosis-related processes. These findings provide novel insights into M8I as a potential therapeutic strategy for depression and futher elucidate the molecular mechanisms underlying its anti-inflammatory effects.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetylcholine nicotinic receptors play a central role in the modulation of rewarding behaviors by interacting with dopamine transmission: evidence from male rat sexual behavior.","authors":"Ana Evelia Hernández-Colín, Ana Canseco-Alba, Gabriela Rodríguez-Manzo","doi":"10.1007/s00213-025-06903-x","DOIUrl":"https://doi.org/10.1007/s00213-025-06903-x","url":null,"abstract":"<p><strong>Rationale: </strong>Nicotinic acetylcholine receptors (nACh) are involved in the regulation of dopamine (DA) transmission at the mesolimbic (MSL) system, which regulates naturally rewarding behaviors like sexual behavior. Acetylcholine (ACh) and DA maintain a balance in the MSL system, which alteration impacts motivated behaviors. Copulation to satiety produces a sustained activation of the MSL system that triggers the instatement of a long-lasting sexual inhibitory period associated with a decreased sexual motivation.</p><p><strong>Objective: </strong>To determine if ACh contributes to the establishment and maintenance of the sexual inhibitory period of sexually satiated male rats through the activation of nAChRs.</p><p><strong>Methods: </strong>Animals copulated to satiety in the presence of different doses of the nAChR antagonist mecamylamine (MEC), systemically administered, to determine nAChR involvement in the establishment of the sexual inhibitory state. The effect of different MEC doses on satiated rats was investigated to determine the role of nAChRs in maintaining the sexual inhibitory state. Combined treatments of MEC with a DA receptor agonist or antagonist were used to determine the possible interaction between DA and ACh.</p><p><strong>Results: </strong>nAChRs blockade during copulation to satiety interfered with the emergence of the sexual inhibitory state. In sexually satiated rats, nAChR antagonism reversed the sexual inhibition, an effect that was cancelled by a DA receptor antagonist.</p><p><strong>Conclusions: </strong>ACh is released during copulation to satiety and contributes to the instatement and maintenance of the sexual inhibitory state of sexually satiated rats through the activation of nAChR. DA is involved in the MEC-induced reversal of sexual satiety.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}