Journal of Psychopharmacology最新文献

{"title":"Nucleus accumbens serotonin 1A receptor expression is altered by female reproduction and regulates postpartum affective and caregiving behaviors.","authors":"Erika M Vitale, Emma G Ford, Margaret S Ahern, Joseph S Lonstein","doi":"10.1177/02698811251340909","DOIUrl":"10.1177/02698811251340909","url":null,"abstract":"<p><strong>Background: </strong>Motherhood is often characterized by a positive affective state and high motivation to interact with potentially rewarding offspring. However, many mothers suffer from postpartum mental health issues that can degrade their maternal motivation and caregiving abilities. Serotonin-modulating drugs are commonly used to treat distressed mothers, but how serotonin (5-HT) in brain sites underlying motivation influences postpartum behaviors is mostly unknown.</p><p><strong>Aims: </strong>Because 5-HT in the nucleus accumbens (NAcs) regulates dopamine release, we hypothesized that the NAc is a critical site where serotonin signaling influences postpartum affective and caregiving behaviors.</p><p><strong>Methods: </strong>We used RT-qPCR and autoradiographic binding to determine changes in NAc 5-HT1A, 5-HT2A, and 5-HT2C receptor expression across pregnancy and postpartum; shRNA-mediated knockdown of NAc 5-HT1A receptors to determine its effects on postpartum behavior; and repeated pregnancy stress to determine its effects on both NAc 5-HT1A and postpartum behavior.</p><p><strong>Results: </strong>Recently parturient rats had higher 5-HT1A (but not 5-HT2A or 5-HT2C) receptor mRNA and 5-HT1A binding in the NAc shell (NAcSh) compared with nulliparae. 5-HT1A knockdown in the maternal NAcSh to prevent this normative increase in receptor expression resulted in high anxiety-like behavior, more off-nest behaviors, and delayed pup retrieval. 5-HT1A knockdown also reduced NAcSh tyrosine hydroxylase. Pregnancy stress reduced postpartum NAcSh 5-HT1A receptor binding at some rostrocaudal levels, as well as disrupted the display of caregiving behaviors.</p><p><strong>Conclusions: </strong>These results provide new insights into how 5-HT signaling in the NAcSh contributes to postpartum affective and caregiving behaviors and offer a mechanism through which serotonin-based pharmacotherapies may help improve maternal caregiving motivation in anxious, depressed, or chronically stressed mothers.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"855-869"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326029","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":"Acute effects of 150 mg caffeine on subjective, physiological, and behavioral components of anxiety in panic disorder and healthy controls - A randomized placebo-controlled crossover trial.","authors":"Johanna M Hoppe, Johannes Björkstrand, Johan Vegelius, Lisa Klevebrant, Malin Gingnell, Andreas Frick","doi":"10.1177/02698811251344692","DOIUrl":"10.1177/02698811251344692","url":null,"abstract":"<p><strong>Background: </strong>Caffeine in doses above 400 mg, approximately four cups of coffee, induces panic attacks in 50% of individuals with panic disorder (PD) and elevates anxiety, but it is not known how individuals with PD respond to normally consumed doses or how caffeine interacts with emotional tasks.</p><p><strong>Aims: </strong>We hypothesized that 150 mg caffeine would increase subjective anxiety (primary outcome) as well as interoceptive attention and anxiety from bodily signals in patients with PD, and more so than in healthy controls (HCs). Additional analyses targeted panic attacks, emotional reactivity, avoidance behavior, and subjective exteroceptive attention.</p><p><strong>Methods: </strong>Twenty-nine patients with PD and 53 HC with low habitual caffeine consumption (⩽300 mg/week) abstained from caffeine 36 h before receiving 150 mg caffeine or placebo in a double-blind randomized crossover design 2-14 days apart.</p><p><strong>Results: </strong>Contrary to our hypotheses, caffeine did not increase subjective anxiety, interoceptive attention, or anxiety from interoceptive signals. Only one panic attack was noted, in the PD group after caffeine intake during the emotional reactivity task. In both PD and HC, caffeine increased skin conductance responses to neutral and emotional faces, augmented costly avoidance behavior, and impaired exteroceptive attention. These results indicate that low caffeine doses do not have differential anxiogenic effects in patients with PD and HC at rest, and that they increase arousal and avoidance behavior in both PD and healthy individuals.</p><p><strong>Conclusions: </strong>In conclusion, we suggest that recommendations for caffeine abstinence for patients with PD should be based on higher doses and ideally on individual assessments.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"836-846"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505971","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":"<i>CYP1A2</i> genotype-dependent effects of smoking on mirtazapine serum concentrations.","authors":"Maike Scherf-Clavel, Heike Weber, Carolin Weiß, Catherina Klüpfel, Saskia Stonawski, Leif Hommers, Stefan Unterecker, Katharina Domschke, Andreas Menke, Sarah Kittel-Schneider, Sebastian Walther, Jürgen Deckert, Angelika Erhardt-Lehmann","doi":"10.1177/02698811251337387","DOIUrl":"10.1177/02698811251337387","url":null,"abstract":"<p><strong>Introduction: </strong>Psychopharmacotherapy with mirtazapine is commonplace. Lower serum concentrations of mirtazapine were reported in smokers due to <i>CYP1A2</i> induction. However, no previous study that investigated <i>CYP1A2</i> genetics and mirtazapine treatment considered <i>CYP1A2-</i>inducing parameters.</p><p><strong>Aim: </strong>We aimed to investigate the association of <i>CYP1A2</i> variants, mirtazapine serum concentration, and treatment outcome, considering the smoking status of the patients.</p><p><strong>Methods: </strong>Two depression cohorts were investigated for the association between serum concentration and treatment response of mirtazapine and <i>CYP1A2</i>-163C>A (rs762551) and -3860G>A (rs2069514) genotype groups, also considering smoking status, sex, and age of the patients. In total, 124 patients (82 non-smokers and 42 smokers) were eligible for the analyses.</p><p><strong>Results: </strong>Dose-corrected serum concentration (CD) of mirtazapine was associated with smoking status, sex, and age, with lower CD in smokers, females, and older patients. Considering non-smokers and genotype-grouped smokers, CD of mirtazapine in <i>CYP1A2</i> normal metabolizer smokers (<i>N</i> = 6) did not differ from CD of non-smokers. By contrast, smokers carrying the <i>CYP1A2</i>*1A/*1F and *1F/*1F genotype groups showed 34.4% and 33.4% lower mirtazapine CD compared to non-smokers.</p><p><strong>Discussion: </strong>As yet, for clinical practice, it may be more relevant to focus on smoking status than on the <i>CYP1A2</i> gene variants. Considering the relevant impact of smoking on the mirtazapine CD, physicians should monitor an increase in side effects due to the expected increase in mirtazapine serum concentrations. In these cases, measurement of mirtazapine CD and/or subsequent dosage reduction is recommended. The clinical relevance of <i>CYP1A2</i> genotyping prior to treatment with drugs metabolized by <i>CYP1A2</i> needs further investigation.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"847-854"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000021","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":"Randomised controlled trial of clozapine in resistant schizophrenia and schizoaffective disorder.","authors":"Marc Peraire, Francisco Arnau-Peiró, Mariano Villar-García, Ana Benito, Iván Echeverria, Gonzalo Haro","doi":"10.1177/02698811251355602","DOIUrl":"10.1177/02698811251355602","url":null,"abstract":"<p><strong>Background: </strong>Clozapine (CLZ) stands out for its unique receptor profile, making it more effective than other antipsychotics, especially in treatment-resistant schizophrenia (TRS). There is growing evidence supporting its use in schizoaffective disorder (SZD), although diagnostic challenges and drug characteristics have complicated the implementation of specific clinical trials.</p><p><strong>Aim: </strong>Compare efficacy and tolerability of CLZ in real-world patients with TRS and SZD.</p><p><strong>Methods: </strong>Prospective, pragmatic, three-month, evaluator-blinded clinical trial with two randomised controlled arms (TRS groups) and a third fixed arm (SZD group). The clinical response was assessed by monthly visits during which the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale (MADRS), Calgary Depression Scale for Schizophrenia (CDSS), Clinical Global Impression (CGI) and Udvalg für Kliniske Undersogelser were administered. One hundred twenty-seven participants (74.8% men, 25.2% women; 84 TRS, 42 SZD; mean age of 38.53) completed the follow-up.</p><p><strong>Results: </strong>Patients treated with CLZ showed a greater reduction in all the PANSS subscales, MADRS and CDSS. In cases of SZD, there was a significant decrease in positive (<i>F</i>: 3.72, <i>p</i> < 0.05) and negative (<i>F</i>: 6.58, <i>p</i> < 0.01) symptoms, the overall score of PANSS (<i>F</i>: 5.64, <i>p</i> < 0.01) and YMRS (<i>F</i>: 12.01, <i>p</i> < 0.01). Patients using CLZ had a better subjective perception of their treatment (χ²: 17.29, <i>p</i> < 0.01). CLZ prescription was the only predictor of better outcomes across all the scales and improved substance use (dual disorders).</p><p><strong>Conclusions: </strong>CLZ was effective in reducing psychotic and affective symptoms in patients with dual psychosis, with better outcomes in SZD compared with TRS.EudraCT protocol trial:2021-001278-44 (Comparative analysis of the effectiveness of clozapine in resistant schizophrenia and schizoaffective disorder; <i>clinicaltrialsregister.eu/ctr-search/trial/2021-001278-44/ES</i>).</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251355602"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760415","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":"Evaluating the efficacy of metformin in reducing hyperprolactinemia among patients with schizophrenia: A meta-analysis of randomized controlled trials.","authors":"Kah Kheng Goh, Chun-Hsin Chen, Mong-Liang Lu","doi":"10.1177/02698811251326945","DOIUrl":"10.1177/02698811251326945","url":null,"abstract":"<p><strong>Background: </strong>Antipsychotic treatment is commonly associated with hyperprolactinemia, leading to menstrual disturbances, sexual dysfunction, and decreased bone mineral density. Nearly all antipsychotic drugs can elevate prolactin levels, affecting up to 70% of patients with schizophrenia. We aim to evaluate the potential therapeutic role of metformin in reducing hyperprolactinemia among these patients.</p><p><strong>Methods: </strong>We systematically searched PubMed, CNKI, Embase, Cochrane, and Web of Science through January 31, 2024, for randomized controlled trials (RCTs) evaluating metformin's effect on prolactin levels in patients with schizophrenia. Data were extracted and synthesized using random-effects meta-analysis.</p><p><strong>Results: </strong>This meta-analysis included 10 RCTs with 1046 participants (584 received metformin and 462 received placebo or no treatment). Metformin significantly reduced prolactin levels compared to control groups (SMD = -0.98, 95% CI: -1.62, -0.35, <i>p</i> = 0.002; transformed MD = -34.88 ng/mL, 95% CI: -57.65, -12.46). Subgroup analyses indicated that higher doses (1500 mg), shorter treatment durations (<24 weeks), higher BMI (>25 kg/m²), and longer illness duration (>1 year) were associated with more significant prolactin reductions. Metformin was well tolerated with no significant increase in adverse events or all-cause discontinuation rates compared to the control group.</p><p><strong>Conclusion: </strong>This meta-analysis suggests that metformin shows potential as a treatment for antipsychotic-induced hyperprolactinemia, with a favorable tolerability profile in patients with schizophrenia, particularly at higher doses, shorter treatment durations, higher BMI, and longer illness duration. Despite the robustness of the findings, high heterogeneity necessitates cautious interpretation. Future research should explore demographic and clinical factors influencing the response to metformin for optimizing treatment.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"815-824"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700046","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":"\"Modulatory role of baseline impulsivity on the acute and persistent effects of CB₁ agonism on impulsive choice\".","authors":"Enzo Pérez-Valenzuela, Victor Azocar, Andrea Gräber-Martinez, Alvaro Vergés, José Fuentealba Evans","doi":"10.1177/02698811251355603","DOIUrl":"https://doi.org/10.1177/02698811251355603","url":null,"abstract":"<p><strong>Background: </strong>Impulsivity may be defined as a heterogeneous construct characterized by difficulties in inhibiting actions and premature decision-making. Although a high level of impulsivity is recognized as a risk factor for cannabis use disorder, the effects of cannabinoids on impulsive choices have been less explored.</p><p><strong>Aims: </strong>This study aimed to determine the acute and persistent effects of CB_1/2 agonism on impulsive choice in rats using a delay-discounting task (DDT).</p><p><strong>Methods: </strong>Trained adult male Sprague-Dawley rats were injected with either vehicle or increasing doses (0.1, 1, and 5 mg/kg) of the CB_1/2 agonist WIN 55212-2 and tested in the DDT.</p><p><strong>Results: </strong>Our results showed that the effect of WIN55212-2 correlated with baseline impulsivity and reduced impulsivity in rats classified as high impulsive, while no effect was observed in rats classified as low impulsivity. Two weeks after the last WIN55212-2 injection, the rats were injected with vehicle and re-exposed to DDT. Rats classified as high impulsive maintained a significantly high AUC_log value, suggesting a long-lasting effect of WIN 55212-2. Finally, the CB₁ receptor antagonist rimonabant (1 mg/kg) reversed the effect of repeated treatment with WIN55212-2 on impulsivity in the high-impulsive population, suggesting an active role of the CB_1/2 receptor in the persistent effect of WIN55212-2.</p><p><strong>Conclusions: </strong>Our results suggest a potential benefit of CB_1/2 agonism in vulnerable subpopulations with high levels of impulsivity. To maximize therapeutic benefits and minimize potential iatrogenic effects, assessing choice impulsivity and other variables is essential, aligning with personalized medicine principles to effectively tailor interventions.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251355603"},"PeriodicalIF":5.5,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753672","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":"High-frequency oscillations in the mammalian brain after ketamine and other NMDA receptor antagonists.","authors":"Mark Jeremy Hunt, Jacek Wróbel","doi":"10.1177/02698811251352454","DOIUrl":"https://doi.org/10.1177/02698811251352454","url":null,"abstract":"<p><p>Subanesthetic doses of ketamine produce complex neuropsychiatric effects, which include rapid psychotomimetic symptoms and antidepressant effects that can last several weeks. Despite over 60 years of research, the mechanism(s) of action underlying ketamine's effects in the brain remains largely mysterious. Neurophysiological field potential recordings provide a direct window into brain activity, with different frequency bands reflecting functionally distinct neural networks. Two decades ago, we reported on the existence of high-frequency oscillations (HFO, >100 Hz) in freely moving rodents that were markedly enhanced by subanesthetic doses of ketamine. Since then, a large body of evidence has shown that HFO after ketamine (and other <i>N</i>-methyl-d-aspartate receptor (NMDAR) antagonists) are largely wake-related and prominent across diverse olfactory and frontostriatal brain regions. This rhythm, which is remarkably coherent across distinct regions, is modulated by slower oscillations with respiration-locked olfactory bulb activity a major driving force behind it. Similar activity has been reported in vivo in a variety of mammals with preclinical validity. This review is the first synthesis of studies reporting on the NMDAR antagonist-enhanced HFO rhythm. We identify current gaps and provide suggestions for future research, including the urgent need for more human studies.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251352454"},"PeriodicalIF":4.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698904","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":"β-blockers and risk of neuropsychiatric adverse events: An active-comparator restricted disproportionality on the FAERS.","authors":"Lujain Ez Eddin, Mohammad Ali Omrani, Niaz Chalabianloo, Flory T Muanda","doi":"10.1177/02698811251349190","DOIUrl":"https://doi.org/10.1177/02698811251349190","url":null,"abstract":"<p><strong>Background: </strong>β-blockers (β-adrenoceptor antagonists), commonly used for cardiovascular conditions, may be linked to neuropsychiatric adverse events (AEs). However, many prevalent ones, including delirium and hallucinations, remain insufficiently studied.</p><p><strong>Aims: </strong>To compare the neuropsychiatric risks of β-blockers with other antihypertensive drugs using data from the FDA Adverse Event Reporting System (FAERS) and differences between lipophilic and hydrophilic β-blockers.</p><p><strong>Method: </strong>An active-comparator restricted disproportionality analysis was conducted using data from the FAERS (2004Q1-2023Q4). Neuropsychiatric AEs were analyzed using Preferred Terms and the System Organ Classes from the Medical Dictionary for Regulatory Activities for β-blockers compared to lisinopril and losartan. Adjusted Reporting Odds Ratios (aRORs) were calculated using logistic regression to account for potential confounders.</p><p><strong>Results: </strong>β-blockers were linked to a significantly higher risk of nervous and psychiatric disorders, compared to lisinopril and losartan. Among the nine types of neuropsychiatric events studied, six-dizziness, nightmares, insomnia, hallucinations, somnolence, and disorientation-showed higher aRORs with β-blockers. Propranolol, a lipophilic β-blocker, exhibited the highest aRORs for psychiatric disorders and six types of neuropsychiatric events, including nightmares, delirium, hallucinations, disorientation, altered mental status, and somnolence, compared to lisinopril and losartan. Compared to atenolol, propranolol remained significantly associated with delirium, hallucinations, and disorientation.</p><p><strong>Conclusion: </strong>β-blockers, especially propranolol, may be associated with a higher risk of neuropsychiatric AEs compared to lisinopril and losartan. These findings highlight the importance of considering the specific β-blocker prescribed, particularly in patients at risk for central nervous system side effects. Further population-based studies are warranted to confirm these results.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251349190"},"PeriodicalIF":4.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698848","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":"Boosting the ventrolateral periaqueductal gray-ventral tegmental area pathway by disinhibition of group II mGluRs alleviates chronic restraint stress-induced depression-like behavior in mice.","authors":"Ming Tatt Lee, Wei-Hao Peng, Tien-Wei Hsu, Tian-Huei Chu, Yu-Ning Teng, Cheng-Chun Wu, Yung-Kuo Lee, Yu-Yan Lan, Yu-Cheng Ho","doi":"10.1177/02698811251351611","DOIUrl":"https://doi.org/10.1177/02698811251351611","url":null,"abstract":"<p><strong>Background: </strong>Major depressive disorder (MDD) is a prevalent psychiatric illness, significantly contributing to disability and suicide rates. While dysfunctions in neurotransmission, notably monoaminergic transmission, are commonly attributed to MDD, involvement of the glutamatergic system in comorbid depressive disorders suggests its potential as a target for antidepressant therapy. Despite evidence of diminished glutamatergic neuron activity in the midbrain ventrolateral periaqueductal gray (vlPAG) in rodent models of depression-which projects to the ventral tegmental area (VTA), a region regulating depression-like behaviors-the precise neurocircuit mechanisms within the vlPAG remain unclear.</p><p><strong>Methods: </strong>To investigate dysregulation of glutamatergic transmission in the vlPAG and its role in depression-like behavior, we combined behavioral testing, pharmacological manipulation, retrograde tracing, and electrophysiological recording in male C57BL/6 mice.</p><p><strong>Results: </strong>Mice receiving intravlPAG infusion of the mGlu2/3 receptor antagonist LY341495 exhibited reversal of depression-like behaviors. Chronic restraint stress (CRS) elicited depression-like behavior, whereas intravlPAG administration of LY341495 reversed these behaviors. VTA-projecting vlPAG neurons exhibited reduced frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) and decreased neuronal excitability. Blocking mGlu2/3 receptors, which act as autoreceptors inhibiting glutamate release, in the vlPAG rescued these effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 inhibitor rapamycin, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione prevented LY341495-induced reversal of depression-like behaviors.</p><p><strong>Conclusions: </strong>This provides the first direct evidence that blockade of mGlu2/3 receptors in the vlPAG ameliorates depression-like behavior, highlighting their role in regulating vlPAG-VTA neurocircuits implicated in MDD pathophysiology.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251351611"},"PeriodicalIF":4.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698903","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":"KarXT combines the partial benefits of haloperidol for positive symptoms and sulpiride for negative symptoms: Evidence from computational biology.","authors":"Chuanjun Zhuo, Chao Li, Xiaoyan Ma, Ranli Li, Ximing Chen, Yachen Li, Qiuyu Zhang, Lei Yang, Hongjun Tian, Lina Wang","doi":"10.1177/02698811251353268","DOIUrl":"https://doi.org/10.1177/02698811251353268","url":null,"abstract":"<p><strong>Objective: </strong>The new drug KarXT targets muscarinic receptors to reduce the positive and negative symptoms of schizophrenia. Haloperidol is effective in treating the positive symptoms of schizophrenia, while sulpiride has shown modest efficacy in alleviating negative symptoms. The shared and distinct molecular mechanisms of these drugs are unclear. This study aimed to determine if the mechanism for KarXT overlaps with the benefits of haloperidol for positive symptoms and sulpiride for negative symptoms.</p><p><strong>Methods: </strong>The putative target genes for the three drugs were identified, and a protein-protein interaction network was constructed to identify core targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the top 20 core targets were conducted. A drug-pathway-target-disease network was constructed.</p><p><strong>Results: </strong>The search yielded 179 common targets for haloperidol against positive symptoms, 96 targets for sulpiride against negative symptoms, and 99 targets for KarXT against schizophrenia. Haloperidol affects positive symptoms by targeting the IL-17 signaling pathway via TNF, IL6, IL1B, MAPK3, and CASP3, and sulpiride affects negative symptoms by targeting the PI3K-AKT signaling pathway via BDNF, INS, AKT1, IGF1, and BCL2. KarXT affects schizophrenia by targeting the MAPK signaling pathway via AKT1, FOS, CASP3, NFKB1, and IGF1. Molecular docking revealed good binding affinities between the drugs and the potential core targets.</p><p><strong>Conclusions: </strong>This study provides insights into the distinct molecular mechanisms by which haloperidol and sulpiride affect distinct symptoms of schizophrenia. KarXT integrates the partial effects of both drugs, including CASP3 with haloperidol and AKT1 and IGF1 with sulpiride. Our results provide a theoretical basis for clinical applications and new directions for drug development.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251353268"},"PeriodicalIF":4.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698847","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}