Journal of Psychopharmacology最新文献

{"title":"The effects of the PDE4 inhibitor roflumilast on cognitive performance after a cerebrovascular accident: a double-blind randomized placebo-controlled trial with an open label extension (ROSTMEMA).","authors":"Jill Kerckhoffs, Ieke Winkens, Arthur Ooghe, Samuel Branders, Jos Prickaerts, Arjan Blokland","doi":"10.1177/02698811261436581","DOIUrl":"10.1177/02698811261436581","url":null,"abstract":"<p><strong>Background: </strong>Effective pharmacological treatments for Post-Stroke Cognitive Impairment (PSCI) remain elusive. Preclinical studies have shown that phosphodiesterase 4 (PDE4) inhibition improved cognition, particularly memory, in post-stroke animal models and in healthy young and elderly individuals. This study tested whether the PDE4 inhibitor roflumilast could improve memory in PSCI patients.</p><p><strong>Methods: </strong>A double-blind randomized placebo-controlled trial (RCT) included 100 community-dwelling participants receiving roflumilast (100 µg q.d.) or placebo (<b><i>N</i></b> = 50 per group). Participants were 41-70 years and had suffered a cerebrovascular accident more than a year ago. They had subjective memory complaints and scored below the normative score on the delayed recall of the verbal learning test (VLT). After the RCT, 42 placebo group participants completed a 3-month open label extension (OLE). The primary outcome was the VLT delayed recall score. Roflumilast efficacy in the RCT was estimated through analysis of covariance (ANCOVA) with (post hoc) and without adjustment for baseline prognostic covariates defined a priori. In the OLE, general linear model repeated measures analyses were used. Secondary outcomes related to cognition, mood, and daily functioning.</p><p><strong>Results: </strong>Of the 97 participants completing the study (roflumilast: 48; placebo: 49), primary ANCOVA indicated a larger response in the roflumilast group on VLT and Rivermead Behavioural Memory Test (stories) at endpoint with non-significant moderate effect sizes (Cohen's <b><i>d</i></b>: 0.31-0.36). When post hoc adjusting for prognostic baseline covariates, effect sizes (0.33-0.40) became significant. Adverse events were similar in both groups. In the OLE, all memory test scores improved with medium to large significant effect sizes (Partial η²: 0.079-0.171).</p><p><strong>Conclusions: </strong>Roflumilast appeared to improve memory and was not associated with adverse effects. Results support further clinical studies.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"1415-1429"},"PeriodicalIF":5.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13490669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774854","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":"Prenatal THC exposure and binge-like alcohol drinking in early adolescence: From sex-specific drinking vulnerability to abnormal endocannabinoid-dopamine nexus in the nucleus accumbens.","authors":"Valentina Castelli, Giuseppe Tringali, Martina Di Bartolomeo, Gianluca Lavanco, Claudio D'Addario, Petr Palivec, Martin Kuchar, Carla Cannizzaro, Anna Brancato","doi":"10.1177/02698811261420097","DOIUrl":"10.1177/02698811261420097","url":null,"abstract":"<p><strong>Background: </strong>Endocannabinoid (eCB) signalling is pivotal for brain programming, including the reward system neurodevelopment. Prenatal exposure to Δ⁹-tetrahydrocannabinol (THC), cannabis psychoactive component, can perturb eCB tone via CB1 receptor and alter the response to salient stimuli.</p><p><strong>Aim: </strong>We hypothesise that prenatal THC exposure disrupts the eCB-dopamine nexus in the nucleus accumbens (NAc), predisposing the offspring to excessive alcohol drinking.</p><p><strong>Methods: </strong>Using a 3-week intermittent access (IA) two-bottle choice paradigm, we tested binge-like alcohol drinking in prenatally exposed to THC (pTHC) rats of both sexes from early adolescence. NAc gene expression of cannabinoid receptor type 1 (CB1R), eCB enzymatic machinery (DAGLα, <i>N</i>-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), monoacylglycerol lipase (MAGL), fatty-acid amide hydrolase (FAAH)), and D2 receptor was quantified before and after alcohol drinking.</p><p><strong>Results: </strong>pTHC females consumed higher alcohol levels than controls from the first session onward. In contrast, pTHC males initially drank less than controls but progressively escalated alcohol consumption, although they did not reach females' drinking levels. Prior to drinking, pTHC females showed increased D2 and DAGLα mRNA expression when compared to controls and to pTHC males. pTHC males displayed CB1R upregulation and reduced DAGLα expression compared to controls and to pTHC females. Following alcohol drinking, both sexes displayed CB1R downregulation and increased NAPE-PLD expression; pTHC males exhibited DAGLα mRNA upregulation; pTHC females showed higher NAPE-PLD expression than pTHC males.</p><p><strong>Conclusions: </strong>Prenatal THC exposure selectively predisposed the female offspring to alcohol vulnerability. The accumbal insight suggests a D2-driven reduced avoidance pathway in the females and a CB1R-driven avoidance behaviour in the males. Over the IA-paradigm, the potentiation in eCB synthesis plays a critical role in excessive alcohol drinking in pTHC offspring of both sexes.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"1493-1505"},"PeriodicalIF":5.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317335","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":"Reward-related neural activity after low doses of LSD in participants with depressed mood.","authors":"James Glazer, Hanna Molla, Royce Lee, Robin Nusslock, Harriet de Wit","doi":"10.1177/02698811251405686","DOIUrl":"10.1177/02698811251405686","url":null,"abstract":"<p><strong>Background: </strong>Lysergic acid diethylamide (LSD) has been considered as a potential treatment for depression for over 75 years, but its therapeutic potential has only recently been considered in mainstream psychiatry. Repeated ingestion of low doses of LSD (\"microdoses\") is thought to reduce depression, but the neurobiology underlying this effect is unknown. We previously reported that low doses of LSD increased event-related potentials (ERPs) during receipt of monetary rewards in healthy adults. LSD also produced more positive subjective effects in participants with mild-to-moderate baseline symptoms of depressed mood, compared to controls.</p><p><strong>Aim: </strong>In this report, we examined the effects of LSD on reward ERPs in participants with mild-to-moderate depressed mood and in non-depressed controls.</p><p><strong>Methods: </strong>Participants with subclinical mild-to-moderate depression (<i>N</i> = 20) or controls with minimal symptoms (<i>N</i> = 19) received LSD (26 μg tartrate) or placebo on two sessions. Primary measures were ERPs during a reward task, and secondary measures included self-reported mood during and 48 hours after the sessions.</p><p><strong>Results: </strong>LSD (vs placebo) increased late positive potential (LPP) amplitude to loss (vs win) reward feedback only in participants with higher baseline depressed mood, suggesting enhanced affective processing given the role of LPP in emotional valuation of reward. This effect of LSD on LPP was associated with its acute positive mood effects, and with lower depressed mood 48-hour after the LSD (vs placebo) session. In the full sample, LSD (vs placebo) decreased feedback-P3 and LPP amplitude to reward (vs neutral) feedback.</p><p><strong>Conclusion: </strong>Although findings must be interpreted with caution, results support the idea that low doses of LSD have potential anti-depressant effects.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"1368-1380"},"PeriodicalIF":5.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966349","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":"Exploring early add-on celecoxib treatment in OCD: Results from a preliminary randomized, double-blind, placebo-controlled trial.","authors":"Shivangini Singh, Anil Nischal, Anuradha Nischal, Satyendra Kumar Singh, Vipul Singh, Adarsh Tripathi","doi":"10.1177/02698811251389556","DOIUrl":"10.1177/02698811251389556","url":null,"abstract":"<p><strong>Background: </strong>Despite multiple treatment options available for obsessive-compulsive disorder (OCD), the response still remains unsatisfactory due to various factors. Hence, there is a continuous need to explore newer treatment modalities for OCD. Neuroinflammation might be one such contributing factor.</p><p><strong>Aim: </strong>We aimed to study the clinical outcome of early Celecoxib (Selective Cyclooxygenase-2 Inhibitor) add-on therapy to fluoxetine treatment in OCD over 8 weeks and explored the association of the outcomes with biochemical parameters, serum interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF).</p><p><strong>Methods: </strong>Forty-four drug-naive patients diagnosed with OCD (as per International Classification of Diseases-10) were recruited and randomized into 2 groups of 22 participants each. The study participants received fluoxetine and celecoxib (800 mg/day), and the control group received fluoxetine and a placebo. The clinical variables were measured at 0, 2, 4 and 8 weeks using the standard Yale-Brown Obsessive Compulsive Scale (YBOCS) for severity of symptoms. Serum IL-6 and BDNF were assessed at 0 and 8 weeks.</p><p><strong>Results: </strong>The study group showed a greater mean change (6.56 ± 1.04) of YBOCS scores over 8 weeks (<i>p</i> ⩽ 0.001, Hedge's <i>g</i> = 1.918). Response rate was higher in the study group (33%) than in controls (11.1%; Number Needed to Treat = 4.2). Reduction in YBOCS scores was positively correlated with the decrease in inflammatory marker (IL-6) in the study group (<i>r</i> = 0.478, <i>p</i> = 0.033). No significant side effects were observed.</p><p><strong>Conclusion: </strong>Celecoxib holds promise as a potentially safe early add-on treatment in OCD for rapid improvement in psychopathology, with further research warranted in this area.</p><p><strong>Clinical trial registration: </strong>The study was registered with the Clinical Trial Registry of India (Reference no. CTRI/2022/01/039407). https://ctri.nic.in/Clinicaltrials/rmaindet.php?trialid=64361&EncHid=59518.51563&modid=1&compid=19.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"1437-1445"},"PeriodicalIF":5.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145635074","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":"A novel approach for evaluating and comparing multiple antipsychotic polypharmacy in adults across specialist intellectual disability services in England and Wales: A retrospective feasibility cohort study.","authors":"Samuel J Tromans, Helen Neilens, Crispin Musicha, Victoria Allgar, Emily Stanyard, Richard Laugharne, Paula McGowan, Angela Hassiotis, Sarah Lennard, Lance V Watkins, Bhathika Perera, Kiran Purandare, Ashok Roy, Indermeet Sawhney, Sujeet Jaydeokar, Ryan Ashford, Chris Rollinson, Hanna Abraham, Nusra Khodabux, Ogheneochuko Akusu, Samuel Paisley, Georgios Mousailidis, Meera Naran, Rohit Shankar","doi":"10.1177/02698811261478609","DOIUrl":"https://doi.org/10.1177/02698811261478609","url":null,"abstract":"<p><strong>Background: </strong>In England and Wales, significant numbers of people with intellectual disability (PwID) are prescribed antipsychotics for a range of licensed and non-licensed indications, particularly behaviours that challenge. There is no system to compare antipsychotic prescribing practices across specialist adult intellectual disability (ID) services.</p><p><strong>Aim: </strong>This study aimed to determine whether converting antipsychotics and their doses to equivalent chlorpromazine units enables comparison of licensed (psychosis, etc.) and non-licensed (behaviours that challenge) prescribing between different services.</p><p><strong>Method: </strong>A feasibility retrospective cohort study using convenience sampling captured anonymized data of PwID on ⩾2 antipsychotics across eight specialist England and Wales adult ID services. The doses prescribed across 2017-2023 were converted to chlorpromazine-equivalent values, and antipsychotic dose burden across services was compared. Patients' characteristics and antipsychotic dosing are summarized descriptively. A mixed-effects regression model determines changes in chlorpromazine unit values across time. Subgroup analysis explores trends. Stata: Release 17 (StataCorp, 2021) and R (R Core Team, 2025) were used.</p><p><strong>Results: </strong>Of the 424 reviewed records, a higher proportion were male (ranging from 58% to 71% across census years) and white individuals (73%-85%). Autism (42%-58%), psychotic illness (61%-71%), and behaviours that challenge (77%-87%) were the most common comorbidities. Chlorpromazine units could be captured for 98% (<i>n</i> = 416). PwID with psychosis, behaviours that challenge, depression, or attention-deficit/hyperactivity disorder were prescribed significantly higher chlorpromazine-equivalent doses. Over 25% were prescribed more than 1000 mg/day chlorpromazine equivalent, which exceeds the British National Formulary-recommended maximum dose.</p><p><strong>Conclusions: </strong>Our study suggests that converting antipsychotic doses to chlorpromazine units is a simple and effective way to understand and compare prescribing burden for PwID. It also facilitates measuring prescribing and implementing best practice.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261478609"},"PeriodicalIF":5.3,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865528","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":"Pharmacokinetics, pharmacodynamics and safety of <i>N,N</i>-dimethyltryptamine administered intravenously in healthy smoking and non-smoking volunteers.","authors":"Katelijne V van der Heijden, Soma Makai-Bölöni, Amir Inamdar, Marije E Otto, Andrew P Hegle, Liam van der Aa, Rob G J A Zuiker, Roman Bohoslavsky, Marieke L de Kam, Ellen H James, Joop M A van Gerven, Gabriel E Jacobs","doi":"10.1177/02698811261473451","DOIUrl":"https://doi.org/10.1177/02698811261473451","url":null,"abstract":"<p><strong>Background: </strong>The serotonergic psychedelic <i>N,N</i>-dimethyltryptamine (DMT) might have therapeutic effects in various psychiatric disorders.</p><p><strong>Aims: </strong>Prior to exploring this clinical potential, it is essential to determine an optimal administration regimen for DMT, explore the relationship between its pharmacokinetics (PK) and pharmacodynamics and identify potential sources of pharmacokinetic variability.</p><p><strong>Methods: </strong>Therefore, DMT was administered as a 90-minute intravenous infusion (0.10, 0.20, 0.40 and 0.81 mg/min DMT) in a randomised, double-blind, placebo-controlled, single-ascending dose part in healthy smokers . Subsequently, DMT was administered as a 5-minute loading dose followed by a 55-minute infusion (3.64 mg/min + 0.81 mg/min and 3.64 mg/min + 1.29 mg/min) in an open-label, single-sequence two-period escalating dose study in healthy non-smokers. Outcome measures included PK of DMT and subjective, autonomic, neurophysiological and adverse effects.</p><p><strong>Results: </strong>All adverse events were mild to moderate in intensity and self-limiting. Two subjects requested their infusion to be discontinued following the loading dose in Part 2 due to anxiety and intense effects. Moderate inter- and intra-individual pharmacokinetic variability was observed, while DMT plasma concentrations at similar infusion rates in smokers were roughly double that of non-smokers, probably due to mono-amine oxidase A-inhibiting compounds in cigarette smoke. Mild to moderate subjective psychedelic effects emerged at plasma concentrations of ~35 ng/mL in both parts, while only limited undesired effects such as sedation or impaired sustained attention occurred for DMT 0.81 ng/mL. Interestingly, no differences were noted in psychoactive effects between smokers and non-smokers.</p><p><strong>Conclusion: </strong>These findings provide a basis for future studies exploring the (inter)relationships between DMT PK, different infusion regimens and subjective, neurophysiological and neuroendocrine effects resulting from 5-HT2A agonism.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261473451"},"PeriodicalIF":5.3,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865648","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":"Differential effects of psilocybin derivatives on fentanyl-induced conditioned place preference in male and female mice.","authors":"Tiffini N Lovell, Peter B James, Skylar L Hodgins, Samuel Johnson Noya, Patrick Arner, Ana-Clara Bobadilla","doi":"10.1177/02698811261478613","DOIUrl":"https://doi.org/10.1177/02698811261478613","url":null,"abstract":"<p><strong>Background: </strong>Fentanyl is the leading cause of fatal overdoses worldwide, and repeated use may lead to substance use disorder (SUD). In SUD, drug-associated contexts can trigger reward-related behavior even in the absence of the drug. Psychedelic compounds may weaken context-drug associations, reducing reward-related behavior to fentanyl.</p><p><strong>Aims: </strong>We evaluated the effects of the psychedelic psilocin and its derivatives, 4-MeO-MiPT and 4-HO-MiPT, on fentanyl-induced conditioned place preference (CPP) in male and female C57BL/6J mice.</p><p><strong>Methods: </strong>Mice were conditioned to distinct fentanyl and saline control contexts, then assessed for fentanyl place preference before and after treatment with one of the test compounds. Anxiety-related side effects of each compound were evaluated using an elevated plus maze (EPM) model.</p><p><strong>Results: </strong>Psilocin reduced fentanyl CPP exclusively in females, 4-MeO-MiPT in both sexes, and 4-HO-MiPT had no effect. None of the compounds significantly altered anxiety-like behaviors in EPM.</p><p><strong>Conclusion: </strong>These findings support further preclinical investigations of the sex-dependent effects of psilocin and 4-MeO-MiPT on fentanyl reward behavior.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261478613"},"PeriodicalIF":5.3,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865471","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":"A randomized crossover trial comparing the acute physiological and psychological effects of botanical formulations of oral psilocybin, oral psilocin, and sublingual psilocin.","authors":"Marlene L Tai, Balázs Szigeti, Amanda E Downey, Jacob S Aday, Lisa Fredenburg, Kimberly Sakai, Cesar Molina, Gisele Fernandes-Osterhold, Ellen R Bradley, Maddie Pantoni, Ryan Moss, Benjamin Lightburn, Franziska Plessow, Aoife O'Donovan, Josh D Woolley","doi":"10.1177/02698811261478603","DOIUrl":"https://doi.org/10.1177/02698811261478603","url":null,"abstract":"<p><strong>Background: </strong>Psilocybin, a serotonergic psychedelic found in hallucinogenic mushrooms, is metabolized to psilocin, the compound responsible for its psychoactive effects. Psilocybin has demonstrated therapeutic potential for neuropsychiatric conditions. While recent trials have primarily used orally administered synthetic psilocybin, alternative formulations and delivery methods may offer therapeutic advantages, yet the effects of these approaches remain poorly characterized.</p><p><strong>Aims: </strong>To compare the pharmacodynamic profiles and tolerability of oral psilocybin, oral psilocin, and sublingual psilocin derived from whole-mushroom extracts in healthy adults.</p><p><strong>Methods: </strong>In this randomized, within-subject, crossover trial, 20 healthy adults (10 men, 10 women; mean age 40.1 ± 5.9 years) completed up to four drug administration sessions involving botanical oral psilocybin (25 mg), oral psilocin (17.5 mg), or sublingual psilocin (2.18, 4.36, or 8 mg). All sessions included therapeutic support and pre- and post-dose psychotherapy. Acute effects were assessed using vital signs and subjective ratings of drug intensity and psychedelic experience.</p><p><strong>Results: </strong>Oral psilocin produced a similar temporal and subjective profile to oral psilocybin, with a lower burden of adverse effects. Sublingual psilocin was well tolerated, though the apparently lower achieved drug exposure limited comparability to oral administration.</p><p><strong>Conclusions: </strong>Oral psilocin may offer tolerability advantages over oral psilocybin. Sublingual psilocin was well tolerated at the dosages tested. Further studies are needed to evaluate botanical formulations and optimize delivery approaches.<b>Clinical trial registration:</b> https://clinicaltrials.gov/study/NCT05317689.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261478603"},"PeriodicalIF":5.3,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857393","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":"Oregon's state-regulated psilocybin services: Early real-world safety signals.","authors":"Jason B Luoma, Christina Chwyl, Don Des Jarlais, Christopher S Stauffer, Ximena A Levander, Ryan R Cook, Adrianne R Wilson-Poe, Dennis McCarty, P Todd Korthuis","doi":"10.1177/02698811261481171","DOIUrl":"https://doi.org/10.1177/02698811261481171","url":null,"abstract":"","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261481171"},"PeriodicalIF":5.3,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850976","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":"Benzodiazepines and GABA_A receptor subtypes: Effects in open-field, elevated plus maze-discriminative avoidance task, and conditioned place preference in male mice.","authors":"Vivian A Gundim, Hítalo C da Silva, Roberta C Dos Anjos Costa, Luis Felipe S Nascimento, Caio Jovita-Farias, V V N Phani Babu Tiruveedhula, Prithu Mondal, Cristiane A Favoretto, James M Cook, James K Rowlett, Eduardo A V Marinho, Alexandre J Oliveira-Lima, Lais F Berro","doi":"10.1177/02698811261473409","DOIUrl":"https://doi.org/10.1177/02698811261473409","url":null,"abstract":"<p><strong>Introduction: </strong>Benzodiazepines (GABA_A receptor positive allosteric modulators) have been used for decades as effective and safe anxiolytic medications. However, they also have addiction/dependence liability and side effects that include sedative-motor and memory impairment. Several of these side effects have been associated with activity at GABA_A receptors containing α1 subunits (α1GABA_A receptors), suggesting that compounds with reduced efficacy at this receptor subtype might have an improved therapeutic profile. In the present study, we investigated the behavioral effects of the novel benzodiazepine-like compounds, HZ-166 and KRM-II-81, which show preferential efficacy for α2/3GABA_A receptors, in comparison with the α1GABA_A-selective compound, zolpidem.</p><p><strong>Methods: </strong>Adult male mice were treated with vehicle or one of the compounds (3, 10, or 30 mg/kg, i.p.) and tested in the open-field, the elevated plus maze-discriminative avoidance task, and conditioned place preference (CPP).</p><p><strong>Results: </strong>In the open-field test, HZ-166 and KRM-II-81 showed anxiolytic-like, but not sedative-like effects. In the discriminative avoidance task, only KRM-II-81 showed anxiolytic-like effects, but, unlike HZ-166, also induced memory deficits in mice. HZ-166 and KRM-II-81 did not have rewarding effects in CPP, with KRM-II-81 inducing conditioned place aversion instead. In contrast, zolpidem induced sedation, memory impairment, and rewarding effects, without displaying anxiolytic-like activity.</p><p><strong>Conclusions: </strong>These findings reinforce the role of α1GABA_A receptors in benzodiazepine-induced sedation, cognitive impairment, and addiction potential, and its lack of a role in anxiety-like behaviors. Drugs with selectivity for α2/3GABA_A receptors might have an improved therapeutic profile compared to conventional benzodiazepines.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261473409"},"PeriodicalIF":5.3,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813408","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}