Psychopharmacology最新文献

{"title":"Dorsomedial striatum calcium permeable AMPA receptors in the development of aversion-resistant alcohol drinking.","authors":"Meredith R Bauer, Claudia Rangel-Barajas, Yanping Zhang, Stephen L Boehm","doi":"10.1007/s00213-026-07189-3","DOIUrl":"https://doi.org/10.1007/s00213-026-07189-3","url":null,"abstract":"<p><strong>Rationale: </strong>Alcohol use disorder is defined by drinking alcohol despite knowledge of negative consequences, often referred to as aversion-resistant drinking (The dorsomedial (DMS) and dorsolateral striatum (DLS) are necessary for goal-directed and habitual action selection, respectively. Leading hypotheses posit that once drug use becomes compulsive, DMS dependence degrades while DLS dependence increases. This shift may be mediated by changes in synaptic weights from glutamatergic inputs.</p><p><strong>Objectives: </strong>Using a combination of western-blot, micro-injections, and ex-vivo electrophysiology in male and female C57BL/6J mice, we investigated the role of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors AMPAR, which drive glutamatergic transmission, during quinine-adulterated alcohol drinking in the DMS and DLS across the development of aversion-resistant drinking.</p><p><strong>Results: </strong>We found that AMPAR subunit composition and function change in the DMS across the development of aversion-resistant drinking whereby, calcium permeable (CP) - AMPARs drive behavior. Western blots revealed a negative relationship between DMS GluA1 and quinine-adulterated alcohol drinking in alcohol naive mice and a positive relationship between DMS Glu A1/A2 ratios and quinine-adulterated alcohol drinking in aversion-resistant mice indicating that aversion-resistance positively predicts likelihood for CP-AMPAR expression in the DMS. Female aversion-resistant mice also had significant positive relationships with DMS or DLS Glu A1/A2 ratios and female aversion-resistant mice had a significant negative relationship with GluA2 and aversion-resistant alcohol drinking. DMS CP-AMPAR antagonism caused an increase in quinine-adulterated alcohol drinking in alcohol naïve mice suggesting that CP-AMPARs in the DMS prevent aversion-resistant drinking. Ex-vivo electrophysiology of DMS spiny projection neurons revealed that aversion-resistant drinking mice had greater inward rectification and CP-AMPAR antagonist sensitivity than alcohol naïve mice indicating that spiny projection neurons in the DMS express more CP-AMPARs following the development of aversion-resistant drinking. However, sensitivity to CP-AMPAR antagonism negatively predicted aversion-resistant drinking in alcohol history mice.</p><p><strong>Conclusions: </strong>These data provide evidence that repeated alcohol binges alter DMS CP-AMPAR activity, where initial DMS activity acts to causally prevent aversion-resistant drinking but after repeated binges that result in aversion-resistant alcohol drinking, DMS spiny projection neurons recruit CP-AMPARs. CP-AMPAR antagonism was negatively association with aversion-resistant drinking within the alcohol history mice suggesting that plasticity of DMS CP-AMPARs is not related to quinine-sensitivity. These data provide evidence for a causal role of the DMS in aversion-resistant drinking and open questions as to the func","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224780","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":"Investigation of the pharmacological and circuit basis for psychedelic drug effects on interval timing in mice.","authors":"Landon M Klein, Jared Kopelman, Richard F Sharp, Susan B Powell, Mark A Geyer, Jared W Young, Adam L Halberstadt","doi":"10.1007/s00213-026-07181-x","DOIUrl":"https://doi.org/10.1007/s00213-026-07181-x","url":null,"abstract":"<p><strong>Rationale: </strong>Classical psychedelic drugs such as the tryptamine psilocybin can alter temporal perception. Previously, the phenylethylamine psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-HT_2A receptor agonist, altered timing precision and accuracy in mice performing the discrete-trials temporal discrimination task (TDT), a retrospective timing task where subjects differentially respond depending on whether a light is illuminated for shorter or longer than 6.5 s.</p><p><strong>Objectives: </strong>Although DOI alters TDT performance, it is unclear whether timing is altered by tryptamine psychedelics, which are less selective for 5-HT₂ subtypes and also activate the 5-HT_1A receptor.</p><p><strong>Methods: </strong>To address this knowledge gap, we tested psilocin (the active metabolite of psilocybin) in male C57BL/6J mice performing the TDT and assessed the involvement of 5-HT_1A and 5-HT_2A receptors in its effects. Because the prefrontal cortex (PFC) is involved in psychedelic drug effects and temporal perception, additional experiments tested whether DOI microinfusion into the medial PFC (mPFC) replicates its systemic effects.</p><p><strong>Results: </strong>Psilocin (0.8 mg/kg SC) altered timing accuracy and precision in mice performing the TDT, similarly to DOI. Psilocin effects were blocked by the 5-HT_2A antagonist M100907 but were unaffected by the 5-HT_1A antagonist WAY-100,635. Infusion of DOI bilaterally into mPFC mimicked the effect of systemic administration on TDT performance. Administration of the selective 5-HT_2A inverse agonists M100907 and MDL 11,939 altered timing accuracy, demonstrating that both increases and reductions in 5-HT_2A receptor activation can modulate perceived clock speed.</p><p><strong>Conclusions: </strong>The mPFC appears to play a role in TDT performance and may mediate the effects of psychedelic drugs on interval timing.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220586","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":"Synthetic cannabinoid-induced changes in thalamo-prefrontal gamma synchrony and thalamic high-voltage spindles.","authors":"Yong-Feng Hu, Qin-Yuan Yu, Hui-Hui Zhuang, Zhi-Peng Yu, Zhong-Yu Zhang, Hao-Wei Shen","doi":"10.1007/s00213-026-07192-8","DOIUrl":"https://doi.org/10.1007/s00213-026-07192-8","url":null,"abstract":"<p><strong>Rationale: </strong>Cannabinoids, including Δ⁹-tetrahydrocannabinol (THC) and potent synthetic analogs, disrupt cognitive and perceptual processes via dysregulated neural oscillations. While these effects within limbic-cortical circuits have been well documented, the contribution of thalamocortical loops, which act as critical hubs for sensory gating and cognitive integration, remains unexplored.</p><p><strong>Objectives: </strong>To characterize the effects of acute synthetic cannabinoid exposure on thalamo-prefrontal oscillatory dynamics, specifically focusing on local gamma power, inter-regional synchrony, and cross-frequency coupling relevant.</p><p><strong>Methods: </strong>We performed simultaneous local field potential (LFP) recordings from the mediodorsal thalamus (MD), prelimbic (PrL), and orbitofrontal (OFC) cortices in freely moving rats following acute administration of the potent synthetic cannabinoid 5F-EDMB-PICA (0.3 mg/kg, i.p.).</p><p><strong>Results: </strong>5F-EDMB-PICA significantly suppressed low- (30-49 Hz) and high-gamma (51-80 Hz) power in PrL and MD, with a transient low-gamma reduction in OFC, while increasing long-range gamma coherence between the MD and prefrontal regions in both sub-bands. Notably, the drug increased the occurrence of high‑voltage spindles (HVS, 6-12 Hz) recorded in the MD, and enhanced phase-amplitude coupling between the phase of both HVS and theta (4-8 Hz) and the amplitude of prefrontal gamma.</p><p><strong>Conclusions: </strong>These results reveal that acute synthetic cannabinoid exposure produces a dissociation between local and long-range oscillatory dynamics in the thalamo-prefrontal circuit, which possibly is driven by increased thalamic rhythmic output. This pattern of network reorganization may underlie cannabinoid-induced deficits in sensorimotor gating and cognitive integration.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216714","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":"Beyond psychedelic exceptionalism: how people combine meditation with psychoactive substances, and how this relates to well-being.","authors":"Andreas Krabbe, Lena Lindström, Pilleriin Sikka, Jussi Jylkkä","doi":"10.1007/s00213-026-07179-5","DOIUrl":"https://doi.org/10.1007/s00213-026-07179-5","url":null,"abstract":"<p><strong>Background: </strong>Combining meditation with psychoactive substances is often assumed to be a niche practice centred on classic psychedelics. We sought to broaden this narrative in two cross-sectional studies.</p><p><strong>Methods: </strong>Study 1 used a broad naturalistic sample (N = 1,391) to examine the prevalence of substance use, meditation, and their simultaneous combination, as well as associations with subjective happiness. Study 2 used a stratified subsample (n = 397) focusing on classic psychedelic and cannabis users, the most common psychedelic-type substances combined with meditation, to assess associations with mental well-being, peace of mind, psychological flexibility, depression, and anxiety.</p><p><strong>Results: </strong>Contrary to prevailing assumptions, alcohol (29%), cannabis (19%), and nicotine (16%) were far more commonly combined with meditation than classic psychedelics (6%). Classic psychedelic use was also embedded within a pattern of pronounced polysubstance use, suggesting that it may reflect a broader substance-use profile rather than an isolated behavioural practice. Regression analyses found no consistent associations between psychedelic or cannabis use, with or without meditation, and any outcome. However, an unexpected pattern emerged for other drugs and alcohol. Other- drug use without meditation was associated with poorer well-being outcomes relative to no other-drug use, whereas other-drug use combined with meditation was not. Alcohol combined with meditation was associated with better well-being outcomes relative to alcohol use without meditation.</p><p><strong>Conclusions: </strong>These findings suggest that combining meditation with substance use is not limited to psychedelics and should be studied within broader patterns of polysubstance use and meditation practice.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216745","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":"Chemogenetic inhibition of the ventrolateral orbitofrontal cortex disrupts novelty-guided updating of spatial memories and alters hippocampal engram reactivation.","authors":"K Kim, D Yu, W F Wade, R Zdziarski-West, Z Ahmad, M Cutler, G Romanelli, A Daki, S L Grella","doi":"10.1007/s00213-026-07180-y","DOIUrl":"https://doi.org/10.1007/s00213-026-07180-y","url":null,"abstract":"<p><strong>Rationale: </strong>Adaptive behavior requires revising memories when outcomes deviate from expectations. The orbitofrontal cortex (OFC) is implicated in representing outcome expectancies, but its role in memory-updating, beyond value-based learning, remains unclear.</p><p><strong>Objectives: </strong>We tested whether the ventrolateral OFC (VLO) contributes to hippocampal-dependent memory-updating in the Objects in Updated Locations (OUL) task, where novelty-driven exploration provides a behavioral readout consistent with successful updating of spatial information.</p><p><strong>Methods: </strong>Using inhibitory DREADDs, in male and female (Swiss Webster and C57BL/6) mice, we suppressed VLO activity during the Updating session, when new object-location information was introduced.</p><p><strong>Results: </strong>Control mice preferentially explored the updated object-location configuration during Updating and discriminated between updated and novel object-location configurations at Test, whereas VLO-inhibited mice did not. VLO inhibition when no updating demand was present did not alter exploration of novel object-location configurations or memory for the original spatial configuration at Test.</p><p><strong>Conclusions: </strong>These results indicate that VLO activity is selectively required when novelty must be interpreted relative to prior experience, implicating this region in evaluating change rather than detecting it. To assess hippocampal ensemble dynamics, we tagged neuronal ensembles, in the dorsal dentate gyrus (dDG) recruited during Updating, followed by quantification of overlap between Updating-tagged cells and ensembles reactivated at Test. We found that VLO inhibition reduced reactivation of Updating-tagged dDG ensembles, paralleling the behavioral impairments observed in the OUL task. These findings support a role for the VLO in hippocampal-dependent memory-updating and extend OFC models beyond reward contexts to include predictive updating of spatial memory representations.</p><p><strong>Clinical trial: </strong>Not applicable.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207895","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":"What goes up must comedown: prevalence rates, characteristics, and coping strategies concerning MDMA aftereffects.","authors":"Sean P Goldy, Kelcy A Klein, David B Yaden, Sandeep M Nayak","doi":"10.1007/s00213-026-07187-5","DOIUrl":"https://doi.org/10.1007/s00213-026-07187-5","url":null,"abstract":"<p><strong>Rationale: </strong>MDMA is increasingly being studied for therapeutic applications, yet the prevalence and characteristics of post-acute negative effects remain debated.</p><p><strong>Objectives: </strong>We aimed to characterize MDMA's post-acute negative effects, including prevalence and symptom profile among recreational users. Given preclinical work and limited human evidence suggesting that certain supplements and antidepressants may mitigate MDMA's negative effects, we also assessed the use of these substances as coping strategies.</p><p><strong>Methods: </strong>We conducted a cross-sectional online survey of 497 MDMA-experienced participants recruited from Prolific. The survey assessed post-acute negative effects prevalence, timing, and duration; post-acute side effects; emotional changes, suicidal ideation; and intentional use of supplements or antidepressants to manage symptoms. We compared characteristics of post-acute side effects between MDMA users who self-reported ever experiencing a negative post-acute MDMA experience (colloquially known as a 'comedown') and those who did not.</p><p><strong>Results: </strong>74.5% of participants reported experiencing a period of post-acute negative effects at least once, with onset occurring approximately 24 hours post-ingestion and lasting an average of 40 hours. The most common symptoms were fatigue (88.1%), difficulty concentrating (85.7%), restlessness (82.9%), and headache (79.7%). 14.6% of post-acute negative effects experiencers endorsed passive suicidal ideation and 6.2% endorsed active suicidal ideation. Regarding coping strategies, 30.3% reported using supplements (most commonly N-acetyl-cysteine, acetyl-L-carnitine, and magnesium) and 5.1% reported using antidepressants, with moderate perceived helpfulness.</p><p><strong>Conclusions: </strong>Post-acute negative effects of MDMA appear prevalent among recreational users in a cross-sectional sample, characterized by fatigue, negative affect, and elevated suicidal ideation. These findings highlight post-acute risks that warrant further investigation.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216674","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":"Adolescent-onset regular cannabis use is associated with altered neural and behavioural responses during anticipation and feedback of monetary reward and loss.","authors":"Giada Lombardi, Grace Blest-Hopley, Martina Maria Tarantini, Aisling O'Neill, Robin Wilson, Owen O'Daly, Vincent Giampietro, Sagnik Bhattacharyya","doi":"10.1007/s00213-026-07183-9","DOIUrl":"https://doi.org/10.1007/s00213-026-07183-9","url":null,"abstract":"<p><strong>Rationale: </strong>Regular cannabis use has been associated with alterations in reward-related neural processes, yet findings remain inconsistent and the relationship between neural activity and behavioural performance is not fully understood.</p><p><strong>Objectives: </strong>The present study aimed to characterise neural and behavioural correlates of reward processing in regular cannabis users (CU) compared with matched non-users (NU) using the Monetary Incentive Delay Task (MIDT).</p><p><strong>Methods: </strong>Twenty adolescent-onset regular cannabis users (CU; ≥4 days/week for 2 years, with regular use initiated before age 18) and twenty age- and sex-matched non-users (NU) completed the Monetary Incentive Delay Task during functional MRI. Firstly, we assessed behavioural performance through reaction times, accuracy and monetary earnings to determine whether potential neural alterations were reflected in task performance. Secondly, focusing on reward-related brain regions, we examined group differences in BOLD functional MRI activity during anticipation and outcome phases separately for monetary win and loss conditions. Finally, we explored the association between behavioural performance and neural activation.</p><p><strong>Results: </strong>Our findings provide preliminary evidence that adolescent-onset regular cannabis use is associated with altered engagement of key nodes within the mesocorticolimbic circuit accompanied by impaired behavioural performance. Particularly, compared with NU, CU showed (I) lower striatal activity during anticipation of monetary win and higher ventral striatum and frontal pole activity during anticipation of monetary loss; (II) different VTA BOLD contrast estimates during outcome of successful monetary win and loss avoidance, and lower frontal pole activity during outcome of unsuccessful loss avoidance; (III) lower monetary rewards and a trend towards slower reaction times and reduced accuracy; (IV) disrupted brain-behaviour coupling.</p><p><strong>Conclusions: </strong>Results from this study may help inform future research on the neurobiological mechanisms underlying changes in reward function and the resultant behavioural consequences of adolescent-onset cannabis use.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216706","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":"Serotonin 1B receptors expressed on forebrain excitatory neurons mediate the post-acute anxiolytic response to psilocybin in mice.","authors":"Sixtine Fleury, Yian Shang, Katherine M Nautiyal","doi":"10.1007/s00213-026-07184-8","DOIUrl":"https://doi.org/10.1007/s00213-026-07184-8","url":null,"abstract":"<p><strong>Introduction: </strong>Psilocybin can produce rapid and sustained antidepressant-like and anxiolytic effects, yet the receptor and circuit mechanisms underlying these behavioral changes remain unclear. While the serotonin 2A receptor mediates psilocybin's acute psychedelic effects, psilocin (the active metabolite of psilocybin) binds many serotonin receptor subtypes. Our prior work has identified the serotonin 1B receptor (5-HT1BR) as being necessary for the post-acute pro-hedonic and anxiolytic effects of psilocybin in mice. 5-HT1BRs are widely expressed throughout the brain on many different neuron subtypes.</p><p><strong>Methods: </strong>In order to assess the role of 5-HT1BR expression on terminals of forebrain excitatory neurons in the response to psilocybin, we used a conditional genetic approach to selectively eliminate expression of htr1b in forebrain excitatory neurons using the Emx1 promoter. We examined acute behavioral responses, post-acute anxiolytic effects, and brain-wide neural activation to a single high dose of psilocybin in male and female mice.</p><p><strong>Results: </strong>The absence of 5-HT1BR expression on Emx1+ neurons did not alter psilocybin's acute behavioral effects, including head twitch responding and hyperlocomotion. However, psilocybin's post-acute anxiolytic effects in the elevated plus maze (EPM) and novelty suppressed feeding (NSF) assays were strongly attenuated in mice lacking these receptors. Whole-brain c-Fos mapping across 190 regions revealed that psilocybin produced robust activation across the brain in both genotypes, including prefrontal cortices, corticolimbic structures, and sensory cortices. Network-level analyses revealed that psilocybin drove broad inter-regional decorrelation in control mice but increased synchronization in knockouts, with thalamic, prefrontal, and amygdala circuits most strongly affected.</p><p><strong>Conclusions: </strong>These findings implicate 5-HT1BRs expressed on terminals of forebrain excitatory neurons as a potential circuit-level excitatory gating mechanism. Overall, these receptors may be important for a coordinated network reorganization following psilocybin that contributes to the anxiolytic behavioral effects.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216728","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":"Sex-specific exploration patterns and noradrenergic modulation in object recognition memory: Role of the perirhinal cortex.","authors":"Lorena Roselló-Jiménez, Raúl Pastor, Marta Miquel, Laura Font","doi":"10.1007/s00213-026-07191-9","DOIUrl":"https://doi.org/10.1007/s00213-026-07191-9","url":null,"abstract":"<p><strong>Introduction: </strong>Object recognition memory (ORM) relies on two processes: familiarity, mediated by the perirhinal cortex (PRH), and recollection, supported by the hippocampus (HIP). These processes are recruited depending on memory strength: brief exploration forms weak traces relying on PRH familiarity, whereas extended exploration produces strong traces requiring HIP recollection. Noradrenaline (NA) modulates these mechanisms via β2-adrenergic receptors (β2-AR), influencing memory strength and consolidation. However, whether this modulation differs between sexes under conditions generating weak versus strong memory traces remains unknown. We examined how NA and β2-AR influence ORM in male and female mice under these conditions.</p><p><strong>Methods: </strong>Swiss mice were tested in the Novel Object Recognition task using training durations of 1-10 min and delays of 24-48 h. Atomoxetine (ATO) was used to increase NA levels, and ICI-118,551 (ICI) to block β2-AR. Neural activation was assessed via c-Fos immunohistochemistry in PRH and HIP.</p><p><strong>Results: </strong>Females showed greater efficiency in object processing, requiring less exploration than males. Under weak training conditions, ATO facilitated the formation of long-term ORM in females but not in males, accompanied by increased PRH c-Fos expression without HIP involvement. β2-AR blockade impaired ORM acquisition only in females, with no significant changes in c-Fos. In males, performance depended on object dissimilarity; increased NA did not enhance ORM unless stimuli were highly distinct.</p><p><strong>Conclusions: </strong>These findings reveal sex differences in noradrenergic modulation of ORM. In females, NA acting via β2-AR supports memory formation through PRH-dependent familiarity, emphasizing the importance of sex as a biological variable in research.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196272","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 the addictive potential of α-methylfentanyl and acetyl-α-methylfentanyl in animal models.","authors":"Deli Xu, Xuesong Shi, Kaixi Li, Lixin Kuai, Xuwen Luo, Yuanyuan Chen, Bin Di, Peng Xu","doi":"10.1007/s00213-026-07185-7","DOIUrl":"https://doi.org/10.1007/s00213-026-07185-7","url":null,"abstract":"<p><strong>Background: </strong>The abuse profiles of α-methylfentanyl and acetyl-α-methylfentanyl remain poorly characterized in preclinical models. This study systematically evaluated their addiction-related behaviours and underlying pharmacological features.</p><p><strong>Methods: </strong>Conditioned place preference (CPP) was tested in mice with gradient doses of fentanyl, α-methylfentanyl and acetyl-α-methylfentanyl. Intravenous self-administration, behavioural economic demand curves, cue- and drug-primed reinstatement, and drug discrimination assays were conducted in rats. ED₅₀ values were calculated and compared across compounds.</p><p><strong>Results: </strong>All three compounds induced significant CPP, with acetyl-α-methylfentanyl showing ~ 30-fold lower potency. In self-administration, all compounds produced inverted U-shaped dose-response curves, with peak infusion rates at 0.5 µg/kg/infusion. Fentanyl exhibited the highest essential value (EV) in demand curve analysis, indicating stronger reinforcing efficacy. A single naloxone pretreatment significantly attenuated both cue- and drug-primed reinstatement. Drug discrimination ED₅₀ was 11.06, 12.65 and 128.3 µg/kg for fentanyl, α-methylfentanyl and acetyl-α-methylfentanyl, respectively.</p><p><strong>Conclusions: </strong>α-methyl substitution selectively reduces reinforcing efficacy without altering reward perception; acetylation attenuates both reward and discriminative stimulus effects while preserving reinforcing capacity. µ-Opioid receptor signalling mediates relapse-like behaviour, supporting long-acting antagonists as potential interventions.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184183","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}