Pharmacology Biochemistry and Behavior最新文献

{"title":"Swiss-Webster and C57BL/6 mice are differentially sensitive to the stimulant effects of methamphetamine","authors":"Bo Jarrett Wood ,&nbsp;Nicole M. Hall ,&nbsp;M. Frances Vest ,&nbsp;Papori Sharma ,&nbsp;Kevin S. Murnane","doi":"10.1016/j.pbb.2025.174093","DOIUrl":"10.1016/j.pbb.2025.174093","url":null,"abstract":"<div><div>Methamphetamine is a highly addictive psychostimulant with significant neurobiological consequences, yet strain-dependent differences in its effects remain poorly understood. This study investigated behavioral and molecular differences in Swiss-Webster and C57BL/6 mice following methamphetamine exposure. Swiss-Webster mice exhibited greater behavioral sensitivity to methamphetamine compared to C57BL/6 mice, as demonstrated by lower peak doses required to elicit locomotor stimulation and conditioned place preference. Gene expression analyses revealed significantly higher striatal dopamine D2 receptor mRNA levels in Swiss-Webster mice, alongside a main effect of strain across multiple dopaminergic receptors, suggesting broader transcriptional differences may contribute to their heightened behavioral response. However, no strain differences were observed in dopamine transporter or dopamine D1 receptor mRNA expression. Following a neurotoxic binge-dosing regimen, both strains showed significant dopamine depletion, but no differences in the dopamine metabolite DOPAC were observed between strains in the striatum. Given the role of dopaminergic signaling in stimulant sensitivity and reward, these findings suggest that strain-dependent differences in methamphetamine response may reflect broader alterations in dopamine system function between these strains. This is the first study to directly compare Swiss-Webster and C57BL/6 mice in methamphetamine-induced CPP and provides novel insight into strain-specific drug reward mechanisms.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174093"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kisspeptin-13 induces hyperalgesia and modulates the expression of opioid and glutamate receptors in mice","authors":"Éva Bodnár,&nbsp;Katalin Eszter Ibos,&nbsp;Kata Filkor,&nbsp;Krisztina Csabafi","doi":"10.1016/j.pbb.2025.174098","DOIUrl":"10.1016/j.pbb.2025.174098","url":null,"abstract":"<div><div>Kisspeptins are hypothalamic neuropeptides well known for their role in reproductive biology. Our previous results have demonstrated that kisspeptin-13 (KP-13) has pronociceptive and anti-opioid effects. In our present experiments, we investigated the effects of KP-13 on nociception under both physiological and inflammatory conditions, as well as on the gene expression of regions involved in mediating pain sensation in C57BL/6 mice.</div><div>Different doses of KP-13 were administered to adult male C57BL/6 mice, and either the tail-flick latency was measured in the tail-flick test or the time spent with nocifensive behavior was determined in the formalin test. In another group of animals, after KP-13 treatment, qPCR was used to determine the relative gene expression of <em>Oprd1</em>, <em>Oprk1</em>, <em>Oprm1</em>, <em>Grin1</em>, <em>Grin2b</em>, <em>Grin2d</em>, and <em>Grm5</em> in samples of the dorsal root ganglion (DRG), amygdala, hypothalamus, and anterior cingulate cortex (ACC).</div><div>Our results showed that KP-13 treatment decreased the tail-flick latency in a dose-dependent manner. In the formalin test, the KP-13-treated group showed increased nocifensive behavior compared to the control group. In DRG, KP-13 caused upregulation of <em>Oprd1</em> and downregulation of <em>Oprk1</em>. In the amygdala, KP-13 decreased the expression of <em>Oprd1</em> and <em>Grin2b</em>. In the hypothalamus, both <em>Oprm1</em> and <em>Oprd1</em> were downregulated. In the ACC, <em>Oprk1</em> and <em>Grm5</em> expression increased, whereas a decrease in <em>Grin2b</em> expression was observed.</div><div>In conclusion, our results suggest that KP-13 has a hyperalgesic effect, which may be mediated by region-specific alterations in the gene expression of opioid and glutamate receptors.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174098"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The therapeutic use of psychedelic drugs: Legal, policy, and neuroscientific perspectives","authors":"Shadan Rahmani ,&nbsp;Rachel Crupi ,&nbsp;Anthony L. Riley ,&nbsp;Terry Davidson","doi":"10.1016/j.pbb.2025.174087","DOIUrl":"10.1016/j.pbb.2025.174087","url":null,"abstract":"<div><div>After many years of stigma and neglect, there is a resurgence of interest in the therapeutic use of psychedelic drugs. Anecdotal and evidence-based reports indicate psychedelics as a possible treatment for depression, anxiety, PTSD, substance abuse, and other disorders resistant to conventional medical interventions. The available data, however, are limited and the use of psychedelic substances in therapy remains controversial. This paper presents a collection of reports based on the talks of eighteen renowned experts in science, policy, and law who spoke at a recent symposium organized by American University's Center for Neuroscience and Behavior titled “The Therapeutic Uses of Psychedelic Drugs: Legal, Policy, and Neuroscientific Perspectives.” These speakers presented their ideas and perspectives concerning (a) the safety and effectiveness of psychedelic-assisted therapies; (b) the brain systems on which psychedelic drugs act; (c) ethical issues for both research and clinical settings; (d) pathways to increasing access to psychedelics for medical and nonmedical purposes; (e) federal and state regulation of psychedelic drugs for research, therapy, and nonmedical uses; and (f) procedures and requirements for psychedelic drug patents and commercialization. In considering these topics, each speaker strove to make their views accessible to diverse audiences of professionals outside of their own disciplines. This paper aims to faithfully convey the substance of each talk, while also providing additional context and updates relevant to the presentations. The symposium revealed the potential of psychedelics for treating psychiatric and behavioral disorders and the scientific, legal, and policy challenges that must be met to realize this potential.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174087"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements in psychedelic research: Effects, mechanisms, and therapeutic potential as emerging antidepressants","authors":"Xian-Qiang Zhang ,&nbsp;De-Nong Liu ,&nbsp;Qing-Shan Miao ,&nbsp;Xu Cai ,&nbsp;Lu-Xin Zong ,&nbsp;Yu-Kun Hou ,&nbsp;Jing Xiong","doi":"10.1016/j.pbb.2025.174099","DOIUrl":"10.1016/j.pbb.2025.174099","url":null,"abstract":"<div><div>Major depressive disorder (MDD) causes great physical and mental suffering to patients while also imposing a tremendous economic burden on the global economy. Psychedelics, also known as serotonergic hallucinogens, are potent psychoactive compounds known for their ability to alter mood, perception, and a range of cognitive functions. Increasing evidence suggests that some psychedelics positively facilitate individual social functions, with rapid and sustained improvement in symptoms associated with MDD. Consequently, the application of psychedelics in the treatment of MDD has garnered considerable attention from researchers in recent years. This review examines recent advancements in evaluating the behavioral and physiological effects of psychedelics in both preclinical animal models and clinical trials focused on MDD. Additionally, we summarize and discuss the cellular, brain region, and circuit-level mechanisms, as well as potential intracellular signaling pathways, that may contribute to the antidepressant effects of psychedelics. Based on current evidence, we conclude that psychedelics hold significant promise as therapeutic agents for MDD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174099"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADHD-like behaviors in adolescent mice prenatally exposed to levetiracetam: No safe gestational dose across sexes","authors":"Jelena Podgorac Kojadinović ,&nbsp;Gordana Stojadinović ,&nbsp;Sanela Popović ,&nbsp;Slobodan Sekulić","doi":"10.1016/j.pbb.2025.174091","DOIUrl":"10.1016/j.pbb.2025.174091","url":null,"abstract":"<div><div>Administering medication during pregnancy is always a challenging task. Levetiracetam (LEV), a second-generation antiepileptic drug, has been recognized as relatively safe based on studies assessing neurodevelopmental outcomes of children exposed to it <em>in utero</em>, despite some animal research reporting skeletal abnormalities. The potential link between intrauterine exposure to subtherapeutic or therapeutic doses of LEV and behavioral abnormalities in adolescent offspring has not yet been examined. The present study aimed to investigate the effects of maternal exposure to LEV at doses of 158, 211, and 316 mg/kg/day during mating and throughout gestation on behavioral abnormalities in offspring during the periadolescent period, using a mouse model. The selected doses correspond to clinical human LEV doses of 750, 1000, and 1500 mg/day. To assess the quantitative and qualitative parameters of behavioral response, the elevated plus-maze test (EPMT) on postnatal day (PND) 37 and the open field test (OFT) on PND45 were used. Experimental animals prenatally exposed to subtherapeutic or therapeutic doses of LEV exhibited complex and qualitatively different behaviors during the periadolescent period. The study's findings suggest that different doses of LEV administered throughout gestation may alter brain maturation patterns in offspring, leading to behavioral changes during periadolescence. In both the EPMT and OFT, offspring of mothers exposed to different doses of LEV displayed hyperactivity and stereotypy, observed in both females and males. The results revealed a non-linear, dose-dependent effect on behavior. This suggests that the model may be applicable as an animal model for attention-deficit/hyperactivity disorder (ADHD).</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174091"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lifelong dietary Omega-3, -6, and -9 ratios shape adult behavior and response to adolescent THC exposure in rats","authors":"Ariel Frajerman ,&nbsp;Aude Marzo ,&nbsp;Boris Chaumette ,&nbsp;Thérèse M. Jay ,&nbsp;Fanny Demars ,&nbsp;Antonin Lamazière ,&nbsp;Oussama Kebir ,&nbsp;Marie-Odile Krebs ,&nbsp;Gwenaëlle Le Pen","doi":"10.1016/j.pbb.2025.174086","DOIUrl":"10.1016/j.pbb.2025.174086","url":null,"abstract":"<div><h3>Background</h3><div>Alterations in membrane lipids are well established in schizophrenia, and diet could be an accessible, modifiable etiological factor. We examined the influence of Polyunsaturated fatty acids (PUFAs) intake throughout the lifespan on behaviour in adult rats. We further explored a possible interaction with adolescent exposure to delta-9-tetrahydrocannabinol (THC), the lipidic psychoactive compound responsible for cannabis's psychotic effects.</div></div><div><h3>Methods</h3><div>Sprague Dawley rats (<em>n</em> = 164, male and female) were separated into 3 groups exposed from conception to specific diets enriched in omega 3, 6, or 9, controlled by gas chromatography, with ratios determined to stay close to physiological balance. They were explored in adulthood in tests acknowledged as modelling symptomatic dimensions of schizophrenia, including locomotor activity, short-term recognition memory, sensorimotor gating, social interactions, anxiety, impulsivity, response inhibition and attention.</div></div><div><h3>Results</h3><div>The effects of diet on social interactions, locomotor activity, anxiety, cognitive flexibility, response inhibition, and impulse control were significant. Omega-3-enriched diet rats were less anxious and more impulsive than those receiving an omega-6 diet. THC exposure in adolescence interacts with diet and gender to influence adult anxiety and impulsivity.</div></div><div><h3>Limitations</h3><div>The diet's impacts are difficult to compare with previous data because we used new ratios of PUFA to be more physiological.</div></div><div><h3>Conclusion</h3><div>These results underline the importance of considering the relative influence of the 3 different families of Unsaturated Fatty acids and the importance of the omega-6/omega-3 ratio in controlled and balanced diets. The results could explain why omega-3 supplementation has only a moderate effect at high dosages and/or possibly only in patients with an initial alteration in lipid membrane composition.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174086"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allosteric modulation of M1 or M4 muscarinic receptors restores eNOS expression and L-arginine metabolism in dementia models and synergizes with NO releasers","authors":"Agata Płoska ,&nbsp;Adrianna Radulska ,&nbsp;Anna Siekierzycka ,&nbsp;Paulina Cieślik ,&nbsp;Michał Santocki ,&nbsp;Iwona T. Dobrucki ,&nbsp;Leszek Kalinowski ,&nbsp;Joanna M. Wierońska","doi":"10.1016/j.pbb.2025.174085","DOIUrl":"10.1016/j.pbb.2025.174085","url":null,"abstract":"<div><h3>Background</h3><div>Positive allosteric modulators (PAMs) of muscarinic receptors (M) have been shown to effectively prevent cognitive dysfunctions associated with dementias, but little is known about their impact on NO֗-dependent pathways, in particular eNOS expression, L-arginine metabolism and its derivatives (ADMA/SDMA/NMMA) production.</div></div><div><h3>Methods</h3><div>Biochemical studies were performed in frontal cortices, hippocampi and plasma samples from mice that were administered with MK-801 (schizophrenia-related dementa) or scopolamine (Alzheimer's disease model) for 14 days alone or together with muscarinic receptors modulators: VU0357017 (M₁) and VU0152100 (M₄). Western blot was used to measure eNOS, DDAH1 and PRMT5, while mass spectrometry was used to measure the levels of L-arginine derivatives. Behavioral studies aimed to investigate the procognitive effects of the combined administration of PAMs with NO^• releasers, spermineNONOate or DETANONOate were performed in novel object recognition (NOR) test, in scopolamine- or MK-801- induced amnesia.</div></div><div><h3>Results</h3><div>Our results indicate that MK-801 or scopolamine disturb eNOS, DDAH1, PRMT5 expression, and L-arginine bioavailability. VU0357017 or VU0152100 prevented scopolamine or MK-801-induced eNOS dysfunction, but L-arginine derivatives synthesis was inhibited only in MK-801 model. Synergistic effect with NO֗ releasers was observed in NOR.</div></div><div><h3>Conclusions</h3><div>eNOS expression and L-arginine bioavailability may contribute to antipsychotic action of VU0357017 or VU0152100. The antialzheimer's effect to a lesser extend involves normalization of L-arginine metabolism. The joint administration of the compounds with NO֗ releaser could be proposed as synergistic treatment for both schizophrenia and Alzheimer's disease.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174085"},"PeriodicalIF":2.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated 5-HT6 receptor activation facilitates flexible behavior in C57BL/6J mice","authors":"Shannon M. Lopez ,&nbsp;Magdalena R. Gonzales ,&nbsp;Bryan D. Alvarez ,&nbsp;Leslie R. Amodeo ,&nbsp;Dionisio A. Amodeo","doi":"10.1016/j.pbb.2025.174063","DOIUrl":"10.1016/j.pbb.2025.174063","url":null,"abstract":"<div><div>The serotonin (5-HT) 6 receptor has recently emerged as a novel target for the treatment of cognitive deficits seen in known neuropsychiatric disorders. While much of the research has concentrated on understanding the therapeutic effects of 5-HT6 receptor antagonists, much less is known regarding the behavioral impact of 5-HT6 agonist treatment. The current study examined the impact of 5-HT6 receptor partial agonist EMD 386088 on behavioral flexibility in an operant probabilistic reversal learning paradigm. Female and male C57BL/6J mice were trained on an 80 %/20 % probabilistic discrimination task until the learning criterion was reached. As predicted, mice did not differ in trials or days to reach criterion during this initial acquisition phase. Once the learning criterion was met, the probabilistic 80 %/20 % contingencies were reversed. Mice received EMD 386088 (1 or 5 mg/kg) or vehicle control administration before each reversal learning session. Mice treated with 1 mg/kg EMD 386088 took significantly fewer trials to reach reversal learning criterion compared to controls. Conversely, the 5 mg/kg dosage did not affect trials or days to reach reversal criterion. While EMD 386088 treated female mice tended to display enhanced reversal learning, there were no significant sex differences. Enhanced reversal learning in the 1 mg/kg group coincided with an increase in the probability of win-stay behavior compared to controls. Thus, the 1.0 mg/kg dose of EMD 386088 may lead to an increase the animals' sensitivity to the reinforced trials during learning. These findings highlight the benefits of repeated 5-HT6 receptor activation on facilitating behavioral flexibility.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174063"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low dose nicotine administration improves attentional performance in rats but is not blocked by nicotinic antagonists","authors":"Megan Stout,&nbsp;Ella Andonov,&nbsp;Amir H. Rezvani,&nbsp;Edward D. Levin","doi":"10.1016/j.pbb.2025.174073","DOIUrl":"10.1016/j.pbb.2025.174073","url":null,"abstract":"<div><div>Nicotine has been found by a variety of studies to improve cognitive function, including attention in both humans and experimental animals. However, it is not known which nicotinic acetylcholine receptor (nAChR) stimulating vs. desensitizing effects of nicotine are responsible for the cognitive improvement. Young adult female Sprague-Dawley rats were trained on an operant visual signal detection task to assess sustained attention. Then, they were administered nicotine subcutaneously (sc) in low doses of 0, 0.01, 0.02 or 0.04 mg/kg (<em>N</em> = 10–11/group), 20 min before the test sessions. In the next phase, nicotine or vehicle saline was given alone or in combination with doses of 4 and 8 mg/kg (sc) of dihydro-β-erythroidine (DHβE), an α4β2 nicotinic receptor antagonist or methyllycaconitine (MLA), an α7 nicotinic receptor antagonist, to determine whether any effects caused by nicotine would be blocked by co-administration of these nAChR antagonists. Our results show that both 0.01 mg/kg and 0.04 mg/kg nicotine doses caused modest, but significant improvement in percent correct on the attentional test relative to control rats, while the 0.02 mg/kg nicotine dose had a marginal (<em>p</em> &lt; 0.10) improvement that did not reach statistical significance. The significant improvement in percent correct performance on the attention test continued to be evident during the second phase of the study in which nAChR antagonists were co-administered. The rats given 0.01 mg/kg of nicotine continued to show a significant improvement in percent correct relative to the saline vehicle even in the face of the higher dose of each nicotinic antagonist. Our results show that low dose nicotine-induced attentional performance was not reversed by specific nAChR antagonists such as DHβE and MLA. This is consistent with the hypothesis that the nAChR desensitizing effect of nicotine, with low dose of nicotine, rather than the receptor stimulatory effect of nicotine underlies its action of improving attentional performance.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174073"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reinforcing and psychostimulant effects of carfentanil and morphine in mice","authors":"Ran An ,&nbsp;Baoyao Gao ,&nbsp;Lei Xiao ,&nbsp;Zhenhua Wang ,&nbsp;Zijun Liu ,&nbsp;Xingyao Chen ,&nbsp;Hongyan Qian ,&nbsp;Yonghong Liu ,&nbsp;Yunlong Sun ,&nbsp;Tao Li ,&nbsp;Jianbo Zhang ,&nbsp;Xinshe Liu","doi":"10.1016/j.pbb.2025.174074","DOIUrl":"10.1016/j.pbb.2025.174074","url":null,"abstract":"<div><div>Carfentanil is a widely used opioid new psychoactive substance (NPS) that possesses a high risk of addiction. However, the positive and negative reinforcement, as well as the psychostimulant effects of carfentanil remain unclear. In the present study, we compared the rewarding (positive reinforcement) and psychostimulant effects between carfentanil and morphine, using the conditioned place preference (CPP, including acquisition, extinction, and reinstatement) and behavioral sensitization paradigms. The withdrawal syndrome and anxiety- and depressive-like behaviors were detected to reveal the drug withdrawal-induced somatic and psychiatric symptoms (associated with negative reinforcement). Our results demonstrated that a low dose (0.5 μg/kg) of carfentanil could induce comparable CPP acquisition to 10 mg/kg morphine. Carfentanil, but not morphine, successfully induced behavioral sensitization. Both carfentanil and morphine withdrawal led to somatic and psychiatric (anxiety- and depressive- like behaviors) symptoms. Notably, carfentanil-exposed mice demonstrated more severe somatic withdrawal symptoms compared to morphine-exposed mice after naloxone-precipitation. In the drug-induced acquisition of CPP, carfentanil-exposed mice, but not morphine-exposed mice, showed an increase of c-Fos expression in the shell of nucleus accumbens (NAcSh) and caudate putamen (CPu). In the naloxone-precipitated drug withdrawal, carfentanil-exposed mice exhibited a higher level of c-Fos expression than morphine-exposed mice in the CPu. Carfentanil, but not morphine, activated the prefrontal cortex (PFC), NAcSh, and dorsal hippocampus (dHPC). Collectively, we found more potent reinforcing and psychostimulant effects of carfentanil compared to morphine. Our findings extend the knowledge and lay the foundation for the mechanistic studies of the reinforcing and psychostimulant effects of NPSs.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174074"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}