{"title":"Nucleus accumbens CD81 regulates methamphetamine-induced locomotor activity, conditioned reward, and reinstatement in male and female rats.","authors":"Amine Bahi, Jean-Luc Dreyer","doi":"10.1007/s00213-026-07167-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Methamphetamine (METH) use disorder is characterized by high rates of relapse and persistent neurobehavioral alterations. CD81, a member of the tetraspanin family, has been implicated in synaptic plasticity and addiction-related behaviors, but its role in METH-induced behavioral adaptations remains unknown.</p><p><strong>Aims: </strong>To determine whether METH-induced conditioned reward is associated with alterations in endogenous nucleus accumbens (NAcc) CD81 expression and to examine the effects of viral-mediated CD81 overexpression on METH-induced behavioral responses.</p><p><strong>Methods: </strong>Male and female rats underwent METH-induced conditioned place preference (CPP), after which endogenous CD81 mRNA expression was quantified in the NAcc. Based on these findings, separate cohorts received bilateral intra-accumbal injections of either control or CD81-expressing lentiviral vectors. The effects of CD81 overexpression on acute METH-induced locomotor activity, CPP acquisition, and METH-primed reinstatement following extinction were subsequently evaluated.</p><p><strong>Results: </strong>METH-conditioned animals exhibited significantly reduced accumbal CD81 mRNA expression, and endogenous CD81 levels were negatively correlated with CPP acquisition. Viral-mediated CD81 overexpression significantly attenuated METH-induced locomotor activation, reduced CPP acquisition, and suppressed METH-primed reinstatement following extinction. Accumbal CD81 mRNA expression was negatively correlated with locomotor activity, CPP magnitude, and reinstatement responses. Although females exhibited greater METH-induced locomotor activity than males, no significant sex differences were observed in CPP acquisition, reinstatement, or the behavioral effects of CD81 overexpression.</p><p><strong>Conclusions: </strong>Reduced endogenous CD81 expression in the NAcc is associated with METH reward learning, whereas restoration of CD81 expression attenuates METH-induced locomotor, rewarding, and relapse-like behaviors. These findings identify CD81 as a previously unrecognized regulator of METH-induced neurobehavioral adaptations and support a role for accumbal CD81 in addiction-related neuroplasticity.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00213-026-07167-9","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Methamphetamine (METH) use disorder is characterized by high rates of relapse and persistent neurobehavioral alterations. CD81, a member of the tetraspanin family, has been implicated in synaptic plasticity and addiction-related behaviors, but its role in METH-induced behavioral adaptations remains unknown.
Aims: To determine whether METH-induced conditioned reward is associated with alterations in endogenous nucleus accumbens (NAcc) CD81 expression and to examine the effects of viral-mediated CD81 overexpression on METH-induced behavioral responses.
Methods: Male and female rats underwent METH-induced conditioned place preference (CPP), after which endogenous CD81 mRNA expression was quantified in the NAcc. Based on these findings, separate cohorts received bilateral intra-accumbal injections of either control or CD81-expressing lentiviral vectors. The effects of CD81 overexpression on acute METH-induced locomotor activity, CPP acquisition, and METH-primed reinstatement following extinction were subsequently evaluated.
Results: METH-conditioned animals exhibited significantly reduced accumbal CD81 mRNA expression, and endogenous CD81 levels were negatively correlated with CPP acquisition. Viral-mediated CD81 overexpression significantly attenuated METH-induced locomotor activation, reduced CPP acquisition, and suppressed METH-primed reinstatement following extinction. Accumbal CD81 mRNA expression was negatively correlated with locomotor activity, CPP magnitude, and reinstatement responses. Although females exhibited greater METH-induced locomotor activity than males, no significant sex differences were observed in CPP acquisition, reinstatement, or the behavioral effects of CD81 overexpression.
Conclusions: Reduced endogenous CD81 expression in the NAcc is associated with METH reward learning, whereas restoration of CD81 expression attenuates METH-induced locomotor, rewarding, and relapse-like behaviors. These findings identify CD81 as a previously unrecognized regulator of METH-induced neurobehavioral adaptations and support a role for accumbal CD81 in addiction-related neuroplasticity.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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