Neuropharmacology最新文献

{"title":"Kinsenoside attenuates ER stress and inhibits inflammatory responses through IL-10/STAT/SOCS3 pathway in chronic pain relief","authors":"Wei Wang ,&nbsp;Yingzhuo Ding ,&nbsp;Chunxia Yu ,&nbsp;Qingqing Chi ,&nbsp;Xia Fu ,&nbsp;Mengjiao Deng ,&nbsp;Dongxia Duan ,&nbsp;Jinbao Wei ,&nbsp;Ronghua Ding ,&nbsp;Yufei Xi ,&nbsp;Qin Li ,&nbsp;Le Ma","doi":"10.1016/j.neuropharm.2025.110463","DOIUrl":"10.1016/j.neuropharm.2025.110463","url":null,"abstract":"<div><div>Neuro-inflammation contributes to neuropathic pain by sensitizing ionic channels. Kinsenoside, a traditional Chinese medicine, has recognized anti-inflammatory properties. However, it remains unclear whether kinsenoside can be used for pain therapy. Network pharmacology analysis revealed that 57 % of its targets are associated with pain, including inflammation and synaptic transmission. The analgesic effects of kinsenoside were confirmed in SNL and formalin rat models, with ED50 values of 47.99 μg and 36.80 μg, respectively. Transcriptome and WGCNA analyses indicated the involvement of cytokine release, anti-inflammatory activity, and synapse enrichment in the blue module. Furthermore, we confirmed that kinsenoside's efficacy was mainly mediated by IL-10 induction, phosphorylation of STAT3, and SOCS3 expression. Pretreatment with kinsenoside significantly inhibited the release of TNF-α, IL-1β, and IL-6. Kinsenoside also attenuated ER stress in both microglia and neural cells. Molecular docking analysis demonstrated significantly high binding energies of IL-10, STAT3, and SOCS3 with MHC. Additionally, whole-cell recordings revealed that bath application of kinsenoside reduced the frequency and amplitude of spinal glutamatergic transmission in a dose-dependent manner. In summary, pharmacological prediction and biological validation collectively indicate that kinsenoside significantly exerts significant analgesic effects by attenuating ER stress and inhibiting inflammatory responses via the IL-10/p-STAT3/SOCS3 axis, precisely regulating spinal glutamatergic transmission for pain relief.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110463"},"PeriodicalIF":4.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Demethylase FTO in the cerebrospinal fluid-contacting nucleus of mice contributes to neuropathic pain via mediating m6A demethylation of P2rx4 mRNA","authors":"Yu-Ting Zhang,&nbsp;Wei-Long Huang,&nbsp;Yi-Jun Zhang,&nbsp;Li-Cai Zhang","doi":"10.1016/j.neuropharm.2025.110462","DOIUrl":"10.1016/j.neuropharm.2025.110462","url":null,"abstract":"<div><div>N6-methyladenosine (m6A) modification plays a crucial role in pain regulation by modulating pain-related gene expression. The cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) is closely associated with pain, and downregulation of P2X4 receptor (P2X4R) expression in this region alleviates hyperalgesia. However, the relationship between m6A modification and P2X4R in CSF-contacting nucleus remains unclear. This study aims to investigate the role and potential mechanisms of the m6A demethylase fat mass and obesity-associated protein (FTO) and P2X4R in neuropathic pain (NP) induced by spared nerve injury (SNI) in male mice. We observed decreased m6A levels and upregulated FTO expression in the CSF-contacting nucleus of SNI mice. FTO was primarily expressed in neurons of the CSF-contacting nucleus, with symmetrical distribution across its bilateral regions. In CSF-contacting nucleus, FTO overexpression reduced m6A methylation and promoted pain, while FTO inhibition increased m6A levels and alleviated pain hypersensitivity. The administration of the FTO inhibitor meclofenamic acid (MA) into CSF-contacting nucleus alleviated pain. FTO regulated the expression of <em>P2rx4</em> mRNA and protein in CSF-contacting nucleus. Furthermore, <em>P2rx4</em> mRNA is a downstream target of FTO-mediated m6A demethylation. In summary, the m6A demethylase FTO contributes to NP by upregulating the expression of <em>P2rx4</em> mRNA and protein through mediating m6A demethylation of <em>P2rx4</em> mRNA. Therefore, the m6A demethylase FTO in CSF-contacting nucleus may represent a novel therapeutic target for NP.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110462"},"PeriodicalIF":4.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trace amine-associated receptor 1 agonists reduce alcohol drinking and differentially modulate dopamine release in the nucleus accumbens of alcohol preferring mice","authors":"Charles Houdant ,&nbsp;Mandy Lamarche ,&nbsp;Grégory Fouquet ,&nbsp;Véronique Debuysscher ,&nbsp;Jolanta Orzelska-Górka ,&nbsp;Marta Kruk-Slomka ,&nbsp;Grażyna Biała ,&nbsp;Jérôme Jeanblanc ,&nbsp;Mickaël Naassila","doi":"10.1016/j.neuropharm.2025.110460","DOIUrl":"10.1016/j.neuropharm.2025.110460","url":null,"abstract":"<div><div>Current treatments for alcohol use disorder have limited efficacy underscoring the need for novel therapeutic targets. Trace amine-associated receptor 1 (TAAR1) is a promising candidate due to its ability to act as a brake on dopaminergic transmission and alcohol consumption. However, both the relative efficacy of full and partial TAAR1 agonists in reducing alcohol-related behaviors and their underlying mechanisms of action remain unclear. In this study, we evaluated the effects of the full agonist RO5166017 and the partial agonist RO5263397 on alcohol consumption using an intermittent access protocol in alcohol-preferring male C57BL/6JRj mice. Given their distinct pharmacological and electrophysiological properties, we also investigated the effects of these agonists on presynaptic dopaminergic transmission using fast-scan cyclic voltammetry in the nucleus accumbens, a key structure involved in alcohol reinforcement. Full and partial TAAR1 agonists reduced alcohol intake by 25 % and 43 %, respectively. We further report that these agonists exhibit opposite effects on dopamine release under basal conditions, but that these effects are reversed in animals chronically exposed to alcohol<em>.</em> The reversal in dopamine release did not result from alcohol-induced modifications of TAAR1 or D2 receptor expression. Our findings highlight the therapeutic potential of TAAR1 agonists for alcohol addiction and reveal important functional differences between full and partial agonists. Further research is needed to determine the clinical relevance of these distinct pharmacodynamic profiles and optimize TAAR1-targeting pharmacotherapies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110460"},"PeriodicalIF":4.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent role of the dorsolateral septum in shaping contextual cocaine memory strength","authors":"S. Qi ,&nbsp;J.L. Ritchie ,&nbsp;D.A. Soto ,&nbsp;A.Y. Pruitt ,&nbsp;D.A. Reeves ,&nbsp;L.M. Artimenia ,&nbsp;R.A. Fuchs","doi":"10.1016/j.neuropharm.2025.110459","DOIUrl":"10.1016/j.neuropharm.2025.110459","url":null,"abstract":"<div><div>Established memories can be destabilized, updated, and reconsolidated into long-term memory stores. Memory updating and reconsolidation can alter the strength of maladaptive contextual drug memories and consequently context-induced drug craving and relapse. The dorsolateral septum (dlS) is a GABAergic nucleus that receives dense direct input from the cornu ammonis 3 regions of the dorsal hippocampus, a brain region that is critical for the maintenance of contextual cocaine memories. Accordingly, we tested the hypothesis that neuronal activity in the dlS regulates the strength of cocaine-predictive contextual memories prior to reconsolidation. Male and female Sprague-Dawley rats received cocaine self-administration training followed by extinction training in two different environmental contexts. After the last extinction training session, the rats were placed back into the cocaine-predictive context to retrieve and destabilize their cocaine-related contextual memories. Immediately or 6 h after memory retrieval, the rats received intra-dlS vehicle or baclofen/muscimol (B/M; GABA_B/A agonists) infusions to inhibit neuronal activity during or after memory updating/reconsolidation, respectively. Resulting changes in cocaine and extinction memory strength were assessed based on the magnitude of unreinforced lever responding in the two contexts. Intra-dlS B/M infusion immediately after memory retrieval increased subsequent context-induced cocaine seeking behaviors in male rats, but not in female rats, whereas delayed B/M treatment had no effects in male rats. Together these findings suggest that the dlS is selectively engaged during memory updating/reconsolidation to reduce the strength of cocaine memories in males, possibly contributing to sex differences in the progression of cocaine use disorder.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110459"},"PeriodicalIF":4.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kappa opioid receptors diminish spontaneous dopamine signals in awake mice through multiple mechanisms","authors":"Conner W. Wallace ,&nbsp;Katherine M. Holleran ,&nbsp;Clare Y. Slinkard ,&nbsp;Samuel W. Centanni ,&nbsp;Christopher C. Lapish ,&nbsp;Sara R. Jones","doi":"10.1016/j.neuropharm.2025.110458","DOIUrl":"10.1016/j.neuropharm.2025.110458","url":null,"abstract":"<div><div>The role of the dynorphin/kappa opioid receptor (KOR) system in dopamine (DA) regulation has been extensively investigated. KOR activation reduces extracellular DA concentrations, but the exact mechanism(s) through which this is accomplished are not fully elucidated. To explore KOR influences on real-time DA fluctuations, we used the photosensor dLight1.2 with fiber photometry in the nucleus accumbens (NAc) core of freely moving male and female C57BL/6J mice. First, we established that the rise and fall of spontaneously arising DA signals were due to DA release and reuptake, respectively. Next, mice were systemically administered the KOR agonist U50,488H in the presence or absence of the KOR antagonist aticaprant. U50,488H reduced both the amplitude and width of spontaneous signals in both sexes. Further, the slope of the correlation between amplitude and width was increased, indicating that DA uptake rates were increased. U50,488H also reduced the frequency of occurrence of signals in males and females. The effects of KOR activation were stronger in males, while effects of KOR antagonism were stronger in females. Overall, KORs exerted significant inhibitory control over spontaneous DA signaling, acting through at least three mechanisms - inhibiting DA release, promoting DA transporter-mediated uptake, and reducing the frequency of signals.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110458"},"PeriodicalIF":4.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does the lateral hypothalamus govern the transition between appetitive and consummatory feeding?","authors":"Mette Kongstorp ,&nbsp;Mahesh M. Karnani ,&nbsp;James E. McCutcheon","doi":"10.1016/j.neuropharm.2025.110438","DOIUrl":"10.1016/j.neuropharm.2025.110438","url":null,"abstract":"<div><div>Feeding is a cyclic behaviour that includes appetitive, consummatory and termination phases. Identifying the neural circuits controlling these phases and triggering specific transitions between phases would be a key advance in understanding feeding behaviour. The lateral hypothalamus (LH) has long been recognized for its central role in feeding. We review evidence suggesting that the LH acts as a regulator of the appetitive-consummatory transition using a switchboard-like circuit architecture. Within the LH, several neuronal subpopulations can be defined based on molecular markers, and - although these subpopulations are functionally diverse - they contribute to appetitive and consummatory behaviours to varying extents. We summarise the current evidence on whether these subpopulations have functional identities and speculate on the role of the LH as a controller of behavioural transitions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"275 ","pages":"Article 110438"},"PeriodicalIF":4.6,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcitonin gene-related peptide (CGRP) exerts membrane, cellular and synaptic actions on serotonergic dorsal raphe neurons ex vivo: Functional implications for a role in dorsal raphe-controlled functions","authors":"Yan Tong Yang ,&nbsp;Cesar R. Romero-Leguizamón ,&nbsp;Majid Sheykhzade ,&nbsp;Yan Zhu ,&nbsp;Kristi Anne Kohlmeier","doi":"10.1016/j.neuropharm.2025.110457","DOIUrl":"10.1016/j.neuropharm.2025.110457","url":null,"abstract":"<div><div>Serotonin (5-HT) plays a role in limbic-controlled behaviors and is implicated in migraine, which is often co-morbid with cognitive-based affective disorders. The neuropeptide calcitonin gene-related peptide (CGRP) regulates vascular tone. Serotonin-acting drugs and CGRP receptor antagonists have proved therapeutic in management of migraine. Clinical interactions between the two systems have been shown, however, whether CGRP exerts direct actions on serotonergic Dorsal Raphe (DR) neurons is unknown. To fully understand the role of CGRP in control of behavior and to predict how CGRP targeted therapies (i.e. CGRP receptor antagonists) could alter DR neuronal activity, investigation of whether CGRP can directly affect 5-HT DR activity was conducted. Patch clamp electrophysiology and single photon calcium imaging in DR brain slices revealed that CGRP (10⁻⁶ M) elicited postsynaptically mediated, potassium-involved outward currents in the majority of 5-HT DR cells. Miniature excitatory synaptic events were reduced in frequency. Further, intracellular calcium was reduced in the majority of neurons, which did not involve actions on the L-type calcium channel. The CGRP agonist SAX replicated effects on the membrane and intracellular calcium. In contrast, the CGRP receptor antagonist MK-3207 blocked the effects on outward current and attenuated the action of CGRP on reducing intracellular calcium. Despite inhibitory membrane and synaptic effects, no change was noted in firing rate. Our findings raise the intriguing possibility that the CGRP system plays a role in mediating limbic-controlled behaviors, at least in part, through direct actions on serotonergic DR neurons, however the effect of CGRP on DR 5-HT output remains to be investigated.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110457"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble tau aggregates decrease the threshold for thalamic oscillations and increase the excitability of thalamic neurons","authors":"Victoria Mitchell ,&nbsp;Bruno G. Frenguelli ,&nbsp;Saskia Bakker ,&nbsp;Richard T. Ngomba ,&nbsp;Magnus Richardson ,&nbsp;Emily Hill ,&nbsp;Mark J. Wall","doi":"10.1016/j.neuropharm.2025.110455","DOIUrl":"10.1016/j.neuropharm.2025.110455","url":null,"abstract":"<div><div>Sleep disturbances frequently occur early in dementias such as Alzheimer's disease (AD) and potentially arise from many factors including cortico-thalamo-cortical (CTC) loop dysfunction. It has been reported that tau filament deposition occurs in the thalamus and there is thalamic atrophy in symptomatic AD patients which could contribute to CTC loop disturbance. Here we have investigated whether human recombinant tau soluble aggregates can induce dysfunction in thalamic circuits. Electrophysiological measurements were made from acutely isolated male and female rat corticothalamic slices following incubation with tau aggregates. Tau aggregates markedly reduced the threshold for inducing spindle-like oscillations and increased the excitability of thalamic neurons. Tau aggregates also significantly enhanced the frequency of miniature excitatory postsynaptic currents recorded in ventrobasal thalamic neurons, suggesting possible changes in terminal Ca²⁺ influx. These pro-excitatory effects of tau aggregates could contribute to the aberrant CTC loop dysfunction observed in AD models and patients, which manifests as sleep disturbances and absence seizures.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110455"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Translocator-Protein Ligand Etifoxine Reduces Pain Symptoms and Protects Against Motor Dysfunction Development Following Peripheral Nerve Injury in Rats","authors":"Yaseen Awad-Igbaria ,&nbsp;Reem Sakas ,&nbsp;Lama Milhem ,&nbsp;Tom Fishboom ,&nbsp;Aviv Ben-Menashe ,&nbsp;Doron Edelman ,&nbsp;Alon Shamir ,&nbsp;Jean F. Soustiel ,&nbsp;Eilam Palzur","doi":"10.1016/j.neuropharm.2025.110456","DOIUrl":"10.1016/j.neuropharm.2025.110456","url":null,"abstract":"<div><div>Peripheral nerve injury enhances mitochondrial translocator protein (TSPO) expression in the spinal cord and dorsal root ganglia (DRG), which is associated with neuroinflammation and mitochondrial dysfunction contributing to chronic pain development. Here, we investigate the effect of TSPO ligand Etifoxine, on the development of chronic pain and motor dysfunction following sciatic nerve injury.</div><div>Mechanical and thermal sensitivity, as well as motor function, were measured in rats before and after sciatic nerve crush (SNC). Rats were treated with the Etifoxine (50 mg/kg, twice daily) for one week. At the end of the experiment, RT-PCR and immunohistochemistry (IHC) were performed to assess mitochondrial stress and neuroinflammation. Additionally, high-resolution respirometry (O2k) was used to evaluate mitochondrial function in the spinal cord following mitochondrial permeability transition pore (mPTP) induction by Ca²⁺.</div><div>Etifoxine treatment post-SNC alleviated mechanical and thermal hypersensitivity, as well as motor dysfunction in rats. In addition, Etifoxine treatment modulates neuroinflammation and mitochondrial stress. Specifically, we found a significant reduction in microglia presence and the transcription of pro-inflammatory cytokines (TNFα, IL-6, IL-1β) in the DRG and spinal cord of the SNC/etifoxine-treated group. Furthermore, Etifoxine treatment prevent the decline in mitochondrial respiration, including non-phosphorylation, ATP-linked respiration, and maximal respiration, after mPTP induction by Ca²⁺.</div><div>Our findings suggest that TSPO-ligand Etifoxine protects against motor dysfunction and the development of chronic pain by reducing neuroinflammation and apoptosis in the DRG and spinal cord. Importantly, the beneficial effects of TSPO-ligands are reflected in the restoration of the mitochondrial function under challenging conditions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110456"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated cocaine exposure and prolonged withdrawal induce spatial memory impairment and dysregulate the glutamatergic synapse composition in the dorsal hippocampus of male rats","authors":"Francesca Mottarlini ,&nbsp;Paolo Miglioranza ,&nbsp;Beatrice Rizzi ,&nbsp;Sofia Taddini ,&nbsp;Susanna Parolaro ,&nbsp;Daniele Caprioli ,&nbsp;Roberto Ciccocioppo ,&nbsp;Lucia Caffino ,&nbsp;Fabio Fumagalli","doi":"10.1016/j.neuropharm.2025.110453","DOIUrl":"10.1016/j.neuropharm.2025.110453","url":null,"abstract":"<div><div>Adolescents are particularly susceptible to various forms of gratification, among which psychostimulants. During adolescence the hippocampus, a brain area relevant to spatial memory domain, undergoes maturational processes, such as structural and molecular reorganization of the excitatory synapses. Our goal was to reveal putatively enduring spatial memory deficits and molecular correlates in male rats exposed to repeated cocaine after a period of withdrawal.</div><div>Towards this goal, adolescent Sprague-Dawley male rats were exposed to chronic cocaine treatment (5 mg/kg/day, subcutaneously) for 15 days and, after 2 weeks of withdrawal, were subjected to spatial order object recognition (SOOR) test, a memory task based on the rat's ability to recognize objects displacement. Next, we investigated subcellular specific expression of markers of the glutamate synapse in the dorsal hippocampus.</div><div>Our findings show that withdrawal from repeated cocaine exposure during adolescence is associated with spatial memory impairment. Such deficit was correlated to a reduced expression and retention of NMDA receptor subunits, GluN1, GluN2A and GluN2B, at both synaptic and extra-synaptic sites, an effect indicative of impaired NMDA receptor trafficking. Analysis of endocytosis markers (Rab family of monomeric GTPase) revealed that cocaine-withdrawn rats favor the degradative pathway (Rab7-Rab9) over the recycling pathway (Rab11). In contrast, saline-treated rats primarily activate the recycling pathway. Our findings, mislocalization of glutamatergic receptors together with sorting of NMDA receptor towards degradation, rather than recycling, may contribute to the understanding of the mechanisms underlying the spatial memory deficits in male rats with an adolescent history of cocaine.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110453"},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}