Psychopharmacology最新文献

{"title":"Reinforcing effects of fentanyl analogs found in illicit drug markets.","authors":"Alexander D Maitland, Shelby A McGriff, Grant C Glatfelter, Charles W Schindler, Michael H Baumann","doi":"10.1007/s00213-024-06641-6","DOIUrl":"10.1007/s00213-024-06641-6","url":null,"abstract":"<p><strong>Rationale: </strong>The potent synthetic opioid fentanyl, and its analogs, continue to drive opioid-related overdoses. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of clandestine fentanyl analogs (FAs).</p><p><strong>Objectives: </strong>Here, we compared the effects of fentanyl and the FAs acetylfentanyl, butyrylfentanyl, and cyclopropylfentanyl on drug self-administration in male and female rats. These FAs feature chemical modifications at the carbonyl moiety of the fentanyl scaffold.</p><p><strong>Methods: </strong>Sprague-Dawley rats fitted with intravenous jugular catheters were placed in chambers containing two nose poke holes. Active nose poke responses resulted in drug delivery (0.2 mL) over 2 s on a fixed-ratio 1 schedule, followed by a 20 s timeout. Acquisition doses were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, and 0.03 mg/kg/inj for acetylfentanyl and butyrylfentanyl. After 10 days of acquisition, dose-effect testing was carried out, followed by 10 days of saline extinction.</p><p><strong>Results: </strong>Self-administration of fentanyl and FAs was acquired by both male and female rats, with no sex differences in acquisition rate. Fentanyl and FAs showed partial inverted-U dose-effect functions; cyclopropylfentanyl and fentanyl had similar potency, while acetylfentanyl and butyrylfentanyl were less potent. Maximal response rates were similar across drugs, with fentanyl and cyclopropylfentanyl showing maximum responding at 0.001 mg/kg/inj, acetylfentanyl at 0.01 mg/kg/inj, and butyrylfentanyl at 0.003 mg/kg/inj. No sex differences were detected for drug potency, efficacy, or rates of extinction.</p><p><strong>Conclusions: </strong>Our work provides new evidence that FAs display significant abuse liability in male and female rats, which suggests the potential for compulsive use in humans.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2375-2383"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535141","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":"Mechanisms involved in the antidepressant-like action of orally administered 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) in male and female mice.","authors":"Karline da Costa Rodrigues, Meliza da Conceição Oliveira, Beatriz Fuzinato Dos Santos, Nelson Luís de Campos Domingues, Mariana Gallio Fronza, Lucielli Savegnago, Ethel Antunes Wilhelm, Cristiane Luchese","doi":"10.1007/s00213-024-06647-0","DOIUrl":"10.1007/s00213-024-06647-0","url":null,"abstract":"<p><strong>Rationale: </strong>The compound 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) has recently been shown to inhibit in vitro acetylcholinesterase activity, reduce cognitive damage, and improve neuropsychic behavior in mice, making it a promising molecule to treat depression.</p><p><strong>Objectives: </strong>This study investigated the antidepressant-like action of MTDZ in mice and its potential mechanisms of action.</p><p><strong>Results: </strong>Molecular docking assays were performed and suggested a potential inhibition of monoamine oxidase A (MAO-A) by MTDZ. The toxicity study revealed that MTDZ displayed no signs of toxicity, changes in oxidative parameters, or alterations to biochemistry markers, even at a high dose of 300 mg/kg. In behavioral tests, MTDZ administration reduced immobility behavior during the forced swim test (FST) without adjusting the climbing parameter, suggesting it has an antidepressant effect. The antidepressant-like action of MTDZ was negated with the administration of 5-HT1A, 5-HT1A/1B, and 5-HT3 receptor antagonists, implying the involvement of serotonergic pathways. Moreover, the antidepressant-like action of MTDZ was linked to the NO system, as L-arginine pretreatment inhibited its activity. The ex vivo assays indicated that MTDZ normalized ATPase activity, potentially linking this behavior to its antidepressant-like action. MTDZ treatment restricted MAO-A activity in the cerebral cortices and hippocampi of mice, proposing a selective inhibition of MAO-A associated with the antidepressant-like effect of the compound.</p><p><strong>Conclusions: </strong>These findings suggest that MTDZ may serve as a promising antidepressant agent due to its selective inhibition of MAO-A and the involvement of serotonergic and NO pathways.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2385-2402"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617039","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":"Retraction Note: Discontinuation of medications classified as reuptake inhibitors affects treatment response of MDMA-assisted psychotherapy.","authors":"Allison A Feduccia, Lisa Jerome, Michael C Mithoefer, Julie Holland","doi":"10.1007/s00213-024-06671-0","DOIUrl":"10.1007/s00213-024-06671-0","url":null,"abstract":"","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2403"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913752","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":"DSP-6745, a novel 5-hydroxytryptamine modulator with rapid antidepressant, anxiolytic, antipsychotic and procognitive effects.","authors":"Maiko Kitaichi, Taro Kato, Hitomi Oki, Ayaka Tatara, Takuya Kawada, Kenji Miyazaki, Chihiro Ishikawa, Katsuyuki Kaneda, Isao Shimizu","doi":"10.1007/s00213-024-06629-2","DOIUrl":"10.1007/s00213-024-06629-2","url":null,"abstract":"<p><strong>Background: </strong>Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention.</p><p><strong>Objectives: </strong>The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms.</p><p><strong>Results: </strong>In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT_2A, 5-HT_2C, and 5-HT₇ receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition.</p><p><strong>Conclusions: </strong>These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2223-2239"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296631","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":"Regulator of G protein signaling 6 (RGS6) in dopamine neurons promotes EtOH seeking, behavioral reward, and susceptibility to relapse.","authors":"Mackenzie M Spicer, Matthew A Weber, Zili Luo, Jianqi Yang, Nandakumar S Narayanan, Rory A Fisher","doi":"10.1007/s00213-024-06631-8","DOIUrl":"10.1007/s00213-024-06631-8","url":null,"abstract":"<p><p>Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). The neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6^fl/fl; DAT-iCreER mice to determine the role of RGS6 in DA neurons on EtOH consumption, reward, and relapse behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse ventral tegmental area (VTA), and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6^-/- mice. Strikingly, RGS6 loss from DA neurons before or after EtOH behavioral reward is established significantly reduced (~ 50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies identify DA neurons as the locus of RGS6 action in promoting EtOH consumption, preference, reward, and relapse. RGS6 is unique among R7 RGS proteins in promoting rather than suppressing behavioral responses to drugs of abuse and to modulate EtOH behavioral reward. This is a result of RGS6's pre-synaptic actions that we hypothesize promote VTA DA transmission by suppressing GPCR-Gα_i/o-DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2255-2269"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11518640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296632","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":"5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice.","authors":"Huili Zhu, Longyu Wang, Xiaoxuan Wang, Yishan Yao, Peilan Zhou, Ruibin Su","doi":"10.1007/s00213-024-06635-4","DOIUrl":"10.1007/s00213-024-06635-4","url":null,"abstract":"<p><strong>Rationale: </strong>The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2 A receptor (5-HT_2A receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear.</p><p><strong>Objectives: </strong>The primary objective of this study is to investigate the modulation of 5-HT_2A/2C/1A receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM.</p><p><strong>Methods: </strong>In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice.</p><p><strong>Results: </strong>The 5-HT_2A receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500 µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615-10 mg/kg, i.p.) in C57BL/6J mice. M100907 (50 µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25 mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10 mg/kg) in C57BL/6J mice. The 5-HT_2C antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1 mg/kg, i.p.) reduced the HTR induced by a dose of 2.5 mg/kg DOM, but did not affect the response to other doses. SB242084 (1 mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615-10 mg/kg, i.p.) in mice. The 5-HT_1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1 mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gα_i/o inhibitor PTX (0.25 µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice.</p><p><strong>Conclusions: </strong>Receptor subtypes 5-HT_2C and 5-HT_1A are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2315-2330"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446887","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":"Involvement of dysregulated hippocampal histone H3K9 methylation at the promoter of the BDNF gene in impaired memory extinction.","authors":"Kenichi Oga, Manabu Fuchikami, Hironori Kobayashi, Tatsuhiro Miyagi, Sho Fujita, Satoshi Fujita, Satoshi Okada, Shigeru Morinobu","doi":"10.1007/s00213-024-06640-7","DOIUrl":"10.1007/s00213-024-06640-7","url":null,"abstract":"<p><strong>Rationale: </strong>Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Impaired extinction of fear memory (EFM) is one of the core symptoms of PTSD and is associated with stress-induced epigenetic change in gene expression.</p><p><strong>Objectives: </strong>In this study, we examined whether the involvement of histone H3 lysine 9 dimethylation (H3K9me2) in EFM is mediated through brain-derived neurotrophic factor (BDNF) expression in the hippocampus, and whether BIX01294, a selective G9a and GLP histone methyltransferase inhibitor, could be treatment for impaired EFM in an animal model of PTSD.</p><p><strong>Methods: </strong>The single prolonged stress (SPS) paradigm was used to model PTSD. We measured BDNF mRNA levels by RT-PCR, and H3K9me2 levels in the BDNF gene promoters by chromatin immunoprecipitation-qPCR. After undergoing contextual fear conditioning and hippocampal injection of BIX01294, male rats were subjected to extinction training and extinction testing and their freezing times and BDNF mRNA levels were measured.</p><p><strong>Results: </strong>Compared to sham rats, SPS rats showed decreased BDNF mRNA levels 2 h after extinction training, no significant changes in levels of global H3K9me2 prior to extinction training, and increased levels of H3K9me2 in BDNF gene promoter IV, but not in BDNF gene promoter I. Administration of BIX01294 ameliorated the decrease in BDNF mRNA levels 2 h after extinction training and subsequently alleviated impaired EFM in extinction tests in SPS rats.</p><p><strong>Conclusion: </strong>We conclude that reduced hippocampal levels of BDNF mRNA due to increase in H3K9me2 levels may play a role in PTSD-associated EFM impairment, and BIX01294 could be a PTSD treatment option.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2363-2374"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470400","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":"Exploring the efficacy of cholinergic agents for the treatment of psychostimulant use disorder: a systematic review.","authors":"Nicolas Salloum, Margot Chouchana, Romain Icick, Vanessa Bloch, Stéphanie Daumas, Salah El Mestikawy, Florence Vorspan, Virgile Clergue-Duval","doi":"10.1007/s00213-024-06696-5","DOIUrl":"10.1007/s00213-024-06696-5","url":null,"abstract":"<p><strong>Rationale: </strong>No drugs are currently validated to treat psychostimulant use disorder (PUD). Pathophysiological studies consistently highlight the contribution of cholinergic mechanisms in psychostimulant use, including the vulnerability to PUD, paving the way for potential therapeutic strategies.</p><p><strong>Objectives: </strong>The aim of this systematic review is to describe and discuss the efficacy of cholinergic agents in drug trials for patients with PUD.</p><p><strong>Methods: </strong>A systematic review was conducted on April 4, 2024 in MedLine, Embase and Cochrane Library databases on controlled clinical drug trial of cholinergic agents in humans with PUD, psychostimulant abuse or dependence and psychostimulant use in recent year.</p><p><strong>Results: </strong>Twenty-eight articles were included, twenty-one on cocaine and seven on amphetamines. Cholinergic agents used in these studies were biperiden (a muscarinic antagonist), mecamylamine (a nicotinic antagonist), nicotinic agonists, acetylcholinesterase inhibitors (AChEI), or citicoline. Two types of trials were identified. There were seventeen randomized controlled clinical trials evaluating cholinergic agents on psychostimulant use reduction in outpatients seeking treatment. Additionally, we retrieved eleven short-term «proof-of-concept» laboratory trials mainly with supervised psychostimulant administration and/or triggered craving challenges. Outpatient trials were heterogeneous and for most, inconclusive. Only two studies on galantamine (AChEI) and citicoline, reported a significant reduction of cocaine consumption. «Proof-of-concept» laboratory trials showed no evidence of efficacy on the selected outcomes, notably on craving.</p><p><strong>Conclusions: </strong>This review does not support the current prescription of cholinergic agents to treat PUD. Replication clinical trials notably on galantamine or other AChEI, and proof-of-concept trials on comedown symptoms will be necessary to identify a potential therapeutic indication for cholinergic agents in PUD.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2205-2222"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473281","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":"Retraction Note: MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials.","authors":"Michael C Mithoefer, Allison A Feduccia, Lisa Jerome, Anne Mithoefer, Mark Wagner, Zach Walsh, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Rick Doblin","doi":"10.1007/s00213-024-06666-x","DOIUrl":"10.1007/s00213-024-06666-x","url":null,"abstract":"","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2405"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913754","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":"Effects of chronic naltrexone treatment on relapse-related behavior and neural responses to fentanyl in awake nonhuman primates.","authors":"Sarah L Withey, Harshawardhan U Deshpande, Lei Cao, Jack Bergman, Stephen J Kohut","doi":"10.1007/s00213-024-06633-6","DOIUrl":"10.1007/s00213-024-06633-6","url":null,"abstract":"<p><p>Naltrexone, an opioid antagonist that blocks the reinforcing properties of opioid agonists, is often prescribed to preclude relapse to opioid use disorder (OUD) following detoxification. However, few laboratory studies have directly investigated the ability of naltrexone to alter relapse-inducing effects of opioid agonists, including their priming strength in reinstatement studies and their impact in brain regions known to be involved in drug-induced reinforcement in MRI studies. Here we directly address this issue by investigating the effects of continuous exposure to naltrexone on 1) fentanyl-induced reinstatement of drug-seeking behavior, 2) fentanyl-induced patterns of blood oxygenation level dependent (BOLD) activation in the nucleus accumbens (NAcc), and 3) fentanyl-induced changes in NAcc functional connectivity (FC) in awake non-human primates that are engaged in ongoing opioid self-administration studies. We found that naltrexone antagonizes the priming strength of fentanyl as shown by a rightward shift in its reinstatement dose-effect curve and that naltrexone surmountably antagonizes the BOLD response induced by fentanyl. However, while naltrexone also countered fentanyl's effects on NAcc FC, the effects were not surmounted by a higher dose of fentanyl. Together, these data suggest that, in contrast to naltrexone's modulation of fentanyl's effects on behavior and BOLD responses, their interactive effects on FC between multiple brain regions do not reflect their receptor-mediated activity. Additionally, we demonstrated opposing effects in the absence and presence of naltrexone on NAcc FC at baseline (i.e., in the absence of any fentanyl prime) suggesting that naltrexone alters FC at baseline, even though naltrexone appears behaviorally silent in the absence of an agonist prime. Together these data provide additional insight into ways in which naltrexone interacts with opioid agonists, both behaviorally and in the brain. Further understanding the effects of opioid agonists on patterns of FC could help elucidate our understanding of the neural processes that contribute to the initiation of and relapse to opioid-seeking behavior in OUD.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2289-2302"},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913751","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}