The psychedelic (-)-2,5-dimethoxy-4-iodoamphetamine [(-)-DOI] demonstrates efficacy in reducing cocaine reward and motivation in male rats.

IF 3.3 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2025-08-01 Epub Date: 2025-03-04 DOI:10.1007/s00213-025-06765-3

Leah M Salinsky, Christina R Merritt, Erik J Garcia, Robert G Fox, Joshua C Zamora, Noelle C Anastasio, Kathryn A Cunningham

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引用次数: 0

Abstract

Rationale and objectives: Overdose fatalities involving cocaine continue to rise with over 5.3 million cocaine users reported in the United States in 2022. The abuse liability of cocaine is reliant upon inhibition of dopamine (DA) reuptake and consequent increase in DA efflux in meso-corticolimbic circuitry that controls reward and motivation. Cocaine also increases serotonin (5-HT) efflux which is integral in cocaine abuse. The 5-HT_2A receptor (5-HT_2AR) is a key regulator of meso-corticolimbic DA release and controls cellular mechanisms underlying cocaine effects. 5-HT_2AR actions contribute importantly to psychedelic mechanisms of action, and the efficacy of these compounds in limiting cocaine intake is unknown. The present studies evaluated the efficacy of acute administration of a psychedelic to reduce cocaine intake using standard and advanced preclinical models of drug self-administration.

Methods: Both a standard fixed ratio (FR) schedule and behavioral economics threshold procedure of cocaine intravenous self-administration were employed to evaluate the efficacy of the psychedelic 5-HT_2AR agonist (-)-2,5-dimethoxy-4-iodoamphetamine [(-)-DOI] to decrease cocaine intake and motivation for cocaine in male rats. The 5-HT_2AR-selective antagonist M100907 was utilized to explore the role of 5-HT_2AR in the effects of (-)-DOI on cocaine intake.

Results: We found that (-)-DOI dose-dependently reduced intake on the FR5 schedule of cocaine IVSA and left shifted the demand curve to evoke greater sensitivity to price increases in the behavioral economics paradigm. Pretreatment with M100907 abated the efficacy of (-)-DOI on cocaine intake in both paradigms.

Conclusion: (-)-DOI 'devalued' cocaine reward and motivation to take cocaine in a 5-HT_2AR-dependent manner. As serotonergic psychedelics emerge as therapeutic candidates, investigations of 5-HT_2AR-acting psychedelics in preclinical analyses of cocaine intake and relapse vulnerability during abstinence will be valuable as prelude to future clinical trials.

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致幻剂(-)-2,5-二甲氧基-4-碘安非他明[(-)- doi]在雄性大鼠中显示出降低可卡因奖励和动机的功效。

理由和目标：涉及可卡因的过量死亡人数继续上升，2022年美国报告的可卡因使用者超过530万。可卡因的滥用倾向依赖于多巴胺（DA）再摄取的抑制和随后在控制奖励和动机的中脑皮质边缘回路中多巴胺外排的增加。可卡因还会增加5-羟色胺（5-HT）的外排，这是可卡因滥用的组成部分。5-HT2A受体（5-HT2AR）是中皮质边缘DA释放的关键调节因子，并控制可卡因效应的细胞机制。5-HT2AR的作用对致幻剂的作用机制起着重要作用，这些化合物在限制可卡因摄入方面的功效尚不清楚。本研究采用标准和先进的药物自我给药临床前模型，评估了急性给药减少可卡因摄入量的效果。方法：采用标准固定比例（FR）方案和行为经济学阈值程序，评价致幻剂5-HT2AR激动剂(-)-2,5-二甲氧基-4-碘安非他明[(-)- doi]对雄性大鼠可卡因摄入量和可卡因动机的影响。利用5-HT2AR选择性拮抗剂M100907，探讨5-HT2AR在(-)- doi对可卡因摄入的影响中的作用。结果：我们发现(-)- doi剂量依赖性降低了可卡因IVSA FR5时间表的摄入量，并使需求曲线左移，从而在行为经济学范式中唤起对价格上涨的更大敏感性。M100907预处理降低了(-)- doi对可卡因摄入的影响。结论：(-)- doi以5- ht2ar依赖的方式“贬低”了可卡因奖励和吸食可卡因的动机。随着5-羟色胺能致幻剂成为治疗的候选药物，研究5- ht2ar致幻剂在戒断期间可卡因摄入和复发脆弱性的临床前分析将为未来的临床试验提供有价值的铺垫。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

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.