Salinsky Leah M, Merritt Christina R, Garcia Erik J, Fox Robert G, Zamora Joshua C, Anastasio Noelle C, Cunningham Kathryn A
The Center for Addiction Sciences and Therapeutics and Department of Pharmacology and Toxicology, John Sealy School of Medicine, University of Texas Medical Branch, Galveston, TX, USA.
Psychopharmacology (Berl). 2025 Mar 4. doi: 10.1007/s00213-025-06765-3.
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 receptor (5-HTR) is a key regulator of meso-corticolimbic DA release and controls cellular mechanisms underlying cocaine effects. 5-HTR 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.
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-HTR agonist (-)-2,5-dimethoxy-4-iodoamphetamine [(-)-DOI] to decrease cocaine intake and motivation for cocaine in male rats. The 5-HTR-selective antagonist M100907 was utilized to explore the role of 5-HTR in the effects of (-)-DOI on cocaine intake.
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.
(-)-DOI 'devalued' cocaine reward and motivation to take cocaine in a 5-HTR-dependent manner. As serotonergic psychedelics emerge as therapeutic candidates, investigations of 5-HTR-acting psychedelics in preclinical analyses of cocaine intake and relapse vulnerability during abstinence will be valuable as prelude to future clinical trials.
涉及可卡因的过量用药致死人数持续上升，2022年美国报告有超过530万可卡因使用者。可卡因的滥用倾向依赖于对多巴胺（DA）再摄取的抑制以及随之而来的中脑 - 皮质 - 边缘系统回路中DA流出的增加，该回路控制奖赏和动机。可卡因还会增加血清素（5 - HT）的流出，这在可卡因滥用中不可或缺。5 - HT受体（5 - HTR）是中脑 - 皮质 - 边缘系统DA释放的关键调节因子，并控制可卡因作用的细胞机制。5 - HTR的作用对迷幻药的作用机制有重要贡献，且这些化合物在限制可卡因摄入方面的功效尚不清楚。本研究使用标准和先进的药物自我给药临床前模型评估了急性给予一种迷幻药以减少可卡因摄入的功效。
采用标准固定比率（FR）给药方案和可卡因静脉自我给药的行为经济学阈值程序，评估迷幻药5 - HTR激动剂（ - ）-2,5 - 二甲氧基 - 4 - 碘苯丙胺[（ - ）-DOI]降低雄性大鼠可卡因摄入量和对可卡因动机的功效。使用5 - HTR选择性拮抗剂M100907探索5 - HTR在（ - ）-DOI对可卡因摄入影响中的作用。
我们发现（ - ）-DOI剂量依赖性地减少了可卡因静脉自我给药FR5方案中的摄入量，并使需求曲线左移，从而在行为经济学范式中对价格上涨产生更高的敏感性。用M100907预处理减弱了（ - ）-DOI在两种范式中对可卡因摄入的功效。
（ - ）-DOI以5 - HTR依赖的方式“贬低”了可卡因奖赏和服用可卡因的动机。随着血清素能迷幻药成为治疗候选药物，在临床前分析可卡因摄入和禁欲期间复发易感性时对作用于5 - HTR的迷幻药进行研究，作为未来临床试验的前奏将具有重要价值。
