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

• DOI: 10.1007/s00213-025-06765-3
• Publication Date: 2025-03-04T13:15:22Z
• Authors: Leah M. Salinsky; Christina R. Merritt; Erik J. Garcia; Robert G. Fox; Joshua C. Zamora; Noelle C. Anastasio; Kathryn A. Cunnin...
• Keywords: Self-administration; Abuse liability; Cocaine abuse; Cocaine dependence; Dopamine Uptake Inhibitors

Abstract Rationale and objectives Overdose fatalities involving cocaine continue to rise with over 5.3 million users reported in the United States 2022. The abuse liability of is reliant upon inhibition dopamine ( DA ) reuptake consequent increase efflux meso-corticolimbic circuitry that controls reward motivation. Cocaine also increases serotonin 5-HT which integral abuse. 2A receptor R a key regulator release cellular mechanisms underlying effects. actions contribute importantly psychedelic action, efficacy these compounds limiting intake unknown. present studies evaluated acute administration reduce using standard advanced preclinical models drug self-administration. Methods Both fixed ratio FR schedule behavioral economics threshold procedure intravenous self-administration were employed evaluate agonist (−)-2,5-dimethoxy-4-iodoamphetamine [ − )-DOI ] decrease motivation for male rats. R-selective antagonist M100907 was utilized explore role effects (−)-DOI on intake. Results We found dose-dependently reduced FR5 IVSA left shifted demand curve evoke greater sensitivity price paradigm. Pretreatment abated both paradigms. Conclusion ‘devalued’ take R-dependent manner. As serotonergic psychedelics emerge as therapeutic candidates, investigations R-acting analyses relapse vulnerability during abstinence will be valuable prelude future clinical trials.