R-(-)2,5-dimethoxy-4-iodoamphetamine [(-)-DOI] decreases cocaine demand in a 5-HT2AR-mediated manner

Abstract

<b>Abstract ID 27882</b> <b>Poster Board 3</b> <b>Aims:</b> Drug overdose deaths within the U.S. reached an unprecedented high, surpassing 100,000 in 2021. Cocaine overdoses account for ∼15,000 deaths each year and cocaine use disorder (<b>CUD</b>) remains a challenge to treat, with the current standard of care reliant primarily on psychosocial interventions, such as cognitive behavioral therapy. Efficacious pharmacotherapeutic support for CUD is an important goal in our field. In the last decade, there has been a resurgence of interest in serotonergic psychedelics as potential therapeutics for substance use and mental disorders, including CUD. Agonist actions at the serotonin (<b>5-HT</b>) 5-HT_2A receptor (<b>5-HT_2AR</b>) contribute importantly to psychedelic mechanisms of action, and the efficacy of these compounds in limiting cocaine intake is unknown. In the present studies, we tested the hypothesis that the psychedelic 5-HT_2AR agonist R-(-)2,5-dimethoxy-4-iodoamphetamine (<b>DOI</b>) will decrease cocaine demand in a rodent behavioral economics model. <b>Methods:</b> Male, Sprague-Dawley rats (n = 28) were trained to self-administer cocaine (0.75 mg/kg) for daily 180-min sessions until stability on an FR3 schedule of reinforcement. Upon stability, daily sessions on the threshold procedure were initiated. During each 110-min session, progressively smaller doses of cocaine were available. The duration of infusion decreased by 0.25 log per block across 11 blocks lasting 10-min each, decreasing the dose of drug earned per infusion from 0.75 mg/kg/inf to 0.003 mg/kg/inf. Pharmacological testing with DOI treatment (0.03, 0.1, 0.3 mg/kg; s.c., 20 min prior to session) began upon establishment of stable demand elasticity (<b>α</b>) and demand intensity (<b>Q₀</b>). Treatment with the selective 5-HT_2AR antagonist M100907 (0.01 mg/kg; i.p., 30 min prior) was employed to assesses the role of the 5-HT_2AR in the behavioral effects of DOI. Demand curves for each subject were plotted with number of reinforcers earned[KC1] (consumption, mg) as a function of FR requirement (price) and the data were fitted using an exponential model. The effect of DOI on measurements of cocaine demand was analyzed with an experimentwise error rate of α=0.05. <b>Results:</b> Analysis indicated that DOI treatment dose-dependently decreased cocaine demand elasticity, price point at maximum expenditure, maximum expenditure, essential value, breakpoint, and the area under the demand curve (<i>p</i> &lt; 0.05) without altering measurements of task disruption. DOI did not significantly alter cocaine demand intensity. The selective 5-HT_2AR antagonist M100907 prevented DOI-induced suppression of most measures in the cocaine demand paradigm (<i>p</i> &lt; 0.05[KC2] ). <b>Conclusions:</b> The current studies reveal that the psychedelic DOI decreases the motivational effects of cocaine, which were reversed by the 5-HT_2AR antagonist M100907. These data suggest that while cocaine may still be reinforcing[ANC3] at minimal prices, the rats are less willing to work for cocaine after DOI pretreatment, and provide support for expanded interrogation of the efficacy of 5-HT_2AR agonist psychedelics in counteracting the behavioral effects of cocaine. This work was supported by Center for Addiction Research at the University of Texas Medical Branch.