Biological sex modulates the efficacy of 2,5-dimethoxy-4-iodoamphetamine (DOI) to mitigate fentanyl demand

Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT_2AR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration.

Male and female Sprague-Dawley rats (n = 25-29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2μg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a ¼ log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q₀ and α.

Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT_2AR activation decreased Q₀ in female rats but increased Q₀ in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency.

DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT_2AR activation sex-dependently alters opioid reinforcement.