MDPV High‐responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder

Abstract

A subset of rats that self-administer 3,4-methelyendioxypyrovalerone (MDPV; a synthetic cathinone commonly identified in “bath salts” preparations) develop unusually high levels of drug-taking, with these “high-responders” earning ~3-5 times as much MDPV as “low-responders” under a fixed ratio schedule of reinforcement. High-responder rats display other behaviors consistent with a SUD-like phenotype (e.g., high levels of drug-seeking, decreased sensitivity to footshock punishment, etc.), and thus provide an appropriate and novel model to evaluate candidate medications for stimulant use disorders. Given MDPV's actions on dopamine, serotonin (5-HT), and sigma systems, the current studies determined whether a dopamine D2-like receptor antagonist (sulpiride), dopamine D2-like and sigma receptor antagonist (haloperidol), sigma receptor antagonist (BD1063), 5-HT2A receptor antagonist (MDL100907), or 5-HT2C receptor agonist (CP809101) could preferentially inhibit drug-taking in high-responders relative to low responders and/or rats responding for cocaine or methamphetamine. Accordingly, adult Sprague Dawley rats responded under a six-component FR5 schedule of reinforcement with food (grain-based pellets) available for responding during the first and sixth components, and increasing unit doses of drug (0.0032-0.1 mg/kg/infusion MDPV, 0.0032-0.1 mg/kg/infusion methamphetamine, or 0.032-1.0 mg/kg/infusion cocaine) available during the second through fifth components. Sulpiride, MDL100907, and CP809101 appeared to be equipotent at decreasing self-administration of MDPV (high- and low-responders), cocaine, and methamphetamine. In contrast, BD1063 selectively attenuated MDPV self-administration in high-responder rats without altering responding in low-responders or rats responding for cocaine or methamphetamine. Similarly, haloperidol effectively decreased MDPV self-administration in high-responders at doses smaller than those that were required to decrease responding in MDPV low-responders and rats responding for cocaine or methamphetamine. These studies provide insight into different targets as treatments for stimulant use disorder, and, importantly, suggest sigma receptors may be a key target for novel pharmacotherapies that aim to normalize high levels of dysregulated drug-taking.