Dopamine D1-Like Receptor Agonist and D2-Like Receptor Antagonist (-)-Stepholidine Reduces Reinstatement of Drug-Seeking Behavior for 3,4-Methylenedioxypyrovalerone (MDPV) in Rats.

Psychostimulant reinforcement is mediated by stimulation of both dopamine (DA) D1-like and D2-like receptors, suggesting that pharmacotherapy agents with a dual DA receptor mechanism may be useful for managing psychostimulant abuse. (-)-Stepholidine (L-SPD) is a Chinese herbal extract that functions as a D1-like receptor agonist and D2-like receptor antagonist. L-SPD has been shown to attenuate the reinforcing effects of heroin; however, its effects on the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) have not been examined. The current study determined the effects of L-SPD on reinstatement of MDPV-seeking behavior in the drug intravenous self-administration (IVSA) and conditioned place preference (CPP) paradigms. To determine whether the effects of L-SPD were specific to psychostimulant reinforcement, we also examined its effects on sucrose-seeking behavior. Using a locomotor activity assay, we tested the locomotor effects of L-SPD, as well as its effects on MDPV-induced hyperactivity. The results of a battery of in vitro binding and functional assays confirmed that L-SPD functioned as a D1-like receptor agonist and D2-like receptor antagonist. In behavioral experiments, L-SPD dose-dependently attenuated cue plus MDPV-primed reinstatement of MDPV-seeking behavior in the IVSA model. The highest dose of L-SPD also attenuated MDPV-primed reinstatement of MDPV CPP, as well as cue-induced reinstatement of sucrose-seeking. L-SPD had no significant locomotor effects, and did not modulate the robust hyperactivity induced by MDPV. The current findings show for the first time a robust reinstatement effect with MDPV, which can be reduced by L-SPD. These results establish a role for DA receptors in drug-seeking behavior for MDPV.

Stereoselective Differences between the Reinforcing and Motivational Effects of Cathinone-Derived 4-Methylmethcathinone (Mephedrone) In Self-Administering Rats.

Mephedrone (4-methylmethcathinone (4-MMC)) (MEPH) is a new psychoactive substance (NPS) of the synthetic cathinone class. MEPH has a chiral center and exists as two enantiomers (R-,S-MEPH), yet stereospecific effects of MEPH have not been extensively investigated in preclinical assays. Because significant behavioral and neurochemical differences can exist between enantiomers, probing effects of stereochemistry on biological activity enables separation of adverse and therapeutic effects. Our prior work showed that R-MEPH, relative to S-MEPH, produced greater locomotor activation, place preference, and facilitation of brain reward thresholds in rodents. The present study sought to determine if MEPH enantiomers display stereospecific reward and reinforcement in rat self-administration assays. In Experiment 1, rats were trained to self-administer racemic MEPH (0.50 mg/kg/inf), and dose substitution effects of R-MEPH (0.50 mg/kg/inf) and S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) were examined. In Experiment 2, separate rats were trained to self-administer R-MEPH (0.25, 0.50, 2.00 mg/kg/inf) or S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) and were thereafter evaluated under progressive-ratio access conditions. Within this cohort, 50 kHz ultrasonic vocalizations (USVs) were recorded to measure potential differences in subjective positive affect associated with MEPH enantiomer self-administration. We identified enantiomer- and dose-dependent effects on infusions earned during self-administration following acquisition of racemic MEPH, with greatest infusions under low-effort, fixed-ratio 1 access conditions from low-dose S-MEPH self-administration. When taxed with progressive-ratio access conditions, rats trained to self-administer R-MEPH showed higher break points than those of rats trained to self-administer S-MEPH. Additionally, R-MEPH elicited greatest rates of 50 kHz USVs compared to S-MEPH. Taken together, these data suggest that the R-enantiomer of MEPH is primarily responsible for the rewarding, reinforcing, and motivational properties of racemic MEPH, which increases our understanding of stereospecific preferences pertaining to MEPH abuse.