Differential effects of 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylmethcathinone (mephedrone) in rats trained to discriminate MDMA or a d-amphetamine + MDMA mixture

Abstract

Rationale Recent reports on the abuse of novel synthetic cathinone derivatives call attention to serious public health risks of these substances. In response to this concern, a growing body of preclinical research has characterized the psychopharmacology of these substances, particularly mephedrone (MEPH) or methylenedioxypyrovalerone (MDPV), noting their similarities to MDMA and cocaine. Few studies have utilized drug discrimination methodology to characterize the psychopharmacological properties of these substances. Objectives The present study employed a rodent drug discrimination assay to further characterize the stimulus effects of MEPH and MDPV in comparison to MDMA and to a drug mixture comprised of d-amphetamine and MDMA. Methods Eight male Sprague-Dawley rats were trained to discriminate 1.5 mg/kg 3, 4-methylenedioxymethamphetamine (MDMA) and eight rats were trained to discriminate a mixture of 1.5 mg/kg MDMA and 0.5 mg/kg d-amphetamine (MDMA+AMPH) from vehicle. Substitution tests were conducted with MDMA, d-amphetamine, MDPV, MEPH, and cocaine. Results Dose response curves generated with MDMA and MEPH were comparable between training groups. In contrast, AMPH, MDPV, and cocaine produced only partial substitution in animals trained to discriminate MDMA but produced full substitution in animals trained to discriminate the MDMA+AMPH mixture. Conclusions These findings indicate MDPV's effects may be more similar to those of traditional psychostimulants, whereas MEPH exerts stimulus effects more similar to those of MDMA. Additional experiments with selective DA and 5-HT receptor antagonists are required to further elucidate specific receptor mechanisms mediating the discriminative stimulus effects of MDPV and mephedrone.

Evaluation of training dose in male Sprague-Dawley rats trained to discriminate 4-methylmethcathinone

“…Other reports that used the structurally-related, ring-substituted phenethylamine, MDMA, as the training drug are partially consistent with number of sessions to criterion obtained in the present study. For example, Harvey and Baker (2016) reported that rats required an average of approximately 29 discrimination training sessions to discriminate 1.5 mg/kg from saline, an outcome that is comparable to the average of ~37 sessions observed in the 1.0 mg/kg 4-MMC group. Additional drug discrimination experiments that include experimental procedures comparable to those used herein are warranted to further evaluate discrimination acquisition of 4-MMC and related drugs.…”

“…Preliminary training and discrimination training were identical to procedures described previously (Harvey and Baker, 2016). Briefly, subjects were initially trained to lever press under a fixed ratio (FR) schedule of reinforcement that was gradually increased from FR1 to FR 20.…”

“…2013; Gatch et al . 2013; Harvey and Baker, 2016; Milewski et al 2017; DeLarge et al 2017), and three of these studies used 4-MMC as the training drug (Varner et al 2013; Milewski et al 2017; DeLarge et al 2017). The results of these initial studies indicate 4-MMC produces interoceptive stimulus effects similar to those of MDMA, cocaine, methamphetamine, and fenfluramine, and the extent of stimulus substitution depends on the drug used as the training stimulus.…”

Effects of D1 and D2 receptor antagonists on the discriminative stimulus effects of methylendioxypyrovalerone and mephedrone in male Sprague-Dawley rats trained to discriminate d-amphetamine

“…Interestingly, Sch 39166 also attenuated MEPH substitution. Previous findings from our laboratory showed that MEPH fully substituted in rats trained to discriminate MDMA (a potent serotonin releaser) from saline (Harvey and Baker, 2016). Considered together, these results may suggest that MEPH produces interoceptive stimulus effects through both dopaminergic (i.e.…”

“…Preliminary training, discrimination training, and stimulus generalization testing procedures were identical to those used in previous studies in our laboratory and described elsewhere (Harvey and Baker, 2016). Rats were trained to reliably discriminate 0.5 mg/kg d- amphetamine (AMPH) from vehicle (saline) under a fixed ratio 20 (FR 20) schedule of food reinforcement.…”