Effects of Serial Polydrug Use on the Rewarding and Aversive Effects of the Novel Synthetic Cathinone Eutylone

Drugs of abuse have rewarding and aversive effects that in balance mediate drug intake.Although such effects have been reported with a variety of abused drugs, recent work with the synthetic cathinones (a class of new psychoactive substances [NPS]) has reported similar dual properties in this group as well. As individual synthetic cathinones become scheduled and regulated by the Drug Enforcement Administration (DEA), new ones regularly are produced and distributed. One such compound is eutylone, a novel third-generation synthetic cathinone. To date, its affective properties (and abuse potential) remain unknown, and the goal of the following experiments was to begin the characterization of these effects and how they may be impacted by drug history (one factor known to affect reward/aversion for other drugs of abuse). Prior to assessing these effects in a design that allows for the concurrent examination of both affective properties, Experiment 1 tested the ability of C57BL/6 mice to display conditioned taste avoidance (CTA) and conditioned place preference (CPP) in a combined CTA/CPP design induced by the structurally related compound methylone for which such effects have been independently reported. Following this demonstration, eutylone was assessed for its ability to induce CTA (aversive effect) and CPP (rewarding effect) and for their relationship in the combined design (Experiment 2). Following this, the effects of drug history (i.e., cocaine or 3,4- methylenedioxymethamphetamine [MDMA]; Experiment 3) on eutylone’s affective properties were investigated to model human users of these compounds who frequently engage in serial polydrug use. Experiment 1 revealed that independent of sex, mice displayed significant methylone-induced CTA and CPP and these two effects were not related. Experiment 2 demonstrated that eutylone, like methylone, produced dose-dependent aversive and rewarding effects, and again these endpoints were unrelated. Finally, Experiment 3 reported that preexposure to cocaine and MDMA differentially impacted the aversive effects of eutylone (MDMA > cocaine) and did not impact eutylone-induced place preference. Taken together, these data indicate that eutylone, like other synthetic cathinones, has co-occurring, independent rewarding and aversive effects that may contribute to its abuse potential and that these effects are differentially impacted by drug history. Although these studies begin the characterization of eutylone, future studies should examine the impact of factors on these affective properties and its eventual reinforcing effects (i.e., intravenous self-administration [IVSA]) to predict its use and abuse liability.