Dissecting the Abuse Liability of Synthetic Cathinone Stimulants

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The use of synthetic psychoactive cathinone drugs (“bathsalts”) continues to expand worldwide and in the United States of America despite legal control efforts internationally, at the US federal level, within multiple US states and even the local US jurisdictions. The established stimulants such as cocaine and methamphetamine are highly addictive, can be acutely lethal and can result in long- term brain alterations with many implications for health and well-being. Recent studies show that 3,4- methylenedioxypyrovalerone (MDPV) is a highly potent and efficacious reinforcer, predicting abuse liability equal to or greater than that of cocaine and methamphetamine. Compounds such as Mephedrone and Methylone produce subjective properties that are similar to 3,4- methylenedioxymethamphetamine (MDMA) but have exhibit much greater propensity for compulsive use in human report and rodent self-administration studies. This project responds to the goals of PAR-14-106 Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects by determining structural determinants of the addiction liability of synthetic cathinones. Tremendous diversity of cathinone structure exists in the recreational market, driven in part by legal control of earlier-appearing drugs. This reality demands approaches which can both advance understanding of the actions of currently popular drugs and generate better predictions regarding which design motifs may convey increased abuse liability in emerging compounds. To that end, studies under Aim I and Aim II will elucidate the contributions of the 3,4-methylenedioxy and 4- methyl aromatic ring substitutions, respectively, to the reinforcement potency and efficacy of cathinones. One distinct feature of MDPV is an extended carbon chain which confers enhanced lipophilicity. The goal of Aim III is to determine if stimulant drug efficacy in intravenous self- administration is affected by lipophilicity, which affects speed of brain entry. In total, these proposed studies on the reinforcing effects of various synthetic cathinones will advance our understanding of the health risks associated with designer stimulant drugs.