- Substantial progress was made on this project, with five original research articles and three reviews published. Along with our collaborators, we have characterized the pharmacological effects of numerous synthetic cannabinoids, cathinones and opioids found in the street drug marketplace. In a representative study, we described the molecular mechanism of action and pharmacological effects for the bath salts constituent methylone and its various metabolites. Methylone is constituent of products sold on the street as MDMA (i.e., counterfeit Ecstasy pills). Our findings from rat experiments show that methylone is extensively metabolized in a manner similar to MDMA. In particular, methylone displays non-linear kinetics after systemic administration, whereby plasma drug concentrations are much greater than dose-proportional. The N-demethylated metabolite, 3,4-methylenedioxycathinone is a potent transporter releaser in vitro and in vivo, suggesting this metabolite can contribute to effects of systemically administered methylone. Our findings in rats highlight the inherent risks to human users who inadvertently abuse methylone as a constituent of counterfiet Ecstasy pills. 3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the -keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (Tmax=15-45min) and were short lived (t1/2=60-90min), while HHMC and HMMC peaked later (Tmax=60-120min) and persisted (t1/2=120-180min). Area-under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.
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