NEUROCHEMICAL ALTERATIONS BY DESIGNER DRUGS

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DESCRIPTION: (Applicant's Abstract) Methcathinone (mCAT) is a phenylisopropylamine which is increasingly abused in the Midwest and across this country due to its potent stimulant properties and the ease with which it is synthesized. Because of its emerging popularity, mCAT was recently classified as a Schedule I drug. Although little research on mCAT has been conducted, its short-term intoxication and severe addiction patterns have been compared to crack cocaine or methamphetamine. We recently reported that single and multiple mCAT administrations caused neurochemical deficits in extrapyramidal and limbic dopaminergic and serotonergic systems as long as 72 h after treatment. Because of these observations, we propose that mCAT exerts profound short- and long-term effects on extrapyramidal and limbic monoaminergic systems and has significant neurotoxic potential. This hypothesis will be tested by achieving the following Specific Aims: A. Identify the short and long-term monoaminergic effects of a single mCAT administration. This will be achieved by [i] assessing with microdialysis the effects of mCAT on the release of monoamines, [ii] determining he persistence of mCAT-induced neurochemical changes in monoaminergic systems after a single administration, [iii] evaluating the role of hyperthermia in the monoamine responses to mCAT, [iv] determining the effects of mCAT on free radical formation and [v] monitoring the presence of mCAT in the brain for 24 h after a single injection. B. Identify long-term consequences of multiple administrations of mCAT on monoaminergic systems. This will be achieved by [i] measuring monoaminergic effects of multiple mCAT administrations up to 30 d after treatment, [ii] identifying factors which are responsible for mediating the long-term changes in the monoaminergic systems after multiple mCAT administrations. C. Compare monoaminergic responses to mCAT with those caused by its naturally occurring (found in the Chat plant) demethylated analog, and possible active metabolite, cathinone. The findings from these studies will help (1) educate current and future users about the risks of mCAT abuse, (2) identify appropriate therapeutic strategies for managing mCAT-induced toxicities, and (3) provide insight to the properties of phenylisopropylamines which make them toxic to either or both the serotonergic and dopaminergic systems.