Cathinone and methcathinone are the -ketone analogs of amphetamine and methamphetamine, respectively, and like their amphetamine analogs, cathinone and methcathinone function as monoamine releasers that selectively promote the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). Cathinone and methcathinone produce amphetamine-like, psychostimulant effects and are classified as Schedule I drugs of abuse by the United States Drug Enforcement Agency (DEA). Recently, synthetic cathinone analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like bath salts in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse display varying selectivity to promote release of DA/NE vs. 5-HT, and selectivity for DA neurotransmission is believed to correlate with abuse liability. This F30 application proposes preclinical research to examine the structural determinants of abuse-related behavioral and neurochemical effects produced by synthetic cathinone bath salts. To evaluate structural determinants of the abuse-related stimulant effects of cathinone derivatives, this application will focus on one feature of the methcathinone scaffold: the para substituent of the benzene ring. A series of six novel methcathinone derivatives will be examined in order to evaluate how physicochemical parameters (steric volume, lipophilicity and electron-donating/withdrawing capacity) of the para substituent of methcathinone derivatives influence in vitro monoamine transporter selectivity as well as in vivo neurochemical and behavioral effects. We hypothesize that electronic features of the para substituent will correlate with neurochemical selectivity to promote DA vs. 5-HT release as determined by in vivo microdialysis and behavioral selectivity to produce abuse-related effects as determined by intracranial self-stimulation (ICSS). Completion of this project will provide an improved understanding of the mechanism of synthetic cathinone analogs' abuse-related effects, allowing for development of novel strategies for treating bath salts intoxication and improvement of clinical outcomes associated with bath salts abuse.
This application proposes to investigate structural determinants of abuse-related neurochemical and behavioral effects of synthetic cathinone 'bath salts,' an emerging class of abused stimulants that poses an imminent threat to public safety. A series of compounds with systematic structural modifications will be examined in (a) in vitro electrophysiological studies in Xenopus oocytes to determine monoamine transporter selectivity, (b) in vivo microdialysis to assess abuse-related neurochemical effects, and (c) a behavioral assay of intracranial self-stimulation in rats to investigate abuse-related behavioral effects. Quantitative Structure-Activity Relationship (QSAR) analysis will be used to correlate structural features of drug molecules to electrophysiological, neurochemical and behavioral effects, and results will provide novel insights on determinants of stimulant abuse that could guide future efforts at drug prevention and treatment.
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