The abuse of an increasing number of structurally diverse synthetic cathinones is a serious public health problem. The abuse of these agents is of concern for many reasons; including the fact that abuse of structurally related agents such as methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) can cause persistent neurochemical and cognitive deficits. Thus, it is likely that some synthetic cathinones might likewise cause detrimental effects. Still, surprisingly little is known concerning the persistent impact of these agents on monoaminergic neuronal function. An important consideration in evaluating the impact of synthetic cathinones is that as increasing numbers of these agents are banned, illicit operations introduce chemically novel replacements to evade regulatory restrictions. Thus, as described in PAR 14-106, it is important to develop interaction profiles of common synthetic cathinones with entities such as transporters in order to classify them according to their potential abuse liability and toxicity profiles. Such templates will also b useful to anticipate the impact of these novel compounds at various developmental stages, another important focus of this PAR. As one contributor to this template, we will test the hypothesis that differential alterations in dopamine transporter (DAT) and vesicular monoamine transporter-2 (VMAT2) function predict differences in the persistent neurochemical, post-synaptic and functional consequences of synthetic cathinones and related agents; an effect impacted by the developmental stage of initial analog exposure. This will be tested by completing the following aims: 1) Evaluate the acute impact of non-contingent exposure to representatives of each of three established classes of synthetic cathinones (mephedrone, methcathinone and 3,4-methylenedioxypyrovalerone) on DAT and VMAT2 localization and function. We will conduct these studies using both adolescent and young adult rats as others and we have established that these transporters' functions can be differentially regulated as a function of age. Additionally, we will evaluate the impact of these agents on parameters demonstrated to contribute to psychostimulant-induced neurotoxicity, including reactive species formation and glutamate release. 2) Investigate the relationship between drug-induced alterations in monoamine transporter function with behavioral and neurochemical functional outcomes, including the likelihood that these agents will: a) cause persistent monoaminergic deficits; b) alter neurotensin levels, and c) be self-administrated. If self-administered, we will evaluate consequent persistent neurochemical effects as recent studies from others and we demonstrate important distinctions between the impact of contingent and non-contingent stimulant exposure. 3) Evaluate the persistent impact of co-administration of synthetic cathinones with each other, cocaine, METH and/or MDMA on the persistent neurochemical impact on dopaminergic neurons. Others and we have demonstrated that dual or sequential exposure to psychostimulants can profoundly alter their neurotoxic profiles, and thus this issue will be evaluated.
The abuse of an increasing number of structurally diverse synthetic cathinones is a serious public health problem. The abuse of these agents is of concern for many reasons; including the fact that abuse of structurally related agents such as methamphetamine (METH) and MDMA can cause persistent neurochemical and cognitive deficits. This proposal will evaluate the impact of these agents, as well as mechanisms contributing to deficits, both in adolescent and young adult models.
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| German, Christopher L; Gudheti, Manasa V; Fleckenstein, Annette E et al. (2017) Brain Slice Staining and Preparation for Three-Dimensional Super-Resolution Microscopy. Methods Mol Biol 1663:153-162 |
