Human subjects who are dependent on methamphetamine (MA) exhibit functional and structuralabnormalities within frontostriatal circuitry that most likely contribute to behavioral sequelae of MA abuse.Still little is known about the specific neurochemical adaptations that result from MA abuse and how theycontribute directly to impaired neurobehavioral function. Project 3 will employ a non-human primate model ofMA dependence to explore the neurochemical mechanisms contributing to impaired response inhibition (asindexed by a reversal learning task) that results from drug exposure (Aim 1). Using both in vivo and ex vivomeasures of brain catecholamine function, we will generate insights about the molecular and neurochemicaladaptations that contribute directly to functional brain abnormalities revealed in Project 1.These studies will then be extended in two important ways. First, we will explore the mechanisms ofaction of modafinil, a drug that improves response inhibition in humans and which may, through thismechanism, have therapeutic efficacy in the treatment of stimulant dependence. We will deliver modafinil tocontrol and MA-experienced monkeys and will test the hypothesis that this agent exerts pro-cognitive effectsby indirect stimulation of a-2 adrenergic receptors (Aim 2). These complex pharmacological experiments,which are not readily performed in human subjects, will allow us to define a mechanism of action formodafinil and will, in turn, provide a greater understanding of how modafinil produces specific behavioraleffects being studied in Projects 1 and 2. Our final goal is to identify more specific targets for pharmacologicalinterventions. As noted above, modafinil may produce indirect stimulation of a-2 adrenergic receptorsand multiple lines of evidence now supports the notion that direct a-2 adrenoceptor agonists can improvecognition. We will therefore conduct experiments to test the idea that selective activation of a-2 receptorsfacilitates response inhibition in MA-exposed monkeys (Aim 3); these results will be compared with effects ofsubtype-specific dopamine receptor agonists or antagonists, based upon direct evidence supporting theirinvolvement in reversal learning. These experiments have the potential to drive a new phase of medicationevaluation in a mature translational research center. Through these Aims, Project 3 proposes to provide amechanistic foundation for clinical data and to direct future hypothesis testing in clinical populations.
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