Although the functional consequences of human methamphetamine (MeAmp) abuse have been extensively documented, the underlying neurobiological mechanisms for those behaviors remain unspecified. Further, neurochemical findings from animal studies have not yielded a cohesive database from which to model the behavioral effects of human MeAmp abuse. The proposed studies will use a unique combination of positron emission tomography (PET), ethological, and immunohistochemical methods to model components of human MeAmp exposure in vervet monkeys. An acute, low dose MeAmp protocol (2 X 2 mg/kg) will be used to produce a pattern of striatal dopamine system neurotoxicity similar to that recently observed in postmortem tissue of human, chronic MeAmp abusers. The results will show that in non-human primates, both the MeAmp-induced striatal dopamine deficits and behavioral sequelae are reversible over an 8 month period; further, that the extent of the neurochemical and behavioral recovery will be reduced in a stressor-environment (unpredictable and unstable social relationships). At 1 month following MeAmp administration, decreases in presynaptic striatal dopamine receptor density will be measured with PET and [11C]WIN35,428, a marker for dopamine transporters. Concurrent with PET, alterations in motor, social and cognitive behaviors will be assessed within a naturalistic setting. With the 1 month WIN deficits as inclusion criteria, the MeAmp subjects will then be divided into two cohorts: one will be maintained normally in its social group, the other subjected to a series of disruptive and unstable social relationships. In this manner, we will determine the significance of an environmental stressor and its evoked behaviors as vulnerability factors for recovery of MeAmp-induced biochemical and behavioral deficits. Postmortem brain analyses of dopaminergic (nigrostriatal, mesolimbic and mesocortical) and glial indices will define the neurotoxicological profile of MeAmp-induced alterations (1 month) and the extent of their reversibility (8 months). These studies will characterize the long-term, neurobiological toxicology of MeAmp in non-human primates and will demonstrate the potential of WIN-PET for evaluating the efficacy of pharmacological therapies designed for treatment of neurotoxic MeAmp exposure.
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