Methamphetamine abuse has significantly increased over the past decade and the availability of relatively pure, high potency forms of the drug has led to more chronic, high dose exposure patterns. Converging evidence suggests that profound neurochemical and neuropsychiatric changes can result from methamphetamine abuse and that alterations in striatal dopamine transmission may be implicated in many of these effects. However, it is unclear whether these changes reflect neurodegeneration or adaptational adjustments, nor if functional recovery occurs after discontinuation of drug. Such information is a critical prerequisite to the rational development of effective therapeutic interventions. The proposed research will use a newly developed methamphetamine treatment paradigm that closely simulates, in rats, the drug exposure conditions associated with a high dose, maintenance pattern of methamphetamine abuse, in order to characterize the temporal changes of a broad spectrum of neurochemical and behavioral indices associated with striatal dopamine neuronal transmission. The specific studies are designed to test our hypotheses that: (1) repeated multiple daily administration of methamphetamine will produce profound neurochemical (striatal dopamine nerve terminal markers) and behavioral (spontaneous activity, behavioral organization, and short-term memory) impairments in the absence of dopamine neuronal degeneration; (2) the changes in dopamine transmission (including measures of the dopamine transporter and the vesicular monoamine transporter, as well as extracellular dopamine) and related behavioral deficits will exhibit complete recovery over time; (3) during the late stages of methamphetamine treatment, a spectrum of behaviors associated with the development of paranoid psychosis in stimulant abusers (hyperarousal, increased aggressivity and responsiveness to stress) will gradually emerge, corresponding to a shift in the relative caudate-putamen and nucleus accumbens dopamine responses; and, (4) both the altered behavioral and dopamine effects in response to acute methamphetamine challenge will exhibit gradual recovery over time after discontinuation of chronic treatment. The results of these studies should provide greater insight into the mechanisms and processes contributing to the behavioral and neurochemical consequences associated with a common pattern of methamphetamine abuse.
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