Amphetamine abuse has severe health consequences. Persistent deficits in CNS function, altered cognition, and comorbid psychiatric conditions are suspected outcomes of long-term amphetamine abuse. The immense costs (medical, legal, societal) associated with any drug of abuse are compounded in the case of methamphetamine (METH) because it causes damage to the nervous system. Research in this project is translational in thrust, and will extend and capitalize on progress made in the study of METH-induced neurotoxicity during the previous funding period. Cellular stress caused by reactive oxygen/nitrogen species has been implicated in METH-induced neurotoxicity, but neither the specific reactant nor its cellular source has been identified. The long-term goal of this proposal is to increase understanding of the biochemical and cellular processes that mediate METH neurotoxicity, with a focus on microglia. Activated microglia produce numerous reactants that cause damage to neuronal tissue. On the other hand, pharmacological stimulation of selected microglial receptors can exert neuroprotective effects by preventing their activation. Therefore, the following specific aims will test the hypotheses that METH-induced microglial activation is a critical element of its neurotoxic cascade, and targeting of receptors on microglia that prevent or reduce their activation will protect against METH neurotoxicity: 1) determine the pharmacological and neurochemical features of METH-induced microglial activation with emphasis on the role of dopamine and its quinone;2) assess the functional consequences of microglial activation on METH-induced toxicity in cell culture and in vivo model systems- microglial activation will be provoked by the neurotoxic HIV Tat protein (and other activators) to enhance METH neurotoxicity, and neuroprotective receptors on microglia will be targeted by caffeine (adenosine) and estrogen (ERa) to protect against drug-induced neurotoxicity;and 3) delineate the mechanisms by which microglial activation alters the function of critical proteins (i.e., dopamine transporter and tyrosine hydroxylase) targeted for damage by METH. Completion of these specific aims will contribute to an increased understanding of the neurotoxicity associated with METH. The results of these studies will also have direct translational application to clinical settings where the comorbid consequences of drug abuse are being manifested with increased frequency. Research in this proposal is especially relevant to AIDS- related neuropathology, Parkinson's disease, and other neurodegenerative conditions in which microglial activation contributes to CNS damage.
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