Methamphetamine and HIV-1: NMDAR/D1 mediated neurologic effects

DESCRIPTION (provided by applicant): The additive effects of HIV infection and methamphetamine (METH) abuse on cognitive function represent a serious medical problem. Experimental evidence indicates that neurotoxic viral proteins, particularly HIV-1 Tat and gp120, can cooperate with METH and promote neurodegeneration. However, mechanisms of such cooperation are elusive. Our prior research and preliminary studies indicate that the molecular mechanism of combined METH/Tat and/or METH/gp120 toxicity may involve concurrent adverse effects of these neurotoxins on key components of dopaminergic and glutamatergic transmission systems. This application will test the hypothesis that pathways of direct METH and HIV-1 protein-mediated neurotoxicity congregate to disrupt normal physical interactions between D1 and NMDA receptors. Thus, neurons, which co- express NMDA receptor complexes (NMDAR) and dopamine (DA) D1 receptors may be selectively sensitive to the injury concurrently incited by individually non-toxic doses of METH and HIV-1 proteins. This hypothesis will be tested in vitro using the primary rodent and human neural cell culture models of Tat/gp120/METH neurotoxicity. Faltered functional D1R/NMDAR interactions, which are often referred as the engine of cognition, may critically influence the development of persistent memory deficits in HIV-positive methamphetamine abusers. The broad goal of our studies is to elucidate the molecular base of additive deleterious cognitive effects of METH and HIV infection. Results of the project will have an impact on the preclinical research of effective protective strategies to improve the health and well-being of METH-dependent individuals living with HIV/AIDS. PUBLIC HEALTH RELEVANCE: The additive effects of HIV infection and methamphetamine (METH) abuse on cognitive function represent a serious medical problem. The present research proposal will investigate the role of D1R/NMDAR interactions in the overlapping pathway of METH/HIV-1 protein neurotoxicity. The broad goal of the research is to elucidate the molecular basis of METH/HIV-induced cognitive deficits.