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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA031604-02
Application #
8227953
Study Section
Special Emphasis Panel (ZRG1-AARR-J (53))
Program Officer
Frankenheim, Jerry
Project Start
2011-04-01
Project End
2014-03-30
Budget Start
2012-04-01
Budget End
2014-03-30
Support Year
2
Fiscal Year
2012
Total Cost
$145,000
Indirect Cost
$45,000
Name
University of South Carolina at Columbia
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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Roscoe Jr, Robert F; Mactutus, Charles F; Booze, Rosemarie M (2014) HIV-1 transgenic female rat: synaptodendritic alterations of medium spiny neurons in the nucleus accumbens. J Neuroimmune Pharmacol 9:642-53
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Moran, Landhing M; Booze, Rosemarie M; Mactutus, Charles F (2013) Time and time again: temporal processing demands implicate perceptual and gating deficits in the HIV-1 transgenic rat. J Neuroimmune Pharmacol 8:988-97
Bertrand, Sarah J; Aksenova, Marina V; Mactutus, Charles F et al. (2013) HIV-1 Tat protein variants: critical role for the cysteine region in synaptodendritic injury. Exp Neurol 248:228-35
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