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Dopaminergic and Non-Dopaminergic Interactions Between HIV Proteins and Drugs of Abuse

A. Nath, Booze RM, Hauser K, Maragos W, Cass W, Mactutus C
Departments of Neurology, Microbiology and Immunology, Anatomy and Neurobiology, University of Kentucky, Lexington, KY

HIV infection selectively targets the basal ganglia resulting in loss of dopaminergic neurons, decreased dopamine levels in the cerebrospinal fluid and increasing susceptibility to Parkinsonism (Mirsattari et al 1998). HIV proteins gp120 and Tat when injected into the basal ganglia cause selective neuronal loss and gliosis (Jones et al 1998). Gp120 produced a much more gliotic reaction as compared to Tat, while Tat leads to loss of nigrostriatal fibers . Gp120 and Tat also cause synergistic neurotoxicity when adminstered together at subtoxic dosages and these proteins may also synergize with other neurotoxic compounds such as glutamate to cause neurotoxicity(Nath et al 2000) Common drugs of abuse such as methamphetamine and cocaine also cause dopaminergic dysfunction (Nath et al., in press). In vitro studies show that gp120 and Tat cause synergistic neurotoxicity with methamphetamine and cocaine, the latter of which can be blocked by estrogen. Such synergistic neurotoxicity, however, may not be limited to dopaminergic drugs, since Tat and morphine also cause synergistic neurotoxicity in striatal neurons that can be blocked by naloxone (Gurvell et al., submitted). The combination of well defined in vitro studies with the use of pharmacologically and physiologically relevant animal models of drug abuse will greatly advance this area of research in identifying the underlying mechanisms responsible for interactions with HIV and drugs of abuse as well as identifying appropriate pharmacological interventions.


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  2. Gurwell JA, Nath A, Martin KM, Chen Y, Hauser KF. Synergistic Neurotoxicity of Opioids and HIV-1 Tat Protein in Striatal Neurons (submitted).

  3. Jones, M., Olafson, K., Del Bigio, M. R., Peeling, J., Nath, A. 1998. Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) Tat protein causes inflammation, gliosis, apoptosis, and ventricular enlargement. J Neuropathol Exp Neurol 57:563-570.

  4. Mirsattari, S. M., Power, C., Nath, A. 1998. Parkinsonism with HIV infection. Mov Disord 13:684-9.

  5. Nath, A., Haughey, N. J., Jones, M., Anderson, C., Bell, J. E., Geiger, J. D. 2000. Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine. Ann Neurol 47:186-94.

  6. Nath A, Jones M, Maragos W, Booze RM, Mactutus C, Bell J, Mattson M. Neurotoxicity and Dysfunction of Dopaminergic Systems Associated with AIDS Dementia. J Psychopharmacology In Press.

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