The goals of this application are to elucidate the cellular and molecular mechanisms by which the HIV envelope protein gpl20 induces dysfunction of peptidergic neurons in the cocaine abused developing brain, with emphasis on one of the most abundant peptidergic neurons -- the neuropeptide Y (NPY) neuron. NPY has been implicated in a wide range of brain functions including mentation and it has been implicated in neuropathological symptoms expressed by cocaine abusing people. Two working hypotheses will be challenged. One, gpl20 induces defective signal transduction (and eventually neuronal death) in the brain of AIDS patients and this is due, in part, to an effect of gpl20 on the neuron itself and/or other cells the secretory products of which regulate neuronal function. Two, cocaine alters the functional state of multiple cellular systems (neurons and/or astrocytes) in the developing brain such that specific neuronal populations become highly susceptible to the neurotaxic effects of gpl20. Two experimental models, operative in our laboratory, are proposed: an in vitro model - fetal NPY neurons derived from intact rats and an in vivo/in vitro model - fetal neurons derived from cocaine-treated pregnant rats. S.A.1. Characterize the biochemical and molecular parameters of cocaine facilitation of gpl20 suppression of the functional state of the cultured NPY neuron. S.A.2. Investigate the nature of the receptor(s) mediating gpl20-induced neuronal dysfunction. S.A.3. Elucidate the role of glial cells in cocaine/gpl20 action on the NPY neurons. The results generated in these studies will provide insight into the mechanisms underlying gpl20 actions in the cocaine abused developing brain, which will serve as the baseline/guide for the design of therapeutic agents for future clinical management and possibly prevention of abnormalities expressed in the brains of HIV-infected people. An important and most timely outcome of this study will be the availability of an in vitro reliable model system to test the efficacy of newly designed therapeutic agents.
| Barnea, A; Aguila-Mansilla, N; Bigio, E H et al. (1998) Evidence for regulated expression of neuropeptide Y gene by rat and human cultured astrocytes. Regul Pept 75-76:293-300 |
