Alcohol-withdrawal induced neurotoxicity and viable options for its treatment have not yet been fully elucidated. However, research indicates a role for polyamine-sensitive sites on the NMDA receptor (NMDAr) system and glucocorticoids in ethanol withdrawal (EWD)-induced neurodegeneration. Further, estimates indicate that approximately 75% of HIV-positive individuals fulfill DSM-IV criteria for alcohol and/or substance abuse. Excessive glucocorticoid release has also been shown to exacerbate certain health problems, including those that contribute to neurodegeneration. Therefore, these studies will examine the role of glutamate and corticosteroid receptors in mediating the superadditive neurotoxic effects of ethanol withdrawal and the HIV- 1 viral protein Tat. For these experiments, adolescent rats will implanted with intra-hippocampal cannula into the CA1 region via stereotaxic surgery. The animals will then be chronically exposed to ethanol and undergo withdrawal, with or without co-exposure to Tat. A subsequent study will investigate the efficacy of novel NMDAr polyamine-site and glucocorticoid receptor antagonists in blocking any resultant neurotoxicity. Brains will be extracted and examined for damage via immunohistochemistry and autoradiographic imaging.
| Butler, T R; Self, R L; Smith, K J et al. (2010) Selective vulnerability of hippocampal cornu ammonis 1 pyramidal cells to excitotoxic insult is associated with the expression of polyamine-sensitive N-methyl-D-asparate-type glutamate receptors. Neuroscience 165:525-34 |
| Self, R L; Smith, K J; Butler, T R et al. (2009) Intra-cornu ammonis 1 administration of the human immunodeficiency virus-1 protein trans-activator of transcription exacerbates the ethanol withdrawal syndrome in rodents and activates N-methyl-D-aspartate glutamate receptors to produce persisting spatial Neuroscience 163:868-76 |
| Self, Rachel L; Smith, Katherine J; Mulholland, Patrick J et al. (2005) Ethanol exposure and withdrawal sensitizes the rat hippocampal CA1 pyramidal cell region to beta-amyloid (25-35)-induced cytotoxicity: NMDA receptor involvement. Alcohol Clin Exp Res 29:2063-9 |
