Hippocampal neurotoxicity induced by ethanol withdrawal

University Of Kentucky, Lexington KY

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Abstract

Alcohol dependence and abuse likely cost more than $200 billion in lost productivity and healthcare annually in the United States. Brain injury is among the most prominent effects of prolonged alcohol use and appears to contribute to the development of neurological abnormalities. Thus, examination of biochemical pathways involved in this form of brain injury may be of value in identifying therapeutic targets to be exploited in treating alcohol-related brain injury. Excess activity of N-methyl-D-asparate (NMDA)-type glutamate receptors has been implicated in both the behavioral and neurotoxic effects of alcoholism, particularly during alcohol withdrawal, when excess release of glutamte and polyamines occurs. Polyamines are endogenous substances that, among other things, act as allosteric activators of NMDA receptors at NR 2 subunits. Substances that further promote activity of NMDA receptor systems, such as glucocorticoids, are hypothesized to exacerbate alcohol withdrawal effects. Indeed, prolonged alcohol intake is associated with hypercortisolemia likely resulting from alcohol effects on hypothalamic corticotropin releasing hormone (CRH) receptors. However, the consequences of elevated stress hormone release with regard to alcoholrelated neuronal injury have been little studied. The proposed in vitro and in vivo rodent studies will test the hypothesis that alcohol-induced activation of the hypothalamic pituitary adrenal axis promotes NMDA receptor-mediated seizure and neurotoxicity during alcohol withdrawal by: (1) stimulating the synthesis and release of polyamines via upregulation of the synthetic enzyme ornithine decarboxylase, an effect dependent upon glucocorticoid receptor (GR) activation; and (2) upregulating the expression of polyamine-sensitive NR2B subunits, thus, promoting NMDA channel opening and neuronal excitation and/or neurotoxicity in a GR-dependent manner. These studies will employ biochemical, immunohistochemical, confocal imaging, and behavioral studies using an in vivo "moderate" binge-alcohol exposure paradigm that produces peak B.A.L.s of ~160 mg/dl and organotypic hippocampal slice cultures, in parallel studies. It is the aim of these studies to elucidate the means by which glucocorticoids may exacerbate alcohol withdrawal behavioral and physiological effects, as these relevant biochemical pathways may represent therapeutic targets to be exploited in the treatment of alcohol withdrawal effects.