Alcoholism is a clinical problem that affects millions of people world-wide. Although various aspects of the disease have been extensively studied, its molecular and biochemical etiologies are not understood. Recently, new tools have become available for use in characterizing the symptomatology of alcoholism, and some potential predisposing factors that may play a role in the development of the disease and (or) its clinical course. Mouse lines have been developed for their susceptibility to seizures during withdrawal from chronic ethanol exposure. Thus, withdrawal seizure prone (WSP) and resistant (WSR) mice provide a behavioral model for use in characterizing physiological changes that accompany physical dependence on alcohol. In addition, molecular and biochemical mechanisms that predispose WSP mice to symptoms of withdrawal, and protect WSR mice, can be examined using new radioligands that bind to sites of anticonvulsant action. Within a three year period, the experiments described in this proposal will examine the hypothesis that alterations in the excitatory amino acid receptor - linked ion channel complex in brain precede and accompany susceptibility to seizures during withdrawal from ethanol. Thus, this project will characterize: (1) the sensitivity of [3H]glutamate receptors to glycine and the sensitivity to glutamate and glycine of the associated ion channel binding site for radiolabelled MK-801, a potent and selective anticonvulsant agent, in brains from WSP and WSR mice. (2) the effects of chronic ethanol exposure on each of the above interactions in brain tissue from WSP and WSR mice, and (3) the effects of withdrawal from ethanol on the interactions among receptor sites in the glutamic acid receptor linked - ion channel complex in brain tissue from WSP and WSR mice. The results of these studies could suggest biochemical mechanisms that are involved in the pathophysiology of symptoms of withdrawal, and indicate new directions in research for the development of specific pharmacotherapies that can be used in the treatment of those symptoms.
| Mason, J N; Eshleman, A J; Belknap, J K et al. (2001) NMDA receptor subunit mRNA and protein expression in ethanol-withdrawal seizure-prone and -resistant mice. Alcohol Clin Exp Res 25:651-60 |
