Although there is both concern and evidence that alcoholism augments age- related CNS abnormalities, the mechanism by which this happens is not understood. Alcohol's potentiation of age-related CNS abnormalities may be partly due to changes in the dopaminergic system because both aging and chronic alcoholism adversely affect several components of the nigrostriatal dopamine system. In addition, recent studies from this and other laboratories emphasize the sensitivity of the mesolimbic dopamine system to acute or chromic alcohol exposure and to aging. The latter finding is potentially important because of the role of the mesolimbic dopamine system in the reinforcement of several drugs of abuse. This grant will investigate two hypothesis. 1) As separate entities, both aging and alcohol adversely affect the nigrostriatal and/or mesolimbic dopamine systems. 2) Dopaminergic abnormalities are more severe in the aged that chronically consume alcohol than in those who abstain from alcohol. Specifically, we will assess the dopamine D1 receptors, the Gs protein with which they interact, and adenylate cyclase, which is activated by D1 agonists via the Gs protein. Similarly, we will study the dopamine D2 receptor, the Gi protein, and D2 agonist inhibition of adenylate cyclase. D1 and D2 receptors will be assessed in terms of total sites, the percentage in the high affinity form, and the conversion of the high to low affinity form by the addition of guanine nucleotides. The latter process is associated with the activation or inhibition of adenylate cyclase. Gs and Gi protein content will be measured by western blot analysis, using antibodies for these proteins. Content of Gs and Gi mRNA will be determined using radiolabelled cDNA probes. Dopamine and metabolite content will be determined by HPLC. The proposed studies will provide important now information about the separate and combined effects of alcohol and aging on components of both the nigrostriatal and mesolimbic dopamine systems. In addition, these studies will significantly expand our understanding of the separate and combined effects of alcohol on the G proteins with which they interact.
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| Tajuddin, N F; Druse, M J (1996) Effects of chronic alcohol consumption and aging on dopamine D2 receptors in Fischer 344 rats. Alcohol Clin Exp Res 20:144-51 |
| Woods, J M; Ricken, J D; Druse, M J (1995) Effects of chronic alcohol consumption and aging on dopamine D1 receptors in Fischer 344 rats. Alcohol Clin Exp Res 19:1331-7 |
| Pellegrino, S M; Woods, J M; Druse, M J (1993) Effects of chronic ethanol consumption on G proteins in brain areas associated with the nigrostriatal and mesolimbic dopamine systems. Alcohol Clin Exp Res 17:1247-53 |
