Mechanism of ethanol-clonidine synergistic sedation

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DESCRIPTION (provided by applicant): Ethanol-induced motor in coordination is synergistically enhanced by clonidine, a centrally acting antihypertensive drug (alpha-2 agonist). Reported findings suggest a role for alpha-2 adrenergic receptor signaling in ethanol-induced motor incoordination. However, a molecular mechanism for the synergistic interaction between ethanol and alpha-2 receptors has not yet been determined. This study will test the hypothesis that ethanol and clonidine act through different pathways to synergistically increase nitric oxide (NO) levels in the locus ceruleus (LC) to produce the synergistic deficit in motor coordination. It is further hypothesized that clonidine, acting at the alpha-2A receptor, enhances the effects of ethanol through a phosphorylation cascade involving p42/44 MARK, which activates nNOS. These hypotheses will be tested by undertaking behavioral (rotorod), immunohistochemical (cFos/cJun), and in vivo electrochemical (NO measurements in the LC) studies. The use of pharmacological (agonists/antagonists) and genetic (antisense) interventions will help identify key molecular players. This project will provide valuable information about the molecular mechanism of a clinically relevant drug interaction and about ethanol-induced motor in coordination.