Mechanism of Ethanol-Clonidine Synergistic Sedation Grant uri icon

abstract

  • Ethanol has been shown to have a synergistic effect on the production of sedation when co-administered with the antihypertensive drug clonidine. Studies in the literature have reported mechanisms for sedation by the individual drugs; however, a molecular mechanism for the synergistic interaction has not yet been determined. The purpose of this study is to test the hypothesis that ethanol and clonidine act through different pathways to synergistically increase nitric oxide (NO) levels in the locus ceruleus (LC) in order to produce the synergistic sedative behavioral response. It is further hypothesized that clonidine, acting at the alpha-2A adrenergic receptor, enhances the effects of ethanol through a phosphorylation cascade involving p42/44 MAPK which activates nNOS. These hypotheses will be tested using behavioral (loss of righting reflex), immunohistochemical (cFos/cJun), and in vivo electrochemistry (NO measurements in the LC) techniques. Treatments will employ pharmacological antagonists and antisense to help identify key molecular players. This project will provide valuable information about the molecular mechanism of a clinically relevant drug interaction.

date/time interval

  • January 2005 - December 2007