The mechanisms regulating alcohol consumption in large part are not well understood. A number of research groups have analyzed expression of inducible transcription factors (ITFs) to identify alcohol-sensitive brain regions. Early studies observed changes in expression of ITF c-Fos in a substantial number of brain regions after involuntary alcohol administration in rodents. In contrast, voluntary alcohol self-administration in rodents leads to c-Fos expression in a much smaller number of brain regions. Importantly, in these paradigms robust induction of c-Fos occurs only in the Edinger-Westphal nucleus (EW). EW is a compact brain structure involved in oculomotor adaptation, nociception, regulation of metabolism, feeding, body temperature and anxiety. This nucleus has gained attention as the primary source of neuropeptide urocortin (Ucn). Recent studies show that inbred strains of mice known for differences in alcohol consumption, and mice genetically selected to differ in measures of alcohol reward differ dramatically in the number of Ucn cells in EW. We hypothesize that the brain Ucn system contributes to regulation of alcohol consumption, and that this regulation occurs via EW projection to the lateral septum (LS). To test this hypothesis four Specific Aims are proposed. ? 1. To confirm relation between level of Ucn in EW and alcohol consumption in a genetically heterogeneous population of mice and in congenic mice carrying chromosomal loci regulating alcohol preference. ? 2. To investigate the effects of EW lesions on alcohol consumption in mice. ? 3. To investigate the role of Ucn projections to LS in alcohol consumption using retrograde neuroanatomical tracing and microinjection of Ucn and its antagonists into LS. ? 4. To investigate the effects of ethanol exposure on the level and activity of the CRH-R2 receptors in LS, and in the level of Ucn mRNA in EW (using receptor autoradiography and in situ hybridization). ? The long-term goal of these studies is to understand the mechanisms regulating alcohol consumption. Such knowledge is important for development of pharmacotherapy of alcoholism ? ?
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