The overall goal of this proposal is to provide mentored career development for a young scientist. The training and research support detailed in this proposal will enable the Candidate to utilize a multidisciplinary approach to understand factors that modulate the stimulus properties of ethanol. Importantly, this training will contribute to her development as an independent investigator. The Candidate will receive broad-based training in alcoholism research as well as several methods that will be required to address the research plan including immunohistochemistry techniques, confocal microscopy, stereotaxic surgeries and microinjection of drugs. The research plan will focus on the role of metabotropic glutamate receptors (mGluRs) in ethanol's discriminative stimulus effects. mGluRs have been shown to influence GABAA and glutamate functioning which are major components of ethanol's stimulus properties. The Candidate will test the hypothesis that mGluRS and mGluR2/3 can modulate ethanol discrimination by interaction with GABAA and NMDA receptor systems.
Specific Aim 1 will utilize behavioral pharmacology techniques to determine if an antagonist of mGluRS and an agonist of mGluR2/3 will modulate ethanol discrimination, and the ethanol-like stimulus properties of GABAA positive modulators and NMDA antagonists.
Specific Aim 2 will use dual-label immunohistochemistry with confocal visualization to evaluate if mGluRS and mGluR2/3 are co-expressed with GABAA and NMDA receptor subunits in ethanol discrimination trained rats.
Specific Aim 3 will use immunohistochemisty techniques (Fos-like immunoreactivity) to assess brain regional involvement in ethanol discrimination and in mGluRS and mGluR2/3 modulation of ethanol discrimination and ethanol substitutes (diazepam and MK-801).
Specific Aim 4 will use microinjection techniques to assess ethanol discrimination and the substitution of diazepam and MK-801 after administration of the mGluRS antagonist and the mGluR2/3 agonist into specific brain regions that show high levels of mGluR co-expression with GABAA and NMDA receptors as determined from Aim 2 and show anatomical involvement as determined from Aim 3. We predict that these experiments will reveal a modulatory role of mGluRS and mGluR2/3 in ethanol discrimination. Further, incorporating these techniques is highly innovative, and these studies will generate novel findings regarding the involvement of mGluRS and mGluR2/3 in the stimulus properties of ethanol. Understanding these mechanisms is important to basic science and has numerous implications for development of therapeutic interventions in alcoholism, especially given that the discriminative stimulus properties of drugs can be important determinants of abuse liability.
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