The primary goal of this project is to understand molecular mechanisms that influence adaptive changes in alcohol self-administration and dependence that result from repeated alcohol exposure and withdrawal. Substantial evidence indicates that neuronal gamma-amino-butyric acid type A (GABAA) receptors modulate alcohol self- administration and alcohol withdrawal severity. Our research has shown that mutant mice lacking the epsilon isoform of protein kinase C (PKCepsilon) are supersensitive to acute alcohol and GABAA allosteric positive modulators. This supersensitivity is associated with reduced alcohol self-administration, absence of the alcohol deprivation effect (ADE), and lack of progression of ethanol withdrawal seizure severity. By contrast, PKCgamma null mutant mice are less sensitive to ethanol modulation of GABAA receptor function and drink more ethanol suggesting that specific isoforms of PKC may differentially modulate GABAA mediated effects of ethanol. The present proposal extends these findings by focusing on alcohol self-administration during relapse and dependence. Using null mutant mice, we will test the hypothesis that PKC epsilon and gamma differentially modulate alcohol self-administration, and withdrawal-related changes in alcohol self-administration, via GABAA receptor activity.
Specific Aim 1 will test the hypothesis that specific PKC isoforms differentially modulate alcohol self-administration during repeated relapse via GABAergic mechanisms. We will first examine operant alcohol self-administration by PKC epsilon and gamma null mutant mice and controls using a model of repeated alcohol deprivation, which we have established in mice.
Specific Aim 2 will examine repeated ethanol withdrawal seizure severity in PKC epsilon and gamma null mice. Studies of Aim 3 will extend the withdrawal findings of Aims 1 and 2 by examining relapse to alcohol self-administration during episodes of repeated dependence and withdrawal. Collaborative studies in each aim will examine multiple brain regions for changes in GABAA receptor subunit expression in the membrane fraction by Western Blot analysis, and MAPK/ERK signaling and neuropathology (Crews component). To confirm functional relevance of molecular changes, we will administer pharmacological agents (i.e., the nonselective GABAA alpha-antagonist flumazenil or the alpha1 selective agonist zolpidem) during repeated relapse and withdrawal. These studies are expected to elucidate molecular mechanisms of adaptive processes that influence alcohol self-administration after deprivation or withdrawal. This information might lead to the identification of novel pharmacological therapeutics for treatment of problems associated with alcoholism, such as loss of control and relapse.
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