The hypothesis being pursued in this application is that there are common behavioral and physiological mechanisms involved in two effects of repeated alcohol experience: the alcohol deprivation effect, and sensitization to the locomotor stimulating effects of alcohol. This proposal seeks to better understand changes which occur in the brain, with a special emphasis on the extended amygdala, as a result of chronic alcohol exposure, to better understand what changes might be caused by excessive drinking in human alcoholics.1 Both locomotor sensitization and the alcohol deprivation effect have been suggested as models of drug dependency and / or craving in humans. This project will use selectively bred High- (HAP) and Low- (LAP alcohol preferring mice, because they offer good control of environmental and genetic factors, and because HAP mice show substantial free-choice alcohol drinking.
Aim 1 of this proposal is to determine whether repeated periods of alcohol access and deprivation in HAP and LAP mice leads to the development of increased drinking. This outcome is known as a repeated alcohol deprivation effect, or RADE. The development of this behavioral model in genetically characterized mice will comprise a useful tool for better understanding the causes of relapse and binge drinking in human alcoholics.
Aim 2 will assess whether the RADE procedure results in long-term increases in sensitivity to the locomotor stimulating effects of alcohol, suggestive of locomotor sensitization. Additionally, experiments will be conducted assessing whether injections of alcohol sufficient to cause locomotor sensitization, induce RADE-like increases in alcohol intake. These studies seek to show a commonality in causes of the RADE and locomotor sensitization.
Aim 3 will determine whether injections of alcohol sufficient to cause locomotor sensitization in HAP mice cause changes in the extended amygdala of HAP and LAP mice, as measured by induction of the immediate early gene, c-Fos.
Aim 4 assesses whether similar changes in the extended amygdala are caused by the RADE procedure as by the locomotor sensitization procedure, suggesting a common neural mechanism for both these behavioral models.
Specific Aim 5 will determine exactly what types of neurons show c-Fos activity as a result of sensitization and the RADE, by using immunocytochemistry aimed at specific neurotransmitter synthetic pathways. The results of these experiments will yield greater understanding of neuroadaptive mechanisms which cause excessive alcohol intake following alcohol exposure.
