Alterations in accumbens glutamate neurotransmission are implicated in the long-term behavioral consequences of repeated alcohol administration. Thus, molecular candidates contributing to individual vulnerability to chronic alcohol-induced changes in brain and behavior are likely those regulating plasticity at glutamate synapses. This project will test the over-arching hypothesis that genetic vulnerability to alcohol reward is related to the capacity of alcohol to augment the expression of the Homer family of post-synaptic scaffolding proteins involved in modulating plasticity at glutamatergic synapses. In vivo microdialysis will be conducted in the nucleus accumbens of two strains of mice that differ in their propensity to voluntarily consume alcohol [C57BL/6 (high) and DBA/2J (low)] to examine for strain differences in basal and alcohol induced changes in extra cellular glutamate. An examination of drinking behavior while pharmacologically manipulating extra cellular glutamate levels will establish a causal relationship between accumbens glutamate and the propensity to consume alcohol in these strains (Specific Aim 1). Immunoblotting will be employed to assess for strain differences in accumbens Homer2 protein content and the effects of manipulating Homer2 protein expression will be assessed on drinking behavior to confirm an active role for this protein in alcohol consumption (Specific Aim 2). It is expected that a strain difference will exist with ? respect to basal and alcohol-induced alterations in glutamate transmission and accumbens levels of ? Homer2. Moreover, it is expected that the genetic propensity to consume large amounts of alcohol will be amenable to changes in accumbens levels of extra cellular glutamate, as well as alterations in accumbens Homer protein expression. The results of these studies will provide insight into the role for Homer proteins in genetic vulnerability to alcohol reward and will increase our understanding of the cellular mechanisms mediating the neural plasticity underlying individual vulnerability to alcoholism. ? ? ?
