There is increasing evidence to suggest that genetic factors play an important role in the development of alcohol drinking behavior. It has also been suggested that innate anxiety level is an important factor in the initiation of alcohol consumption. Animal lines, such as alcohol-preferring (P) and nonpreferring (NP) rats, appear to be suitable models to investigate the neurobiological basis of genetic vulnerability to anxiety and alcohol abuse. P rats are more anxious and also consume larger amounts of alcohol than NP rats. Neuropeptide Y (NPY) has been shown to play a crucial role in anxiety and alcohol abuse. The levels of NPY are lower in the central amygdala of P rats than of NP rats. The mechanisms by which NPY are regulated in the neurocircuitry of the central amygdala of P rats and also how NPY is involved in anxiety and alcohol drinking behavior of P rats are unknown. The cAMP-responsive element-binding protein (CREB), which represents a common intracellular target for the action of a number of neurotransmitters, has been found to be decreased in the amygdala of P rats compared with NP rats. The proposal is based on the hypothesis that decreased expression of the CREB and CREB-related target genes, i.e., NPY, in the central amygdala, is responsible for the genetic predisposition to anxiety and to alcohol drinking behavior. This hypothesis will be tested by the following Specific Aims: 1) To compare a) the expression and phosphorylation of CREB, and b) mRNA and protein levels of NPY, and c) the expression and activity of PKA in the amygdala of alcohol-naive P rats and NP rats; 2) To examine a) if the increased phosphorylation of CREB and the increased expression of NPY elicited by PKA activator infusion into the central amygdala attenuate anxiety and alcohol preference in P rats; and b) if the decreased phosphorylation of CREB and the decreased expression of NPY elicited by PKA inhibitor infusion into the central amygdala provoke anxiety and also increase alcohol preference in NP rats; 3)To evaluate if the decreased expression of NPY due to decreased CREB expression caused by CREB anti-sense oligonucleotide infusion into the central amygdala, provokes anxiety and also increases alcohol preference in NP rats; 4)To examine if the increased phosphorylation of CREB and the increased levels of NPY due to NPY infusion into the central amygdala attenuate anxiety and alcohol preference in P rats. Thus, the proposed studies will provide evidence that a downregulation of PKA - CREB - NPY signaling in the central amygdala acts as a genetic vulnerability factor to induce anxiogenic and desperate alcohol-drinking behaviors of P rats.
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