There is increasing evidence to suggest that genetic factors play an important role in the development of alcohol drinking behaviors. It has also been suggested that innate anxiety is an important factor in the initiation of alcohol consumption. Animal lines, such as alcohol-preferring (P) and non-preferring (NP) rats, appear to be suitable models to investigate the neurobiological basis of genetic vulnerability to anxiety and alcohol abuse. The cAMP-responsive element-binding protein (CREB) gene transcription factor and its target gene.neuropeptide Y (NPY), in the central amygdala, have been shown to play a crucial role in anxiety and alcohol abuse. It has been shown that extended amygdaloid circuitries may represent important brain areas as neurobiological substrates that may be involved in anxiety and alcohol drinking behaviors. The mechanisms by which CREB and NPY are regulated ,and also how these signaling molecules in the extended amygdala are involved in anxiety and alcohol drinking behaviors of P rats are unknown. The CREB mediated activation of histone acetyl-transferases (HATs) activity of CREB binding protein (CBP) appears to be an important step in the remodeling of chromatin structure via histone acetylation thereby modulating gene expression. Our proposal is based on the hypothesis that decreased CREB function will alter chromatin remodeling due to decreased acetylation of histones in the extended amygdala, thereby decreasing NPY expression, which in turn could be responsible for the genetic predisposition to anxiety and alcohol-drinking behaviors. The first objective of the proposed study is to examine the role CREB signaling in amygdaloid and bed nucleus of stria terminalis (BNST) structures in relation to anxiety and alcohol drinking behaviors in P and NP rats. The second objective is to investigate the epigenetic mechanisms (histone modifications) by which expression of NPY and NPY-Y1 receptors are altered in the extended amygdala of P rats. A series of genetic and pharmacological manipulations are proposed to study the role of CREB and NPY mechanisms in specific circuitry of extended amygdala of P and NP rats in relation to anxiety-like and alcohol drinking behaviors. Thus, the proposed studies will provide an important clue about the extended amygdala as a neurobiological substrate for the genetic vulnerability toward anxiety and alcoholism.
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