There is increasing evidence in recent years to suggest that genetic factors play an important role in the development of alcohol drinking behaviors. Evidence also indicates the association of innate anxiety levels with the initiation of ethanol consumption. The molecular mechanisms responsible for such associations are not clearly identified. The camp-responsive element binding (CREB) protein is the common denominator of signaling cascades for a number of neurotransmitter receptors, and is regulated via phosphorylation by several protein kinases. Phosphorylated CREB regulates the downstream expression of CAMP-inducible genes such as brain-derived neurotrophic factor (BDNF). Our laboratory recently demonstrated that decreased CREB phosphorylation (Serine-133) in the central but not in the basolateral amygdala is involved in anxiety and alcohol drinking behaviors. The mechanism by which decreased CREB phosphorylation in the central amygdala regulates anxiety and alcohol drinking behaviors is unknown. One mechanism could be related to the regulation of synaptic strength via modulation of brain-derived neurotrophic factor (BDNF) gene expression and associated Arc (activity-regulated cytoskeleton associated protein) signaling in the amygdala. The specific hypotheses are 1) That the decreased CREB phosphorylation and Arc expression due to decreased BDNF expression in central nucleus of amygdala are responsible for the predisposition to anxiety and to alcohol-drinking behaviors. 2) That the decreased Arc expression due to decreased BDNF function is responsible for decreased spine density (synaptic strength) in the central amygdala associated with anxiety and alcohol drinking behaviors. The following Specific Aims will test this hypothesis: 1) To evaluate a) whether decreased CREB phosphorylation, BDNF, and Arc expression caused by infusions of BDNF anti-sense oligodeoxynucleotides (ODNs) into the central amygdala provokes anxiety, and increases alcohol preference in rats; b) whether intra-central amygdaloid infusions of BDNF attenuate anxiety and alcohol preference in BDNF ODN-infused rats; 2) To evaluate a) whether decreased CREB phosphorylation, BDNF, and Arc expression caused by infusions of MEK inhibitor or CREB antisense ODNs into the central amygdala provokes anxiety, and increases alcohol preference in rats; b) whether intra-central amygdaloid infusions of BDNF attenuate anxiety and alcohol preference and normalize the dendritic spines in MEK inhibitors or CREB antisense ODN infused rats; 3) To evaluate a) whether decreased Arc expression caused by infusions of Arc anti-sense ODNs into central amygdala decreases spine density and increases alcohol preference and anxiety-like behaviors in rats; b) whether intra-central amygdaloid infusions of BDNF attenuate anxiety and alcohol preference, and normalize spine density in Arc ODN-infused rats. The proposed studies will provide a better understanding of the role of BDNF signaling in the vulnerability to alcohol-drinking and anxiety behaviors, and will facilitate new directions for the development of drugs that can be used in prevention and/or treatment of alcoholism with or without co-morbid anxiety disorders
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