Alcohol abuse and anxiety disorders are prevalent in our society and are expressed with a high degree of comorbidity. Repeated cycles of withdrawal after binge alcohol drinking may cause persistent adaptations in brain regions that regulate alcohol drinking and anxiety-related behaviors, including the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) in the extended amygdala. These changes can lead to a dysregulated stress response, increased levels of anxiety, and relapse behavior. Neuropeptide Y (NPY) signaling is one endogenous neurochemical system that modulates alcohol drinking and anxiety-related behaviors. Activation of the NPY Y1 receptor (Y1R) produces behavioral anxiolysis and decreases ethanol consumption, while Y2 receptor (Y2R) activation produces behavioral anxiogenesis and increases ethanol consumption. While there is evidence that Y2R-mediated effects of NPY may occur via modulation of inhibitory synaptic transmission in the BNST, there remains a lack of a detailed mechanistic understanding of Y1R-specific NPY signaling. In addition, repeated exposure to alcohol may lead to dysregulation of NPY signaling and subsequent alterations in behavior, though the specific mechanisms by which this occurs are poorly understood. Therefore, the overarching goals of this proposal are to 1) characterize the effect of Y1R-mediated signaling on inhibitory synaptic transmission in the mouse BNST and 2) determine the acute and protracted effects of chronic alcohol self-administration on Y1R and Y2R-specific NPY signaling in the BNST of mice and rhesus monkeys. Understanding the mechanisms of the endogenous NPY system may be useful for treating both anxiety disorders and alcoholism. I hypothesize that chronic voluntary alcohol drinking leads to dysregulation of receptor-specific NPY signaling in the BNST, which is ultimately manifested in altered alcohol drinking and anxiety-related behaviors.
Examination of the effects of chronic alcohol exposure on Y1R and Y2R-mediated mechanisms of NPY on BNST function are crucial to understanding the link between alcohol use and anxiety disorders and may provide therapeutic targets for future pharmacological treatments of these conditions.
|Jennings, Joshua H; Sparta, Dennis R; Stamatakis, Alice M et al. (2013) Distinct extended amygdala circuits for divergent motivational states. Nature 496:224-8|