PROJECT SUMMARY Binge ethanol consumption is the most common form of alcohol intake and represents over three-quarters of the financial burden associated with alcohol use in the United States. In addition to associated negative health effects such as heart disease and diabetes, binge intake is a significant risk factor for the development of alcohol dependence, is a widespread public health concern. Despite this, there are limited treatment options available for binge drinking or alcohol use disorders as a whole. Stress-related neuropeptides in the central amygdala (CeA) have emerged as important targets for development of novel pharmacotherapies, however the role of one of the most densely expressed ‘anti-stress’ neuropeptides within the brain, somatostatin (SST), in binge drinking behavior has gone essentially neglected. This omission is of particular note as SST is well known as both a neuromodulator and a neurotrophic factor, allowing it to alter CeA activity by direct interactions with neurons and indirectly through modulating astrocytic activity. I hypothesize binge-ethanol intake will dysregulate SST receptors expressed on both neural and astrocytic populations and, further, that astrocyte modulation of inhibitory transmission on to SST-expressing cells will likewise be dysregulated, resulting in decreased ability of this important ‘anti-stress’ peptide to regulate CeA activity. These dysregulations would be perfectly poised to significantly contribute to the well-established increase in CeA activity known to occur during alcohol dependence. Dissecting binge-ethanol induced alterations in CeA SST system expression and function in non- dependent animals will therefore enable both discovery of novel treatments for this risky pattern of intake and provide important insights into initial ethanol-induced alterations of a region critically involved in the development and maintenance of alcohol dependence. The K00 phase of these proposed studies employ 1) cutting-edged analysis of astrocyte morphology (using training in immunohistochemical and confocal microscopy techniques) to characterize ethanol-induced changes in SST receptor expression on astrocytic and neuronal populations in the CeA, as well as changes in overall astrocyte morphology and expression of the astroglial perisynaptic sheath at synapses onto SST-containing neurons; and 2) use of ex vivo whole cell patch-clamp electrophysiology to assess alterations in GABAergic transmission on to SST-expressing cells, and changes in astrocyte modulation of this transmission (using training in duel-patching technique to silence astrocyte activity). The R00 phase of the proposed studies will use these techniques in combination with my existing expertise in chemogenetic technology and behavioral pharmacology to 1) assess the role of the SST-expressing CeA neuron to bed nucleus of the stria terminalis (BNST) projection in binge-drinking behavior; and 2) assess binge-ethanol induced changes in SST re...