Role of Central Amygdala Somatostatin in Heavy Alcohol Drinking

ABSTRACT A characteristic symptom of alcohol use disorder (AUD) is “hyperkatifeia,” a hypersensitivity to emotional distress, which is thought to be caused by specific neuroadaptations in the extended amygdala. Specifically in the central nucleus of the amygdala (CeA), the recruitment of pro-stress neurotransmitter systems results in the establishment of negative reinforcement and in excessive alcohol drinking, while, concurrently, the activation of anti-stress neurotransmitter systems attempts to buffer the aversive states brought about by the excess activation of pro-stress systems. Somatostatin (SST) is a polypeptide highly expressed in the CeA, region highly implicated in alcohol drinking and stress. Administration of either SST or SST receptor 2 (SST2R) agonists in rodents produces anxiolytic- and antidepressant-like effects; stressors increase SST levels in the brain and SST signaling counteracts various components of the stress response. However, the role of CeA SST (putatively anti-stress) in AUD is currently unknown. The overall hypothesis of this application is that the activation of the SST/SST2R system in CeA represents a major brain anti-stress element that buffers the hyperactivity of stress systems and thereby act as a brake to heavy alcohol drinking. This application will test the hypothesis that the activation of the SST/SST2R system in CeA reverts the increased GABA transmission induced in CeM neurons by chronic alcohol and blocks heavy alcohol drinking. Our team will test these hypotheses by using a well-established animal model of heavy alcohol drinking, combined with pharmacological, molecular, and electrophysiological approaches. If successful, these experiments will have identified a key brain anti-stress system contributing to alcohol addiction which will be investigated in greater depth in future studies. A deeper understanding of the molecular mechanisms underlying heavy drinking and the neuroadaptations occurring in the amygdala neurocircuitry may uncover novel and more effective strategies for treating AUD.