L-type voltage-gated calcium channels (LTCCs) are implicated in several psychiatric disorders that are co-morbid with alcoholism and involve amygdala dysfunction. Within the amygdala, the central nucleus (CeA) is critical in acute alcohol's reinforcing actions, and its dysregulation in human alcoholics drives their negative emotional state and motivation to drink. Here we investigated the specific role of CeA LTCCs in the effects of acute alcohol at the molecular, cellular physiology and behavioral levels, and their potential neuroadaptation in alcohol-dependent rats. Alcohol increases CeA activity (neuronal firing rates and GABA release) in naïve rats by engaging LTCCs, and intra-CeA LTCC blockade reduces alcohol intake in non-dependent rats. Alcohol dependence reduces CeA LTCC membrane abundance and disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. Collectively, our data indicate that alcohol dependence functionally alters the molecular mechanisms underlying the CeA's response to alcohol (from LTCC- to CRF1-driven). This mechanistic switch contributes to and reflects the prominent role of the CeA in the negative emotional state that drives excessive drinking.
The central amygdala (CeA) plays a critical role in the development of alcohol dependence. As a result, much preclinical alcohol research aims to identify relevant CeA neuroadaptions that promote the transition to dependence. Here we report that acute alcohol increases CeA neuronal activity in naïve rats by engaging L-type calcium channels (LTCCs) and that intra-CeA LTCC blockade reduces alcohol intake in non-dependent rats. Alcohol dependence disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. This switch reflects the important role of the CeA in the pathophysiology of alcohol dependence and represents a new potential avenue for therapeutic intervention during the transition period.
This is manuscript number 29019 from The Scripps Research Institute. We thank Dr. Matthew Buczynski, Maury Cole, Courtney Leiter and Dr. Miranda Staples for their technical support and Drs. Floyd Bloom, Michal Bajo, Candice Contet, Sean Farris, Sophia Khom, Reesha Patel and Igor Ponomarev for valuable comments on the manuscript. R121919 was synthesized by Dr. Kenner Rice at the National Institute on Drug Abuse, National Institutes of Health. This study was supported by grants from the NIH: AA015566, AA021491, AA017447, AA006420, AA013498, AA020608, AA022977 and AA021802. The authors declare no competing financial interests.