Involvement of Sigma receptors in the detrimental effects of chronic alcohol exposure
Quadir, Sema G.
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Alcohol Use Disorder (AUD) is complex psychiatric disease characterized by increased alcohol intake, inability to control consumption, and a negative emotional state during withdrawal. In particular, one often-ignored feature of this negative state is the emergence of alcoholic-induced pain states, manifesting as both allodynia (when a non-noxious stimulus induces a nociceptive response) and hyperalgesia (when a noxious stimulus produces a heightened nociceptive response). Here, we first present evidence identifying standard chow diet as a factor in determining the amount of ethanol consumed as well as the preference for alcohol in an intermittent access to two bottle choice paradigm in mice. Additionally, while all ethanol experienced mice exhibit allodynia during withdrawal compared to the water drinking controls, the type of chow diet does not appear to affect its severity. We then investigated, using the same mouse model, the role of each of the two known subtypes of Sigma receptors, Sig-1R and Sig-2R, in both heavy alcohol drinking and associated pain states. We found that Sig-1R antagonists and Sig-2R modulators are able to decrease ethanol intake and hyperalgesia. Both excessive alcohol drinking and heightened pain states were found to be common outcomes also of another well-established model of alcohol dependence, the chronic intermittent ethanol vapor exposure (CIE), together with an increase of impulsive action. We, therefore, further investigated the role of Sig-1R in this post-dependent phenotype, and found that CIE increases Sig-1R levels in the prefrontal cortex, specifically in the anterior cingulate cortex (ACC) and the prelimbic cortex (PrL). Notably, knockdown of Sig-1Rs in the ACC via viral approach rescues hyperalgesia, but not allodynia nor impulsive action, suggesting that the ACC may be a critical area for alcohol-induced hyperalgesia, but not allodynia or impulsive action. Altogether, the results of this work give important insights into the role of Sig-1Rs in alcohol addiction, and have the potential to lead to novel pharmacological treatments for AUD.