Alcohol Addiction-like Behaviors in Operant Ethanol Self-Administration Mediated by the mPFC Reward Circuit

초록

Ethanol is readily accessible and is one of the representative substances in substance use disorders. Despite the ease of access to ethanol, only a small number of individuals experience alcohol use disorder. Differentiation in behavior in response to ethanol exposure, ranging from avoidance to compulsive intake, suggests the complexity of the neurobiological mechanism underlying alcohol addiction. Addiction is a brain dysfunction that causes people to persistently or compulsively seek out or take addictive drugs despite the negative psychological and physical effects. In most drug addictions, the same or different neural circuits mediate characteristic addictive behaviors according to the development and differentiation of addictive behaviors. Therefore, we developed alcohol addictive-like behavior models in operant ethanol oral self-administration to identify addictive-like behavioral differentiation. We clustered the behavioral phenotypes using the three factors – fixed ratio (FR), progressive ratio (PR), and aversive-tasting ethanol solution – to establish the point of reference for alcohol addictive-like behaviors. Then, we discovered that operant interaction patterns in the PRs are the most highly associated with the alcohol-drinking phenotype. We hypothesize that reward circuits involved with the medial prefrontal cortex (mPFC) intricately regulate complex behaviors in ethanol self-administration. Accordingly, we identified changes in operant behaviors in PR using the DREADD system, targeting four reward circuits associated with the mPFC (mPFC-NAc, mPFC-VTA, mPFC-DMS, and mPFC-BLA). This suggested that each of the four mPFC circuits plays a distinct role in alcohol-addictive-like behaviors. Also, this multi-circuit relation may mediate individual alcohol addictive-like behavioral differentiation. Further research is required to investigate individual differences in the distinct behaviors of alcohol addiction in the operant ethanol oral self-administration.