The results of these experiments in animal models will provide critical new information about the brain regions and molecules that drive compulsive alcohol intake, where intake continues despite aversive consequences. Since compulsive intake is a major clinical hurdle in the treatment of alcoholism, our experiments investigating the molecular bases of aversion-resistant, compulsive alcohol intake will help identify novel therapeutic targets for the treatment of human alcoholism and other human diseases involving compulsion.
This proposal is aimed at studying mechanisms that drive compulsion-like alcohol drinking. Compulsive alcohol intake is characterized by drinking that persists even when alcohol is paired with adverse social, legal and physical consequences, and this aversion-resistant intake is a major obstacle to treating alcohol use disorders (AUDs). Thus, we have pioneered the use of rat models to identify brain circuits that underlie compulsion-like intake, where drinking continues even when alcohol is paired with aversive stimuli. However, little is known about brain circuits that promote compulsive addiction, especially the role of brain areas that control responding to aversion. Human and animal studies implicate anterior insula (aINS) and connected brain regions in abuse of drugs and alcohol. In humans, alcohol-cues activate aINS circuitry, and the level of activity can predict future intake, suggesting a causal role in driving addictive behaviors. The few animal studies support these human data, and our recent work found that the aINS, through inputs to nucleus accumbens, promotes compulsion-like drinking. Given the importance of aversion-resistant responding during compulsion-like intake, it is interesting that the aINS also regulates aversion-related behavior, and projects to powerful regulators of stress and aversion, the central amygdala (CeA) and locus coeruleus/parabrachial areas (LCPB). The CeA mediates conditioned and unconditioned responses to aversive stimuli, as well as excessive alcohol intake. The LCPB mediates stress responses through activation of noradrenaline receptors (NAdrRs), and NAdrRs promote excessive drinking in rodents and humans. Given the importance of these pathways for responding to aversion, we hypothesize that aINS activation of CeA and LCPB, and subsequent activation of NAdRs, promote compulsion-like drinking. In addition, aINS glutamate receptors are likely to be essential for activating these aINS projections, and, based on our preliminary results, we further hypothesize that calcium-permeable AMPA-type glutamate receptors (CP- AMPARs) within the aINS mediate compulsion-like drinking. We will test these hypotheses using powerful opto- and chemo-genetics techniques to functionally isolate and define the role of aINS-CeA and aINS- LCPB inputs during alcohol drinking, in combination with receptor pharmacology, projection tracing methods and ex vivo electrophysiology. Aim 1 and Aim 2A will determine whether aINS projections to CeA or LCPB promote compulsion-like alcohol intake, with little effect on drinking of quinine-free alcohol or saccharin±quinine. Aim 2B and Aim 3 will examine receptor mechanisms that could promote compulsion-like drinking. Aim 3 will determine the role of cortical NAdrRs during compulsion-like drinking. Aim 3 will examine whether different aINS cells project to CeA versus LCPB, and how CP-AMPARs impact the activity of these aINS neurons ex vivo. Our studies will provide important and novel information about how aversion-related brain circuits become coopted to drive compulsion-like alcohol drinking.