Targeting the OFC-DMS Circuit to Disrupt Compulsive Alcohol Drinking Following Binge and High-Intensity Drinking in Crossed High Alcohol Preferring (cHAP) Mice

Abstract

Binge and high-intensity (HID) drinking are risk factors for the development of alcohol use disorder. Preclinical models show that repeated binge drinking can lead to compulsive-like alcohol consumption, characterized by drinking despite negative consequences. This behavior is thought to result from a shift from goal-directed to habitual behavior, involving different brain regions. Notably, the orbitofrontal cortex (OFC) and dorsomedial striatum (DMS) play key roles in goal-directed decision-making and reward processing and are implicated in addiction and obsessive-compulsive disorder. Repeated binge drinking functionally alters the intrinsic and extrinsic properties of the OFC and the DMS. The OFC sends glutamatergic and GABAergic projections to the DMS, which promotes top-down control over habitual behaviors. Since selectively bred crossed high alcohol (cHAP) mice engage in alcohol drinking that results in blood alcohol concentrations that are twice or more that of a binge (i.e., HID), we can postulate that alcohol-induced deficits in the OFC-DMS pathway would arise; however, there has not been research on this pathway regarding alcohol intake and compulsive-like alcohol drinking in mice. We conducted two experiments: first, we examined differences between binge and HID drinking in cHAP mice (n = 34) and tested for differences in compulsive-like drinking behavior. Second, we chemogenetically excited the OFC-DMS pathway following a history of alcohol binge drinking in cHAP mice (n = 42). We hypothesized that excitation of DMS-projecting OFC neurons would decrease alcohol and compulsive-like alcohol drinking after two weeks of alcohol binge and HID. In experiment 1, we found that a two-week history of alcohol intake led to greater quinine-adulterated alcohol intake compared to a naïve group and that regardless of history, mice showed similar degrees of sensitivity to quinine. In experiment 2, we found that excitation of the OFC→DMS circuit did not significantly alter alcohol intake or compulsive-like alcohol intake. We did find, however, that excitation of these projections decreased sensitivity to quinine-adulterated water. Our findings suggest that while cHAP mice exhibit binge and HID drinking, the OFC→DMS pathway does not play a direct role in regulating compulsive-like alcohol consumption.