Rgs7bp-Deficient Mice Show Increased Ethanol Drinking and Quinine Resistance with Altered Negative Affective Behaviors in Intermittent Access to Ethanol Paradigms

Alcohol use disorder (AUD) is a prevalent, deadly disease associated with both psychological and physiological comorbidities. Here, in studies involving Rgs7bp knockout (KO) mice and their wildtype littermates (WT) (total n = 138), we identify the regulator of G-protein signaling 7 binding protein (encoded by RGS7BP/Rgs7bp) as a novel genetic factor influencing AUD-related phenotypes in mice. Rgs7bp KO mice showed elevated ethanol intake and preference in two intermittent-access, two-bottle choice paradigms, with a stronger genotype effect in males. This difference was not attributable to altered ethanol clearances, which was similar between KO and WT mice. In a concentration-response study with two test blocks, male KO mice drank more ethanol than WT in both tests, but preferred the ethanol solution more than WT only in Test 2, suggesting an experience-dependent change in ethanol preference. After seven weeks of intermittent ethanol during the concentration-response period, KO males, but not females, displayed more quinine-resistant drinking than WT mice. On the elevated plus-maze, KO mice exhibited increased anxiety-like behavior during acute ethanol withdrawal, in contrast to decreased anxiety-like behavior when ethanol-naive. In the marble burying task, withdrawn KO mice showed less compulsive-like behavior than WT, a difference also present in ethanol-naive males. Finally, regardless of ethanol exposure, KO mice spent more time climbing in the forced swim test, suggesting a more active-oriented stress-coping strategy. Together, these findings implicate Rgs7bp in ethanol consumption, aversion-resistant drinking, and affective behavior, with sex-dependent components.