THE ROLE OF DOPAMINE D2 RECEPTORS IN MODULATING ALCOHOL-RELATED BEHAVIORS

Alcohol administration causes a brief period of stimulant effects, followed by sedative and depressant effects. Clinical literature suggests that people who experience the stimulant effects more intensely are more likely to abuse and develop dependency on alcohol. In animal studies, stimulant and depressive effects of alcohol can be quantified by locomotive activity. Previous research indicates a role for dopamine D2 receptors in the locomotive effects of alcohol. However, dopamine D2 receptors are found on a variety of cell types, and until recently, the limitation in research tools has made it impossible to discern the effects of specific subpopulations of D2 receptors. The current study examines the role that specific subpopulations of dopamine D2 receptors play in modulating the stimulant and depressant effects of alcohol. Using genetically engineered mice lacking D2 receptors on medium spiny neurons (MSNs) in the striatum or D2 autoreceptors on dopamine neurons, and littermate controls for each, we recorded dose-dependent alcohol-induced locomotion. We also conducted a Loss of Righting Reflex (LORR) test, to assess differences in alcohol-induced sedation in each of the mouse lines. The data show that when compared with littermate controls, MSN D2 knockout mice show a significantly increased locomotor response to alcohol, while the mice lacking D2 autoreceptors are more sensitive to the depressive effects of alcohol. LORR test data show that MSN D2 knockout mice are more resilient to the sedative effects of alcohol, with only 50% of mice losing the righting reflex, while D2 autoreceptor knockout mice lose and regain the righting reflex after a high dose of alcohol similarly to control mice. These results suggest that striatal dopamine D2 receptors may be playing an important role in modulating the stimulatory effects of alcohol, and may provide an explanation for the variation in individuals’ responses to the stimulant effects of alcohol and the resulting susceptibility to abuse and dependence.