Lack of operant ethanol self-administration in dopamine D-2 receptor knockout mice

Rationale: Dopamine D-2, receptors are postulated to play an important role in modulating the reinforcing effects of abused drugs including ethanol. O bjectives: This experiment examined operant ethanol self-administration in dopamine D2 receptor knockout (KO) mice and wild-type (WT) mice using a con tinuous access procedure. Methods: Adult male KO and WT mice were trained i n 30-min sessions to perform a lever press response for access to 10% v/v e thanol. After training, the mice were placed in test chambers on a continuo us (23 h/day) basis with access to food tone lever press, i.e., FR1), 10% v /v ethanol (four lever presses, i.e., FR4), and water from a sipper tube (p hase 1). After 30 consecutive sessions, response patterns were determined f ur 0, 5, 10, 20 and 30% v/v ethanol (phase 2). Saccharin (0.2% w/v) was sub sequently added to the ethanol mixture and responding was examined for 0, 5 , 10 and 20% ethanol (phase 3). Results: During phase 1, WT mice displayed higher ethanol-lever responding compared to KO mice. Food lever responding and water intake was the same in both genotypes. During phase 2, WT mice di splayed concentration-dependent ethanol lever responding, whereas KO mice r esponded at low rates regardless of ethanol concentration. WT mice also res ponded more for food compared to KO mice. Each genotype showed similar wate r intakes except at the 20% ethanol concentration, where WT mice had lower intakes. During phase 3, WT mice continued to show higher responding for al l concentrations including saccharin alone. WT mice also continued to respo nd more for food compared to KO mice, but drank less water. In each phase, WT mice displayed episodic (bout) responding on the ethanol lever. KO mice did not respond for ethanol in bouts. Conclusions: Reduced responding in th e KO mice for several reinforcers including ethanol indicates a more genera l role for dopamine D-2 receptors in motivated responding rather than a spe cific role in ethanol reinforcement.