Background: Although dopamine D1 and D2 receptors have been implicated in ethanol's motivational effects, little is known about the contribution of dopamine D4 receptors. The present experiments examined the effects of clozapine, a dopamine D4 receptor antagonist, on ethanol's aversive, rewarding, stimulant, and reinforcing properties.
Methods: For taste conditioning, adult male Swiss-Webster mice received five conditioning trials consisting of 1-hr access to 0.2 M NaCl. After NaCl access on trials 1-4, subjects received clozapine (0, 1, or 2 mg/kg) followed 30 min later by 0, 2, or 4 g/kg ethanol. For place conditioning, Swiss-Webster mice received six pairings of a tactile stimulus with ethanol (2 g/kg, intraperitoneally), clozapine (1 mg/kg, intraperitoneally) + ethanol, or clozapine alone. Locomotor activity in a 30-min test was determined in Swiss-Webster mice receiving 0, 0.5, or 1.0 mg/kg clozapine and 0, 1, or 2 g/kg ethanol. In a drinking study, separate groups of adult male C57BL/6J mice were allowed 30-min access to either 10% v/v ethanol mixed in 10% w/v sucrose or 10% sucrose without ethanol. During testing, both groups were given 0 or 1 mg/kg clozapine 30 min before fluid access.
Results: Ethanol flavor pairings during taste conditioning reduced subsequent flavor intakes, indicating the development of conditioned taste aversion. Clozapine reduced the magnitude of 4 g/kg ethanol-conditioned aversion only on trial 4 at the 2 mg/kg dose. Conditioned place preference for the ethanol-paired stimulus was not altered by clozapine. Clozapine alone did not produce either conditioned preference or aversion. Ethanol-stimulated activity was reduced by clozapine treatment. However, clozapine alone did not alter locomotor activity levels. Clozapine reduced sucrose consumption but did not alter ethanol/sucrose intake.
Conclusions: These data suggest that clozapine influences a limited range of ethanol-motivated behaviors. Specifically, dopamine D4 receptors appear important for ethanol's stimulant effect and possibly ethanol aversion, but not ethanol reward and reinforcement.