Clozapine's effects on ethanol's motivational properties

Background: Although dopamine D1 and D2 receptors have been implicated in e thanol's motivational effects, little is known about the contribution of do pamine D4 receptors. The present experiments examined the effects of clozap ine, a dopamine D4 receptor antagonist on ethanol's aversive, rewarding, st imulant, and reinforcing properties. Methods: For taste conditioning, adult male Swiss-Webster mice received fiv e conditioning trials consisting of 1-hr access to 0.2 M NaCl. After NaCl a ccess on trials 1-4, subjects received clozapine (0, 1, or 2 mg/kg) followe d 30 min later by 0, 2, or 4 g/kg ethanol. For place conditioning, Swiss-We bster 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 Swis s-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 sucro se 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 subseque nt flavor intakes, indicating the development of conditioned taste aversion . Clozapine reduced the magnitude of 4 g/kg ethanol-conditioned aversion on ly on trial 4 at the 2 mg/kg dose. Conditioned place preference for the eth anol-paired stimulus was not altered by clozapine. Clozapine alone did not produce either conditioned preference or aversion. Ethanol-stimulated activ ity was reduced by clozapine treatment. However, clozapine alone did not al ter locomotor activity levels. Clozapine reduced sucrose consumption but di d not alter ethanol/sucrose intake. Conclusions: These data suggest that clozapine influences a limited range o f ethanol-motivated behaviors. Specifically, dopamine D4 receptors appear i mportant for ethanol's stimulant effect and possibly ethanol aversion, but not ethanol reward and reinforcement.