A functional role for the dopamine D3 receptor in the induction and expression of behavioural sensitization to ethanol in mice.

RATIONALE: We previously reported that mice lacking dopamine D3 receptors (D3R) were resistant to behavioural sensitization to ethanol (EtOH). Since knockout mice have permanent receptor inactivation, we investigated how temporary pharmacological blockade and activation of D3Rs affected the induction or expression of EtOH sensitization. MATERIALS AND
METHOD: In induction studies, DBA/2 mice received 0, 10 or 75 mg/kg, subcutaneous (s.c.) of the D3R antagonist, U99194A ,before each of seven EtOH (2.2 g/kg, intraperitoneal) or saline injections. Locomotor activity (LMA) was assessed in activity chambers. In expression studies, mice received seven injections of EtOH or saline, followed 14 days later with U99194A or vehicle immediately before a test dose of EtOH (1.8 g/kg). In separate experiments, the effects of the D3R agonist PD128907 (0.01 mg/kg, s.c.) were similarly examined during and after EtOH sensitization.
RESULTS: Chronic co-administration of low-dose U99194A blocked the induction of EtOH sensitization, while acute U99194A had no effect in mice that were already sensitized. Chronic co-administration of PD128907 resulted in decreased LMA but this effect was also seen in saline-treated mice, suggesting a simple subtractive effect. In previously sensitized mice, acute PD128907 significantly attenuated the expression of EtOH sensitization, indicating an enhanced response to the drug.
CONCLUSIONS: Results suggest a modulatory role for the D3R in behavioural sensitization to EtOH, where D3R blockade is associated with induction and D3R stimulation is associated with expression of EtOH sensitization. A model is suggested to account for these complementary functions of the D3R at different stages of EtOH sensitization.