Cocaine self-administration in dopamine D₃ receptor knockout mice

The dopamine D₃ receptor has received attention over the last two decades as a target for medications development for substance abuse disorders. Results have remained mixed. Despite emergence of more D₃-selective ligands, possible attribution of observed effects to D₂ receptors remains a concern. Knockout mice may help shed light on mechanisms. Here we evaluated the effect of constitutive D₃ receptor inactivation ("knockout") on the reinforcing effects of cocaine. We tested D₃ wild-type (WT), heterozygous (D₃⁺/⁻), and knockout (D₃⁻/⁻), mice in acquisition and maintenance of intravenous self-administration across a broad range of cocaine doses, using a fixed ratio (FR) 1 and a progressive ratio (PR) schedule of reinforcement, along with parallel food-reinforced studies. Generally, D₃⁻/⁻ mice showed cocaine self-administration comparable to WT controls across assays. Moderate and nonsignificant trends toward lesser reinforcing effects of a low cocaine dose (0.32 mg/kg) were apparent in acquisition and PR studies, consistent with the idea that the D₃ receptor may play a subtle role in the reinforcing effects of low cocaine doses under low FR conditions. However, those effects with cocaine self-administration were more subtle than the lower responding of D₃ knockout mice observed with food-maintained behavior. In addition, the D₃ antagonist PG01037 failed to affect cocaine self-administration under an FR 1 schedule in WT mice. The present data do not support a necessary role for the D₃ receptor in the direct reinforcing effects of cocaine.