Cocaine-induced locomotor activity and cocaine discrimination in dopamine D4 receptor mutant mice

Rationale. Previous studies have found a role for dopamine D-2-like receptors in many of the behavioral effects of cocaine, including its stimulation of locomotor activity and interoceptive discriminative-stimulus effects. However, given the lack of selectivity of most of the available pharmacological tools among D-2, D-3 and D-4 dopamine receptors, the roles of these specific receptors remain unclear. Objectives. The roles of specific dopamine D-4 receptors in the behavioral effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects were investigated using dopamine D-4 receptor knockout (DA D4R KO) and wild-type (WT) mice. Methods. The mice were trained in daily sessions to discriminate IP injections of saline from cocaine (10 mg/kg). Responses on one of two response keys intermittently produced a food pellet; one response was reinforced in sessions following cocaine injection (10 mg/kg), and the other response was reinforced in sessions following saline injection. Each 20th response produced a food pellet (fixed-ratio, or FR20 schedule of reinforcement). The dose-effects of cocaine and its interaction with the D-2-like antagonist, raclopride, were assessed. Horizontal locomotor activity was also assessed in each genotype. Results. As previously shown), cocaine was a more potent stimulant of locomotor activity in the DA D4R KO mice compared to WT littermate mice. In addition, cocaine was more potent in producing discriminative-stimulus effects in DA D4R KO mice (ED50 value=0.50 mg/kg) compared to their WT littermates (ED50 value=2.6 mg/kg). Raclopride shifted the cocaine dose-effect curve in both DA D4R KO and WT mice, though the shift was greater for the DA D4R KO mice. Conclusions. The present results on the stimulation of activity and interoceptive/subjective effects of cocaine are consistent with the previously reported disregulation of dopamine synthesis in DA D4R KO mice, and further suggest a role of the DA D4R in vulnerability to stimulant abuse.