Differential effects of dopamine receptor subtype blockade on performance of rats in a reaction-time paradigm

Abstract 

Rationale: Pharmacological manipulation of the dopaminergic system with antipsychotic agents disrupts motor behavior. Although most antipsychotic drugs have high affinity for D₂ receptors, they also interact with other dopamine receptor subtypes. Therefore, the role of each of these receptor subtypes on motor performance is unclear. Objective: The present study sought to investigate the relative importance of D₁, D₂, and D₃ receptors on performance in a conditioned reaction-time task known to be extremely sensitive to dysfunction of the dopaminergic nigrostriatal pathway. Methods: Rats were trained to release a lever in response to a visual cue within a reaction-time limit to receive a reinforcer (45-mg food pellet). After the behavior of the rats had stabilized, the effects of a D₁ (A69024), D₂ (eticlopride), and D₃ (nafadotride) receptor antagonists were assessed. Results: A-69024 had no effect on performance at any dose tested (0.3, 0.6, and 1.3 mg/kg s.c.). Nafadotride (0.1, 0.3, and 1 mg/kg s.c.) produced only a mild deficit in performance at the highest dose. This deficit was characterized by an increase in the number of delayed responses with a non-significant decrease in the number of premature responses indicative of non-specific sedative effects. In contrast, the D₂ receptor antagonist eticlopride (0.005, 0.01, and 0.02 mg/kg s.c.) produced profound deficits in performance as evidenced by a dose-dependent decrease in the number of correct responses. This decrease was accompanied by an increase in the number of delayed responses and a lengthening of the reaction time at the highest doses. Conclusions: These results provide further evidence that the execution of the reaction-time task is dependent preferentially upon the activation of D₂ receptors, but not D₁ or D₃ receptors.