D-1 AND D-2 DOPAMINE-RECEPTOR ANTAGONISTS REVERSE PREPULSE INHIBITION DEFICITS IN AN ANIMAL-MODEL OF SCHIZOPHRENIA

The amplitude of the acoustic startle response is decreased if the startle stimulus is preceded by a non-startle eliciting stimulus. This sensorimotor gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the dopamine agonist apomorphine disrupts prepulse inhibition and this disruption is reversed by classical and atypical antipsychotics. Furthermore, the ability of antipsychotics to reverse the apomorphine disruption is correlated with clinical potency and D-2 receptor affinity. In the present study, the role of the D-1 receptor in prepulse inhibition of the acoustic startle response was studied; the effects of the D-1 receptor antagonist SCH 23390 were examined and compared to the effects of the D-2 receptor antagonist eticlopride. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB noise bursts presented alone or preceded by a 75 dB noise burst. Trials consisting of no stimulus and the 75 dB prepulse stimulus alone were also included. These six trial types (ten each) were randomly presented within a 35-min session. Rats treated with 2.0 mg/kg apomorphine (SC) demonstrated a significant disruption of prepulse inhibition compared to vehicle controls. Pretreatment with the D-1 antagonist SCH 23390 (0.01, 0.05, 0.1 mg/kg SC) or the D-2 antagonist eticlopride (0.01, 0.05, 0.1 mg/kg SC) attenuated the disruptive effects of apomorphine. These results indicate that selective blockade of either the D-1 or D-2 receptor subtype is sufficient in reversing the sensorimotor gating deficits produced by apomorphine. The effects of eticlopride and SCH 23390 on prepulse inhibition in saline-treated rats were also examined. Each antagonist produced a dose-related facilitation of prepulse inhibition, suggesting that endogenous DA acting at either receptor subtype plays a role in the tonic modulation of sensorimotor gating.