Effects of D3/D2 Dopamine Receptor Agonists and Antagonists on Prepulse Inhibition of Acoustic Startle in the Rat

Abstract

Prepulse inhibition (PPI) is the normal reduction in a startle response that occurs when a weak stimulus (“prepulse”) precedes the startling stimulus by 30 to 500 msec. Schizophrenic patients are deficient in this operational measure of sensorimotor gating; therefore, animal models of deficient PPI may provide information useful in the understanding and treatment of schizophrenia. Prepulse inhibition is disrupted in rats by systemic administration of direct dopamine agonists having affinity for the D2 subtype family (D2, D3 and D4) of dopamine receptors. This study tested the hypothesis that dopamine agonists and antagonists with different affinities for D3 and D2 receptors differ in their relative potencies to modulate PPI. The dopamine agonists quinpirole, 7-hydroxy-N,-N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and apomorphine were approximately equipotent in decreasing PPI. Pretreatment with haloperidol (13 to 130 nmol/kg sc), but not equimolar doses of UH 232, prevented the disruption of PPI produced by the highest dose (0.6 μmol/kg sc) of each agonist. Given the 100-fold higher affinity of haloperidol relative to UH 232 for D2 receptors, and equal relative affinities of these antagonists for D3receptors, these data are consistent with previous studies suggesting that dopamine agonists may modulate PPI in the rat through the D2 subtype of dopamine receptors.