Differential effects of direct and indirect dopamine agonists on prepulse inhibition: A study in D1 and D2 receptor knock-out mice

Abstract

Stimulation of the dopamine (DA) system disrupts prepulse inhibition (PPI) of the acoustic startle response. On the basis of rat studies, it appeared that DA D2 receptors (D2Rs) rather than D1 receptors (D1Rs) regulate PPI, albeit possibly in synergism with D1 Rs. To characterize the DA receptor modulation of PPI in another species, we tested DA D1R and D2R mutant mice with direct and indirect DA agonists and with the glutamate receptor antagonist, dizocilpine (MK-801). Neither the mixed D1/D2 agonist apomorphine (5 mg/kg) nor the more selective D1-like agonist SKF82958 (0.3 mg/kg) altered PPI in D1R knock-out mice, although both compounds disrupted PPI in D2R mutant and wild-type mice, suggesting that the D1R alone might modulate PPI in mice. However, amphetamine (10 mg/kg) significantly lowered PPI in each genotype of D1R mice, suggesting that the D1R is not necessary for the PPI-disruptive effect of the indirect agonist in mice. As reported previously, amphetamine (10 mg/kg) failed to disrupt PPI in D2R knock-out mice, supporting a unique role of the D2R in the modulation of PPI. Dizocilpine (0.3 mg/kg) induced similar PPI deficits in D1R and D2R mutant mice, confirming that the influences of the NMDA receptor on PPI are independent of D1 Rs and D2Rs in rodents. Thus, both D1Rs and D2Rs modulate aspects of PPI in mice in a manner that differs from dopaminergic modulation in rats. These findings emphasize that further cross-species comparisons of the pharmacology of PPI are essential to understand the relevance of rodent PPI studies to the deficits in PPI observed in patients with schizophrenia.