Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock-out mice - PubMed (original) (raw)

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

Rebecca J Ralph-Williams et al. J Neurosci. 2002.

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 D1Rs. 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 D1Rs 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.

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Figures

Fig. 1.

Fig. 1.

PPI levels in D1R and D2R mice after pretreatment with vehicle (0.1% ascorbic acid; open bars) or apomorphine (APO) (5.0 mg/kg; hatched bars). A, The mixed D1/D2 agonist apomorphine decreased PPI in both the D1R wild-type (WT, +/+) and heterozygous (HZ, +/−) mice but was ineffective in the D1R knock-out (KO, −/−) mice. **p < 0.01 compared with vehicle control.B, Apomorphine disrupted PPI in all D2R mutant mice, regardless of genotype (overall drug effect,### p < 0.001). Error bars indicate mean % PPI ± SEM.

Fig. 2.

Fig. 2.

PPI levels in D1R and D2R mutant mice with vehicle control (water; open bars) or SKF82958 (SKF) (0.3 mg/kg; hatched bars).A, The D1-like agonist SKF82958 produced deficits in PPI in the D1R wild-type (WT) (+/+) mice but failed to produce deficits in the D1R knock-out (KO) (−/−) mice.HZ, Heterozygous. **p < 0.01 compared with vehicle control. B, SKF82958 significantly reduced PPI in each of the D2R genotypes (overall drug effect,### p < 0.001). Error bars indicate mean % PPI ± SEM.

Fig. 3.

Fig. 3.

PPI levels for D1R and D2R mutant mice with vehicle control (water; open bars) or amphetamine (AMPH) (10 mg/kg; hatched bars).A, All D1R mice treated with the indirect DA agonist amphetamine displayed significant reductions in PPI compared with vehicle-treated mice (overall drug effect,### p < 0.001). B,Post hoc ANOVAs revealed that amphetamine significantly reduced PPI at the 4, 8, and 16 dB prepulse intensities in D2R wild-type (WT) (+/+) mice (**p < 0.01 compared with vehicle control) but had no significant effect in the heterozygous (HZ) (+/−) or knock-out (KO) (−/−) mice. Error bars indicate mean % PPI ± SEM.

Fig. 4.

Fig. 4.

PPI levels in D1R and D2R mice after pretreatment with vehicle control (water; open bars) or dizocilpine (DIZ) (0.3 mg/kg; hatched bars). Regardless of genotype, the noncompetitive NMDA receptor antagonist dizocilpine significantly disrupted PPI in the D1R (A) and D2R (B) wild-type (WT) (+/+), heterozygous (HZ) (+/−), and knock-out (KO) (−/−) mice (overall drug effect,### p < 0.001). Error bars indicate mean % PPI ± SEM.

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