Activation of D1, but not D2 Receptors Potentiates Dizocilpine-Mediated Disruption of Prepulse Inhibition of the Startle

Abstract

Although substantial evidence has shown interactions between glutamatergic and dopaminergic systems play a cardinal role in the regulation of attentional processes, their involvement in informational filtering has been poorly investigated. Chiefly, little research has focused on functional correlations between the dopaminergic system and the mechanism of action of N-methyl-D-aspartate (NMDA) receptor antagonists on sensorimotor gating. The present study was targeted at evaluating whether the activation of D 1 and D 2 receptors is able to interact with the disruption of prepulse inhibition (PPI) of startle mediated by dizocilpine, a selective, noncompetitive NMDA receptor antagonist. We tested the effects of SKF 38393 ((7)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (10 mg/kg, s.c.), a selective D 1 agonist, and quinpirole (0.3, 0.6 mg/kg, s.c.), a D 2 agonist, in rats, per se and in cotreatment with different doses of dizocilpine, ranging from 0.0015 to 0.15 mg/kg (s.c.). Subsequently, the effect of the D 1 antagonist SCH 23390 ((R)-( þ )-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (0.05, 0.1 mg/kg, s.c.) on PPI disruptions mediated by dizocilpine and by combination of dizocilpine and SKF 38393 was tested. Two further experiments were performed to verify whether the synergic effect of the D 1 agonist with dizocilpine was counteracted by effective doses of haloperidol (0.1, 0.5 mg/kg, i.p.) and clozapine (5, 10 mg/kg, i.p.). All experiments were carried out using standard procedures for the assessment of PPI of the acoustic startle reflex. SKF 38393, while unable to impair sensorimotor gating alone, induced PPI disruption in cotreatment with 0.05 and 0.15 mg/kg of dizocilpine, both ineffective per se. Furthermore, this effect was reversed by SCH 23390, but not by haloperidol or clozapine. Conversely, no synergistic effect was exhibited between quinpirole and dizocilpine, at any given dose. These findings suggest that D 1 , but not D 2 receptors, enhance the disruptive effect of dizocilpine on PPI.

PPI deficit induced by amphetamine is attenuated by the histamine H1 antagonist pyrilamine, but is exacerbated by the serotonin 5-HT2 antagonist ketanserin

“…These effects resulted in a significant amphetamine×pyrilamine interaction (p<0.025) pyrilamine did not have a significant main effect on the PPI magnitude in Experiment 1, but was able to attenuate the amphetamine-induced PPI disruption. Pyrilamine reduced the startle response magnitude in startle-alone trials, an outcome similar to findings reported in some earlier studies with clozapine (Bortolato et al 2005;Bubenikova et al 2005;Conti et al 2005), though other reports show no significant changes on the startle amplitude with clozapine (Caceda et al 2005;Tenn et al 2005). Still, it is believed that the results of antipsychotics on PPI are independent of their effects on the startle response magnitude (Johansson et al 1995).…”

“…Different experimental methods to induce PPI deficits in rats include the stimulation of dopamine receptors, activation of serotonin systems, blockade of N-methyl D-aspartate (NMDA) receptors, and developmental manipulations such as isolated rearing (for a complete review of different models of PPI disruption and the effects of various pharmacological manipulations, see Geyer et al 2001). For instance, the NMDA glutamate receptor antagonist dizocilpine robustly disrupts PPI in rats (Mansbach and Geyer 1989), and the antipsychotic clozapine has been show to reverse that disruption (Bakshi et al 1994;Bubenikova et al 2005;Bortolato et al 2005;Caceda et al 2005).…”

Enhanced effect of dopaminergic stimulation on prepulse inhibition in mice deficient in the alpha subunit of Gz

“…However, some of the effects of NMDA receptor antagonism involve changes in dopamine release and dopamine receptor activation in the nucleus accumbens. For example, stimulation of dopamine D1 receptors, but not D2 receptors, potentiates the disruption of PPI caused by treatment with MK-801 in rats (Bortolato et al 2005). Unlike the effect of apomorphine, this interaction is apparently not influenced by G z .…”

Effects of Topiramate on the Prepulse Inhibition of the Acoustic Startle in Rats

“…Dizocilpine induces popping plausibly through a dopaminergic mechanism, since haloperidol is able to reverse this behavior in a dose-dependent manner (Deutsch and Hitri, 1993). In contrast, the weight of evidence supports the idea that dizocilpine-mediated PPI disruption is mainly independent by dopaminergic mechanisms, although it might be potentiated by acute D 1 receptor activation (Bortolato et al, 2005) or blunted by chronic D 2 agonist treatment (Krupin and Hammer, 2005). Indeed, atypical, but not typical antipsychotics, are able to attenuate dizocilpine-induced PPI deficits , suggesting that D 2 receptors are not critically involved in the psychotomimetic mechanisms of NMDA receptor antagonists.…”