Activation of D1, but not D2 receptors potentiates dizocilpine-mediated disruption of prepulse inhibition of the startle.

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 D1 and D2 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 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (10 mg/kg, s.c.), a selective D1 agonist, and quinpirole (0.3, 0.6 mg/kg, s.c.), a D2 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 D1 antagonist SCH 23390 ((R)-(+)-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 D1 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 D1, but not D2 receptors, enhance the disruptive effect of dizocilpine on PPI.

The CB receptor agonist WIN 55,212-2 fails to elicit disruption of prepulse inhibition of the startle in Sprague-Dawley rats.

RATIONALE: A growing evidentiary body indicates cannabinoid exposure is conducive to cognitive impairment and psychotic phenomena in vulnerable individuals. In this respect, recent studies have displayed controversial results on the ability of cannabinoids to elicit sensorimotor gating alterations and attentional filtering, whose disruption is a distinctive feature of psychosis. OBJECTIVES: The goal of this study was to investigate the effects of acute, subchronic, and chronic treatment with the synthetic CB receptor agonist WIN 55,212-2 (WIN) on prepulse inhibition (PPI) of the acoustic startle reflex (ASR), a powerful paradigm for evaluation of sensorimotor gating. METHODS: Different groups of adult Sprague-Dawley rats were treated with 0.5, 1, and 2 mg/kg WIN (i.p.) acutely, as well as for 7 days and 21 days. All animals underwent testing 40 min after the last treatment and their evaluation was compared with that of animals treated with vehicle. In a separate group, the effects of WIN withdrawal were also analyzed, 24 h after discontinuation of a 21-day treatment. RESULTS: No variation in PPI was detected in any of the test groups when compared with controls, whatever the dosage and the treatment. CONCLUSIONS: These findings suggest WIN does not impair sensorimotor gating in Sprague-Dawley rats and confirm clinical evidence according to which cannabis is an unlikely causative of psychosis among non-vulnerable individuals. Nonetheless, since in other studies the same compound was shown to induce PPI alterations in Wistar rats, our results are also suggestive that genetic differences might be critical for the development of cannabis-induced cognitive disorders.