Reduced G i and G o protein function in the rat nucleus accumbens attenuates sensorimotor gating deficits

Abstract

Prepulse inhibition of the acoustic startle response (PPI) is a cross-species measure of sensorimotor gating, which is severely disrupted in patients with schizophrenia. PPI deficits can be produced in experimental animals by administration of selective D 2-like dopamine receptor agonists in the nucleus accumbens (NAc). G proteins coupled to these receptors reportedly are altered in the NAc of patients with schizophrenia. Therefore, we sought to determine whether experimental inactivation of intracellular G proteins in the NAc alters PPI. In adult male Sprague–Dawley rats, baseline PPI was determined by presenting acoustic pulse stimuli (120 dB) alone or preceded 100 ms earlier by prepulse stimuli (3, 6 or 12 dB above 70 dB ambient noise). PPI disruption was assessed in the presence of quinpirole (0.0, 0.05, 0.1, 0.5 mg/kg, sc), and pertussis toxin (PTX; 0.05 μg/side) was then infused into the NAc bilaterally. Ten days later, quinpirole-mediated disruption of PPI was significantly reduced; neither PTX alone, nor heat-inactivated PTX had any effect on quinpirole-induced PPI reductions. PPI was significantly higher after PTX infusion upon moderate quinpirole challenge, suggesting that D 2-like receptors were less effective. PTX treatment significantly reduced basal and dopamine-stimulated [ 35S]GTPγS binding in the NAc core and shell, and reduced G i α protein immunoreactivity in the NAc. The results suggest that PPI disruption mediated by D 2-like receptor activation in the NAc depends on coupling to G i and G o proteins, alteration of which could cause sensorimotor gating deficits in schizophrenia.