Reduced G(i) and G(o) protein function in the rat nucleus accumbens attenuates sensorimotor gating deficits.
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 microg/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]GTPgammaS binding in the NAc core and shell, and reduced G(i)(alpha) 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.
Culm
Kerry E
KE
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA.
Lim
Antonio M
AM
Onton
Julie A
JA
Hammer
Ronald P
RP
D000161:Acoustic Stimulation; D000818:Animals; D001522:Behavior, Animal; D004298:Dopamine / Q000494:pharmacology; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D008297:Male; D009043:Motor Activity / Q000502:physiology*; D009433:Neural Inhibition; D009714:Nucleus Accumbens / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000502:physiology; D012677:Sensation / Q000187:drug effects / Q000502:physiology*
D011518:Proto-Oncogene Proteins; D019257:Quinpirole; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D037342:Pertussis Toxin; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498017:Gnai2 protein, rat; D020962:Heterotrimeric GTP-Binding Proteins; D004298:Dopamine