Recovery of Sensorimotor Gating without G Protein Adaptation after Repeated D₂-Like Dopamine Receptor Agonist Treatment in Rats

Sensorimotor gating, a neural process severely disrupted in patients with schizophrenia, can be measured by assessing prepulse inhibition (PPI) of acoustic startle responses. PPI is disrupted in experimental animals by stimulation of D₂-like dopamine receptors in the nucleus accumbens (NAc). We examined the effect of repeated treatment with a selective dopamine D₂-like receptor agonist, quinpirole, and characterized the molecular substrates of the resulting PPI adaptation. Animals were treated once daily for 10 or 28 consecutive days with quinpirole (0.0, 0.05, 0.1, or 0.3 mg/kg, s.c.), and the effect on PPI was assessed throughout the treatment period. PPI was reduced after acute quinpirole administration, but gradually increased with repeated treatment. Quinpirole-induced PPI disruption was attenuated after 10 days of treatment at lower doses, but complete recovery was not apparent until the treatment period was extended to 28 days. Since chronic drug exposure can alter the dopamine system, we sought to characterize the effects of repeated quinpirole treatment on G proteins coupled to D ₂-like receptors in the NAc. Guanosine 5′-O-(3-[ ³⁵S]thiotriphosphate) ([³⁵S]GTPγS) binding and Western blot analysis revealed that repeated quinpirole treatment had no effect on NAc D₂-like receptor G protein function or G protein levels. These data indicate that repeated activation of D₂-like receptors by quinpirole produces tolerance in the absence of receptor or G protein changes, suggesting that the locus of dopaminergic adaptation might be at the intracellular level.