Long-term neuroleptic treatments counteract dopamine D2 agonist inhibition of adenylate cyclase but do not affect pertussis toxin ADP-ribosylation in the rat brain.

We have investigated the response of adenylate cyclase to GTP and to dopamine (DA) in striatal membranes of rats treated for 3 weeks with chlorpromazine or haloperidol, and further measured the level of Gi (an inhibitory GTP-binding protein) or Go (a similar GTP-binding protein of unknown function) in 3 areas (cerebral cortex, striatum and hippocampus) utilizing pertussis toxin-catalyzed ADP ribosylation. In saline-treated control membranes, GTP exerted a biphasic effect on basal and DA-stimulated enzyme activity--peak levels of stimulation by DA plus GTP were observed at 1 microM GTP. Conversely, dopaminergic inhibitory effects at 10-100 microM GTP were completely attenuated in chlorpromazine or haloperidol-treated membranes. D2 inhibition of adenylate cyclase by the selective D2 agonist PPHT was also attenuated due to these neuroleptic treatments, while an increase in D2 receptor binding was observed. The pertussis toxin ADP-ribosylation of G-proteins (Gi/Go) did not differ significantly in any area. This indicates that long-term neuroleptic treatments increased D2 receptor binding, but attenuated D2 inhibition of adenylate cyclase, and exercised no influence on pertussis toxin ADP-ribosylation.