LONG-TERM NEUROLEPTIC TREATMENTS COUNTERACT DOPAMINE D-2 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 d opamine (DA) in striatal membranes of rats treated for 3 weeks with ch lorpromazine or haloperidol, and further measured the level of Gi (an inhibitory GTP-binding protein) or Go (a similar GTP-binding protein o f unknown function) in 3 areas (cerebral cortex, striatum and hippocam pus) utilizing pertussis toxin-catalyzed ADP ribosylation. In saline-t reated control membranes, GTP exerted a biphasic effect on basal and D A-stimulated enzyme activity-peak levels of stimulation by DA plus GTP were observed al 1 mu M GTP. Conversely, dopaminergic inhibitory effe cts at 10-100 mu M GTP were completely attenuated in chlorpromazine or haloperidol-treated membranes. D-2 inhibition of adenylate cyclase by the selective D-2 agonist PPHT was also attenuated due to these neuro leptic treatments, while an increase in D-2 receptor binding was obser ved. The pertussis toxin ADP-ribosylation of G-proteins (Gi/Go) did no t differ significantly in any area. This indicates that long-term neur oleptic treatments increased D-2 receptor binding, but attenuated D-2 inhibition of adenylate cyclase, and exercised no influence on pertuss is toxin ADP-ribosylation.