ANTIPSYCHOTICS WITH INVERSE AGONIST ACTIVITY AT THE DOPAMINE D-3 RECEPTOR

In NG 108-15 cells expressing the recombinant human D-3 receptor, dopa mine agonists enhance [H-3]thymidine incorporation and decrease cAMP a ccumulation. In these cells, but not in wild type cells, haloperidol, fluphenazine, and various other antipsychotics inhibited basal [H-3]th ymidine incorporation in a concentration-dependent manner. In contrast , other dopamine antagonists such as nafadotride or (+)AJ 76, two D-3- preferring antagonists, were without effect. The concentration-respons e curve of haloperidol was shifted to the right in presence of nafadot ride, with a potency compatible with its nanomolar apparent affinity a s neutral antagonist. Pertussis toxin treatment abolished or markedly reduced the responses to haloperidol or fluphenazine. In contrast, no significant enhancement of cAMP accumulation could be observed, under the influence of haloperidol or eticlopride. These data indicate that some dopamine antagonists behave as inverse agonists, and thus appear to inhibit an agonist-independent activity of the D-3 receptor on [H-3 ]thymidine incorporation pathway, but not on the cAMP pathway.