Evidence that antipsychotic drugs are inverse agonists at D2 dopamine receptors

1 The effects of a number of D-2-like dopamine receptor antagonists have been determined on forskolin-stimulated cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing the human D-2short dopamine receptor (CHO-D2S cells). 2 Dopamine inhibited the effect of forskolin (as expected for a D-2 receptor). However, all of the antagonists tested, apart from UH232 and (-)-butaclamol, were able to increase cyclic AMP accumulation above the forskolin control level. (+)-Butaclamol elicited a similar stimulation of forskolin-stimulated cyclic AMP accumulation in a CHO cell line expressing human D-2long dopamine receptors whereas it exhibited no stimulating effect on forskolin-stimulated cyclic AMP accumulation in untransfected CHO-K1 cells. 3 There was a strong correlation between the EC50 values of these compounds for potentiation of cyclic AMP accumulation and their K-i values from radioligand binding experiments in CHO-D2S cells. 4 The effects of both (+)-butaclamol and dopamine in CHO-D2S cells were inhibited by pre-treatment with pertussis toxin indicating a role for Gi/Go proteins. 5 UH232 did not significantly affect forskolin-stimulated cyclic AMP accumulation but this substance was able to inhibit the effects of both dopamine and (+)-butaclamol in a concentration-dependent manner. Thus the effects of (+)-butaclamol on forskolin-stimulated cyclic AMP accumulation an mediated directly via the D-2 receptor rather than by reversal of the effects of an endogenous agonist. 6 These data suggest that the D-2 dopamine receptor antagonists tested here, many of which are used clinically as antipsychotic drugs, are in fact inverse agonists at human D-2 dopamine receptors.