Evidence that antipsychotic drugs are inverse agonists at D₂ dopamine receptors

Abstract

1. The effects of a number of D₂-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 D₂ 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 are mediated directly via the D₂ receptor rather than by reversal of the effects of an endogenous agonist.

6. These data suggest that the D₂ dopamine receptor antagonists tested here, many of which are used clinically as antipsychotic drugs, are in fact inverse agonists at human D₂ dopamine receptors.

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