INVERSE AGONISM AT DOPAMINE D-2 RECEPTORS - HALOPERIDOL-INDUCED PROLACTIN-RELEASE FROM GH(4)C(1) CELLS TRANSFECTED WITH THE HUMAN D-2 RECEPTOR IS ANTAGONIZED BY R(-)-N-PROPYLNORAPOMORPHINE, RACLOPRIDE, AND PHENOXYBENZAMINE

Our earlier observation that the antipsychotic drug haloperidol in the absence of dopamine increases cAMP formation and prolactin release in two prolactin-producing cell lines expressing mt dopamine D-2 recepto rs (GH(3), GH(4)ZR(7)), but not in similar cells devoid of D-2 recepto rs (GH(4)C(1)), prompted us to suggest that haloperidol may act Its an inverse (or negative) agonist, rather than as a neutral antagonist, a t the D-2 receptor (Nilsson and Eriksson 1993). In the present study i t is shown that haloperidol elicits a dose-dependent increase in prola ctin release also in prolactin-producing GH(4)C(1) cells transfected w ith the human dopamine D-2 receptor (short isoform) (GH(4)C(1)-hD(2)s) ; in addition, it is shown that another antipsychotic drug, flupenthix ol, also causes prolactin release per se in this cell line. The effect of haloperidol on prolactin release in GH(4)C(1)-hD(2)s is calcium de pendent and counteracted by pretreatment either with the D-2 receptor agonist R(-)-n-propylnorapomorphine or with a D-2 receptor antagonist that does not affect prolactin release per se (raclopride). In additio n, pretreatment with the alkylating compound phenoxybenzamine at a con centration causing a marked reduction of D-2 receptor density in GH(4) C(1)-hD(2)s cells significantly counteracted haloperidol-induced prola ctin release.