Stimulation by risperidone of rat prolactin secretion in vivo and in cultured pituitary cells in vitro
Bowden, C.R.; Voina, S.J.; Woestenborghs, R.; De Coster, R.; Heykants, J.
Journal of Pharmacology and Experimental Therapeutics 262(2): 699-706
1992
ISSN/ISBN: 0022-3565 PMID: 1380082 Document Number: 389848
Risperidone, a new antipsychotic agent which antagonizes both 5-hydroxytryptamine-2 (5-HT-2) and dopamine-2 (D-2) receptors, was evaluated for its effect on prolactin release. One hr after either p.o. or i.p. dosing, risperidone was 3 to 5 times more potent than the classical D-2 receptor antagonist haloperidol in stimulating rat prolactin levels in vivo. This result was unexpected because haloperidol is a more potent D-2 receptor antagonist than risperidone in vitro. Mechanisms which might explain these observations were investigated. Compared to haloperidol, risperidone was 0.34 (95% confidence interval: 0.23, 0.48) times as potent in reversing the suppression by dopamine of rat anterior pituitary cell prolactin release in vitro, which is consistent with the compounds' striatal D-2 receptor binding potencies in vitro. Administration of ketanserin, a 5-HT-2 receptor antagonist, along with haloperidol did not modify haloperidol's activity on either in vitro pituitary cell prolactin release (up to 1000 nM ketanserin) or in vivo prolactin concentrations (5 mg/kg ketanserin, i.p.). In vitro incubation of haloperidol and risperidone with a liver homogenate supernatant (S-9) led to extensive ( gt 86%) metabolism of each compound. S-9 treatment abolished haloperidol's effects on pituitary cell prolactin release. Risperidone's ability to increase prolactin release was unchanged after S-9 treatment, and 9-hydroxy-risperidone, identified as a major metabolite in the S-9 conditioned media, was equipotent to risperidone in modulating prolactin release in vitro. After identical oral doses of risperidone and haloperidol, risperidone plasma levels in rats were up to 8-fold greater than those of haloperidol, whereas 9-hydroxy-risperidone plasma levels were 3- to 6-fold higher than those of risperidone. The unexpected potency ratio between risperidone and haloperidol on rat prolactin levels in vivo was thus due to pharmacokinetic differences and not to risperidone's known D-2/5-HT-2 receptor interactions. These differences include the conversion of risperidone to its equipotent 9-hydroxy-risperidone metabolite, as well as to the higher circulating levels of risperidone and 9-hydroxy-risperidone compared to those of haloperidol.