Stimulation by risperidone of rat prolactin secretion in vivo and in cultured pituitary cells in vitro

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 262; no. 2; pp. 699 - 706
• Main Authors: BOWDEN, C. R, VOINA, S. J, WOESTENBORGHS, R, DE COSTER, R, HEYKANTS, J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.08.1992
• Subjects: Animals; Antipsychotic Agents - pharmacology; Biological and medical sciences; Cells, Cultured; Haloperidol - pharmacology; Isoxazoles - metabolism; Isoxazoles - pharmacology; Ketanserin - pharmacology; Male; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Piperidines - metabolism; Piperidines - pharmacology; Pituitary Gland - drug effects; Pituitary Gland - secretion; Prolactin - secretion; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Inbred Strains; Risperidone; Spiro Compounds - pharmacology; Stimulation, Chemical; Cell culture; Rat; Dopamine antagonist; Serotonin antagonist; Rodentia; Stimulation; In vitro; Protein hormone; In vivo; Vertebrata; Mammalia; D2 Dopamine receptor; Adenohypophyseal hormone; Prolactin; Animal; Pituitary gland; Release
• ISSN: 0022-3565; 1521-0103

Risperidone, a new antipsychotic agent which antagonizes both 5-hydroxytryptamine-2 (5-HT2) and dopamine-2 (D2) receptors, was evaluated for its effects on prolactin release. One hr after either p.o. or i.p. dosing, risperidone was 3 to 5 times more potent than the classical D2 receptor antagonist haloperidol in stimulating rat prolactin levels in vivo. This result was unexpected because haloperidol is a more potent D2 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 D2 receptor binding potencies in vitro. Administration of ketanserin, a 5-HT2 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 (greater than 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.