The effect of clozapine on prolactin secretion at the level of the lactotroph

Abstract

Clozapine is an antipsychotic drug which is unusual in that it has no dopamine receptor-blocking activity. Previous studies gave conflicting results whether administration of clozapine induces hyperprolactinemia. In the present study it was shown that a wide concentration range of clozapine does not interfere with dopamine-mediated inhibition of prolactin (PRL) secretion by normal cultured rat pituitary cells. This in contrast to other neuroleptics, like haloperidol and trifluoperazine. Clozapine does also not antagonize norepinephrine-mediated inhibition of PRL secretion. Clozapine exerts at micromolar concentrations a direct inhibitory action on PRL release by cultured normal rat pituitary cells. In cultured rat pituitary tumor cells, these high concentrations of clozapine directly inhibit PRL release as well as the DNA content of the cells, suggesting a direct antimitotic action. In this model clozapine was about 5-10 times less potent than trifluperazine. Clozapine and trifluoperazine exert an additive inhibitory action both on PRL release and on the DNA content of the pituitary tumor cells. It is concluded that clozapine does not interfere at the pituitary level with dopamine-mediated inhibition of PRL release. At micromolar concentrations clozapine may act on lactotrophs as a calmodulin-inhibitor. These observations suggest that the transient PRL-releasing effects which have been observed in both animal and human studies after clozapine administration are mediated via supra-pituitary actions of the drug.

New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine

“…The previous findings indicate that the minimal effect of clozapine on prolactin secretion might also be due to interaction with the serotoninergic system at the suprapituitary level (Coward 1992). The inability of clozapine to effectively block the pituitary D2 receptors (Meltzer and Gudelsky 1992;Lamberts et al 1990) is in agreement with the data from biochemical and behavioral studies (see section 2.2.2) showing that this drug is relatively weak in blocking D2 receptors.…”

“…The minimal effect of clozapine on prolactin has been suggested to be due to a compensatory enhancement of dopamine synthesis in tuberoinfundibular neurons (Gudelsky et al 1989). However, unlike typical neuroleptics, clozapine does not antagonize the inhibitory effect of dopamine on prolactin release from anterior pituitary cells in culture (Lamberts et al 1990). The previous findings indicate that the minimal effect of clozapine on prolactin secretion might also be due to interaction with the serotoninergic system at the suprapituitary level (Coward 1992).…”

General Pharmacology of Clozapine

“…This may be due to a compensatory increase of dopamine synthesis in tuberoinfundibular neurons not seen with classical neuroleptics (Gudelsky et al, 1989). However, unlike classical neuroleptics, clozapine does not block dopamine-induced inhibition of prolactin release from cultured rat pituitary cells (Lamberts et al, 1990). Taken together, these findings suggest that chlorpromazine, fluphenazine or loxapine (Stilleet al, 1971).…”

Hyperprolactinemia associated with psychotropics—a review

“…Morphine and morphine analogues increase prolactin release in short‐term (Tolis et al ., 1975; Zis et al ., 1984) and long‐term studies (Chan et al ., 1979; Afrasiabi et al ., 1979). µ receptor is predominantly involved in prolactin release and κ is implicated to a lesser extent (Panerai et al ., 1985; Pfeiffer et al ., 1986; Leadem and Yagenova, 1987). Methadone produces a transient increase 2‐4 h after intake (Bart et al ., 2003).…”