Interaction of SCH 23390, a D-1-selective antagonist, with the anterior pituitary D-2 receptors and prolactin secretion in the rat

Abstract

The affinity of the dopamine-1 (D-1) selective antagonist SCH 23390 (SCH) towards the dopamine-2 (D-2) receptor population present in the anterior pituitary (AP) was assessed in vitro and in vivo. [3H]Spiperone binding was used as biochemical marker for D-2 receptors in the rat AP and prolactin (PRL) was determined as a measure of the functional response to AP-D-2 blockade. SCH displayed weak activity in inhibiting [3H]spiperone binding in both AP and striatal membranes. The affinity was similar to that exhibited by sulpiride (mu molar range) but lower than that of haloperidol (HAL) (nmolar range). However inhibition of [3H]spiperone by SCH in the AP occurred in a biphasic manner indicating the existence of two D-2 sites with different affinity for the compound. SCH produced a transient and dose-dependent increase in plasma PRL levels when given by the subcutaneous (s.c.) route. A significant rise of PRL levels was observed only 30 min after the administration of high doses of SCH by the intraperitoneal (i.p.) route. SCH counteracted the inhibiting effect of apomorphine on PRL release and potentiated the stimulation effect of low doses of sulpiride on PRL secretion. The low affinity of SCH towards AP-D-2 receptors could be responsible for the small and short-lived increase in PRL secretion. This effect occurred at doses higher than those active in tests predictive for antipsychotic activity, which may depend directly on interaction with D-1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)