Tolerance to the serotonin 5-HT1 agonist RU 24969 and effects on dopaminergic behaviour.

The pharmacological responses to intraperitoneal injection of the serotonin (5-HT) 5-HT1 agonist RU 24969 (0.25-5 mg/kg) were studied in rats either after single administrations or after repeated treatment (5 mg/kg per day for 3 days). The following effects were recorded after a single dose: (A) a strong increase in locomotor activity in intact rats and its potentiation after 5,7-dihydroxytryptamine lesion of 5-HT neurons; (B) at a low dose, a potent enhancement of the circling behaviour induced by the dopamine (DA) D2 agonist LY 171555 in 6-hydroxydopamine-lesioned rats; (C) an early reduction (2 h) of 5-hydroxyindole acetic acid levels in the striatum and the nucleus accumbens followed by a late increase (24 h) in the latter structure. The following modifications were observed 24 h after the repeated treatment with RU 24969: (A) the locomotor effect of the drug was strikingly reduced both in intact and 5,7-dihydroxytryptamine-lesioned animals. On the contrary, the locomotion elicited by the DA releaser d-amphetamine, or the 5-HT1A agonist 8-OH-DPAT, was unchanged; (B) the rotation scores of 6-hydroxydopamine-lesioned rats injected with LY 171555 after a low dose of RU 24969, were greatly reduced. Moreover, the circling response was almost abolished in rats treated with the DA agonist alone; (C) the early reduction of 5-hydroxyindole acetic acid levels was antagonized while the late increase was enhanced. It is concluded that both the state of tolerance and the reversal of the action of RU 24969 that followed repeated treatment might be related to down-regulation of a subtype of the 5-HT1 receptor, possibly the 5-HT1B subtype, that would play a critical role in the expression of DA-mediated behaviour, locomotor activity and 5-HT metabolism.