Repeated treatment with 8-OH-DPAT induces tolerance to its ability to produce the 5-HT(1A) behavioural syndrome, but not to its ability to attenuate haloperidol-induced catalepsy

When administered acutely, 5-hydroxytryptamine(1A) (5-HT(1A)) agonists attenuate the cataleptic side effects of antipsychotics. We investigated whether tolerance occurs to these effects after repeated administration of the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). For comparison, we also assessed the ability of 8-OH-DPAT to produce elements of the 5-HT(1A) behavioural syndrome (i.e. forepaw treading, flat body posture and lower lip retraction), some of which readily demonstrate tolerance. Catalepsy was measured in rats using both the cross-legged position test and the bar test. Repeated treatment with 8-OH-DPAT (0.63-2.5 mg/kg subcutaneously), once daily for 4 days, did not significantly alter the ability of acute treatment with 8-OH-DPAT (0.01-2.5 mg/kg) to inhibit catalepsy induced by haloperidol (2.5 mg/kg) in either test. In contrast, the ability of 8-OH-DPAT to produce the 5-HT(1A) behavioural syndrome was significantly attenuated by the repeated treatment. The present data, showing an abscence of tolerance to the anti-cataleptic effects of a 5-HT(1A) agonist, indicate that mixed dopamine antagonist / 5-HT(1A) agonist compounds may continue to have a low propensity to induce extrapyramidal side effects during chronic treatment. (C) 2000 Lippincott Williams and Wilkins.