Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine_1A receptor-mediated behavioral effects overlap its other properties in rats

Abstract

Rationale. There is substantial evidence that lisuride can produce effects linked to 5-HT_1A receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT_2A/2C receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT_1A receptors has been demonstrated in several different laboratories and that activation of 5-HT_1A and 5-HT_1B receptors can modulate dopaminergically mediated responses.

Objective. The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification as a dopamine agonist in the literature.

Results. In drug discrimination studies, lisuride fully mimicked the 5-HT_1A agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for (+)-amphetamine. Lisuride produced a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation of behavior by action at central 5-HT_1A receptors. Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective 5-HT_1A antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect on any behavior induced by LSD. Lisuride dose dependently decreased body temperature in rats with a potency similar to that of the selective 5-HT_1A agonist LY 293284. The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol.

Conclusion. We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT_1A receptors.