EFFECT OF 5-HT1A RECEPTOR AGONISTS AND ANTAGONISTS ON CANINE CATAPLEXY

Pharmacological studies using a canine model of narcolepsy have demons trated that adrenergic rather than serotonergic or dopaminergic uptake inhibition is the primary mode of action of antidepressants on catapl exy, a pathological manifestation of rapid eye movement (REM) sleep at onia that occurs in narcolepsy. This result is in line with the known involvement of adrenergic systems in the regulation of REM sleep. Howe ver, the lack of anticataplectic effects of selective serotonergic com pounds was puzzling as serotonergic neurons of the dorsal raphe nuclei are known to decrease activity during the REM sleep in a manner simil ar to the adrenergic neurons of the locus coeruleus. To further explor e the role of serotonergic systems, we tested the effect on canine cat aplexy of six 5-HT1A agonists and five 5-HT1A antagonists. Results ind icate that 5-HT1A agonists significantly suppress cataplexy in correla tion with their in vitro affinities to the canine central 5-HT1A recep tors. Anticataplectic effects were, however, accompanied by various be havioral changes, such as flattened body posture, increased panting an d agitation. In contrast, the selective 5-HT1A antagonists did not agg ravate cataplexy, although a 5-HT1A antagonist was able to block the a nticataplectic effect of a 5-HT1A agonist. These results suggest that the anticataplectic effects of 5-HT1A agonists are truly mediated by 5 -HT1A receptor stimulation. It is, however, likely that anticataplecti c effects occur due to the behavioral side effects rather than the dir ect involvement of this receptor subtype in the regulation of cataplex y. Further studies are therefore necessary to address the question of whether these 5-HT1A agonists hold promise in the pharmacological trea tment of human cataplexy.