Involvement of central cholinergic mechanism in RU-24969-induced behavioral deficits

The present study was undertaken to investigate the role of cholinergic mechanisms in the behavioral effects of RU-24969, a compound with serotonin1B (5-HT1B) receptor agonist properties. RU-24969 caused an increase in locomotion (2-5 mg/kg IP) and an impairment of spontaneous alternation (SA) behavior in a T-maze (0.5-2.0 mg/kg IP) in mice, effects that were also induced by the cholinergic hypofunction with scopolamine treatment (0.5-5.0 mg/kg IP), an acetylcholine (ACh) receptor antagonist. The impairment of the SA behavior by RU-24969 was enhanced by scopolamine. Both the hyperlocomotion and the SA impairment by RU-24969 were markedly reduced by propranolol (20 mg/kg IP) which has 5-HT1A/5-HT1B receptor antagonist properties, as well as by physostigmine (0.05-0.2 mg/kg IP), an ACh esterase inhibitor, and oxotremorine (0.005-0.01 mg/kg IP), an ACh receptor agonist. Moreover, these behavioral deficits of RU-24969 were diminished in mice pretreated intracerebroventricularly with AF64A (30 nmol/body), a presynaptic cholinergic neurotoxin, whereas scopolamine induced the deficits even in animals with the same treatment. These results suggest that the serotonergic behavioral deficits observed after RU-24969 treatment may be caused by an inhibition of ACh release through its action on the presynaptic receptor (particularly RU-24969-sensitive sites) localized on the cholinergic terminals.