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.
Noda
Y
Y
Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
Ochi
Y
Y
Shimada
E
E
Oka
M
M
D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002794:Choline / Q000031:analogs & derivatives / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000502:physiology*; D010277:Parasympathomimetics / Q000494:pharmacology; D012601:Scopolamine / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology
D001388:Aziridines; D007211:Indoles; D009466:Neuromuscular Blocking Agents; D010277:Parasympathomimetics; D012702:Serotonin Antagonists; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; D012701:Serotonin; C044894:ethylcholine aziridinium; D012601:Scopolamine; D002794:Choline