title: Biphasic effects of zonisamide on serotonergic system in rat hippocampus.
abstract: To study the mechanisms of antiepileptic action of zonisamide (ZNS), we determined the effects of ZNS on extracellular, total levels and re-uptake activity of serotonin (5-HT) in rat striatum and hippocampus. After acute administrations, plasma ZNS concentrations associated with anticonvulsive action (effective concentrations) increased the total levels of 5-HT, its metabolise (5-hydroxyindoleacetic acid: 5-HIAA) and precursor (5-hydroxytryptophan: 5-HTP). After chronic administration of ZNS, effective plasma concentrations also increased the extracellular and total levels of 5-HT, 5-HIAA, and 5-HTP. On the other hand, after both acute and chronic administrations of ZNS, a supra-effective ZNS concentration either decreased or did not affect the total levels of these substances. Therefore, the stimulatory effects of ZNS on the 5-HT system were reduced by an increase in ZNS concentration to supra-effective concentrations. ZNS concentrations of 30-1000 microM did not affect hippocampal 5HT re uptake activity in vitro. These results suggest that ZNS has biphasic effects on the 5-HT system, in that effective concentrations of ZNS enhance and supra-effective concentrations of ZNS reduce the function of the 5-HT system. These biphasic effects of ZNS on the 5-HT system may be involved in the mechanisms of action of the antiepileptic and psychotropic effects, and side effects of ZNS.
authors: Department of Neuropsychiatry, School of Medicine, Hirosaki University, Japan. okadamo@cc.hirosaki-u.ac.jp
authors: M
authors: M
authors: Okada
authors: T
authors: T
authors: Hirano
authors: Y
authors: Y
authors: Kawata
authors: T
authors: T
authors: Murakami
authors: K
authors: K
authors: Wada
authors: K
authors: K
authors: Mizuno
authors: T
authors: T
authors: Kondo
authors: S
authors: S
authors: Kaneko
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007555:Isoxazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D012701:Serotonin; D000078305:Zonisamide; D006897:Hydroxyindoleacetic Acid; D006916:5-Hydroxytryptophan