Effects of carbamazepine on hippocampal serotonergic system.
To establish the mechanism of action of the antiepileptic and psychotropic effects of carbamazepine (CBZ), its effects on serotonin (5-HT) transmission, metabolism and re-uptake activity in the rat hippocampus were studied. After acute and chronic administrations of 25 mg/kg CBZ, the plasma concentration of CBZ was found to be within the therapeutic range, whereas both acute and chronic administrations of 50 and 100 mg/kg CBZ resulted in a supratherapeutic plasma concentration. Acute administration of the therapeutic dose of CBZ resulted in an increase in the hippocampal extracellular and total level of 5-HT, its metabolite, 5-hydroxydoleacetic acid (5-HIAA) and its precursor, 5-hydroxytryptophan (5-HTP). The acute administration of 50 mg/kg CBZ resulted in an increase in the hippocampal levels of extracellular 5-HT and 5-HIAA as well as in the total levels of 5-HTP, whereas hippocampal levels of extracellular 5-HTP, total 5-HT and 5-HIAA remained unaffected. CBZ at a dose of 100 mg/kg decreased the levels of all of these substances. After chronic administration, 25 mg/kg/day CBZ increased hippocampal total levels of 5-HT, 5-HTP and 5-HIAA, whereas 100 mg/kg/day CBZ decreased all of these total levels. CBZ at a dose of 50 mg/kg/day decreased total levels of 5-HT, however neither total levels of 5-HIAA nor 5-HTP were affected. Both therapeutic and supratherapeutic plasma concentrations of CBZ inhibited 5-HTP accumulation, and did not affect 5-HT re-uptake activity in vitro. These results suggest that a therapeutic concentration of CBZ enhances 5-HT turnover and transmission, whereas a supratherapeutic concentration of CBZ inhibits 5-HT turnover and transmission without affecting 5-HT re-uptake activity. These effects of CBZ on serotonergic systems may be, at least partially, involved in the mechanisms of action of CBZ.
Department of Neuropsychiatry, School of Medicine, Hirosaki University, Japan. okadamot@cc.hirosaki-u.ac.jp
M
M
Okada
T
T
Hirano
K
K
Mizuno
Y
Y
Kawata
K
K
Wada
T
T
Murakami
H
H
Tasaki
S
S
Kaneko
D006916:5-Hydroxytryptophan / Q000032:analysis; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D002220:Carbamazepine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000032:analysis / Q000502:physiology*
D000927:Anticonvulsants; D012701:Serotonin; D002220:Carbamazepine; D006897:Hydroxyindoleacetic Acid; D006916:5-Hydroxytryptophan