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.
Okada
M
M
Department of Neuropsychiatry, School of Medicine, Hirosaki University, Japan. okadamot@cc.hirosaki-u.ac.jp
Hirano
T
T
Mizuno
K
K
Kawata
Y
Y
Wada
K
K
Murakami
T
T
Tasaki
H
H
Kaneko
S
S
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