Pharmacological discrimination between effects of carbamazepine on hippocampal basal, Ca(2+)- and K(+)-evoked serotonin release.
To elucidate mechanisms of hippocampal serotonin release and possible mechanisms of clinical action of carbamazepine (CBZ), we determined interaction between antagonists of N-type (omega-conotoxin GVIA:GVIA), P-type (omega-agatoxin IVA:IVA) Ca(2+) channels, Na(+) channel (tetrodotoxin: TTX) and CBZ on hippocampal basal, Ca(2+)- and K(+)-evoked serotonin releases, using microdialysis in freely moving rats. Basal release was reduced by TTX, GVIA and IVA (GVIA>IVA). Ca(2+)-evoked release was reduced by GVIA but unaffected by TTX and IVA. K(+)-evoked release was reduced by TTX, GVIA and IVA (GVIA<IVA). TTX inhibited actions of IVA and GVIA on respective basal and K(+)-evoked releases, without affecting Ca(2+)-evoked release. Perfusion with 100 microM CBZ (estimated-concentration in hippocampal tissue: 19+/-2 microM) enhanced basal and Ca(2+)-evoked releases, but reduced K(+)-evoked release, whereas 1000 microM CBZ (estimated-concentration in hippocampal tissue: 188+/-16 microM) reduced three types of releases. Under condition of pretreatment with 100 and 1000 microM CBZ, TTX unaffected basal and K(+)-evoked releases. Under condition of pretreatment with 100 microM CBZ, IVA and GVIA unaffected basal and K(+)-evoked releases, respectively, but GVIA reduced basal, Ca(2+)-evoked releases and IVA also reduced K(+)-evoked release. Under condition of pretreatment with 1000 microM CBZ, GVIA unaffected three types of releases, and IVA unaffected basal release but reduced K(+)-evoked release. These findings contribute towards the possible mechanisms of concentration-dependent antiepileptic action of CBZ, which possibly inhibits Na(+) channel related neurotransmitter release mechanisms during K(+)-evoked stage, and simultaneously enhances N-type Ca(2+) channel related basal serotonin release at the resting stage.
Kawata
Y
Y
Department of Neuropsychiatry, School of Medicine, Hirosaki University, Hirosaki 036-8562, Japan.
Okada
M
M
Murakami
T
T
Kamata
A
A
Zhu
G
G
Kaneko
S
S
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002220:Carbamazepine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
D018692:Antimanic Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D012701:Serotonin; D002220:Carbamazepine; D013779:Tetrodotoxin; D020866:omega-Conotoxin GVIA; D011188:Potassium; D002118:Calcium