title: Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local-anesthetics-induced convulsions and the counteraction by co-administration with local anesthetics.
abstract: Alterations of norepinephrine transporter (NET) function by chronic inhibition of NET in relation to sensitization to seizures induce by cocaine and local anesthetics were studied in mice. Daily administration of desipramine, an inhibitor of the NET, for 5 days decreased [(3)H]norepinephrine uptake in the P2 fractions of hippocampus but not cortex, striatum or amygdalae. Co-administration of lidocaine, bupivacaine or tricaine with desipramine reversed this effect. Daily treatment of cocaine increased [(3)H]norepinephrine uptake into the hippocampus. Daily administration of desipramine increased the incidence of appearance of lidocaine-induced convulsions and decreased that of cocaine-induced convulsions. Co-administration of lidocaine with desipramine reversed the changes of convulsive activity of lidocaine and cocaine induced by repeated administration of desipramine. These results suggest that down-regulation of hippocampal NET induced by chronic administration of desipramine may be relevant to desipramine-induced sensitization of lidocaine convulsions. Inhibition of Na(+) channels by local anesthetics may regulate desipramine-induced down-regulation of NET function. Repeated administration of cocaine induces up-regulation of hippocampal NET function. Desipramine-induced sensitization of lidocaine seizures may have a mechanism distinct from kindling resulting from repeated administration of cocaine.
authors.affiliation: Department of Dental Pharmacology, Division of Integrated Medical Science, Hiroshima University Graduate School of Biomedical Sciences, Minami-ku, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kitayama
authors.forename: Liqiu
authors.initials: L
authors.lastname: Song
authors.forename: Katsuya
authors.initials: K
authors.lastname: Morita
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Dohi
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000779:Anesthetics, Local; D050484:Norepinephrine Plasma Membrane Transport Proteins; D026941:Sodium Channel Blockers; D008012:Lidocaine; D003042:Cocaine; D003891:Desipramine; D009638:Norepinephrine