title: Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics.
abstract: The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.
authors.affiliation: Department of Dental Pharmacology, Division of Integrated Medical Science, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Arai
authors.forename: Katsuya
authors.initials: K
authors.lastname: Morita
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kitayama
authors.forename: Kei
authors.initials: K
authors.lastname: Kumagai
authors.forename: Michio
authors.initials: M
authors.lastname: Kumagai
authors.forename: Kenji
authors.initials: K
authors.lastname: Kihira
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Dohi
mesh_terms: D018759:Adrenergic Uptake Inhibitors; D000779:Anesthetics, Local / Q000009:adverse effects*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D015283:Citalopram / Q000494:pharmacology; D003042:Cocaine / Q000009:adverse effects*; D003891:Desipramine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D008376:Maprotiline / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D027981:Symporters / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000779:Anesthetics, Local; D015283:Citalopram; D003042:Cocaine; D003891:Desipramine; D018765:Dopamine Uptake Inhibitors; D008012:Lidocaine; D008376:Maprotiline; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493228:Slc6a2 protein, mouse; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine