title: Attenuated methamphetamine-induced locomotor sensitization in serotonin transporter knockout mice is restored by serotonin 1B receptor antagonist treatment.
abstract: Repeated administration of methamphetamine (METH) enhances acute locomotor responses to METH administered in the same context, a phenomenon termed as 'locomotor sensitization'. Although many of the acute effects of METH are mediated by its influences on the compartmentalization of dopamine, serotonin systems have also been suggested to influence the behavioral effects of METH in ways that are not fully understood. The present experiments examined serotonergic roles in METH-induced locomotor sensitization by assessing: (a) the effect of serotonin transporter (SERT; Slc6A4) knockout (KO) on METH-induced locomotor sensitization; (b) extracellular monoamine levels in METH-treated animals as determined by in-vivo microdialysis; and (c) effects of serotonin (5-HT) receptor antagonists on METH-induced behavioral sensitization, with focus on effects of the 5-HT1B receptor antagonist SB 216641 and a comparison with the 5-HT2 receptor antagonist ketanserin. Repeated METH administration failed to induce behavioral sensitization in homozygous SERT KO (SERT-/-) mice under conditions that produced substantial sensitization in wild-type or heterozygous SERT KO (SERT+/-) mice. The selective 5-HT1B antagonist receptor SB 216641 restored METH-induced locomotor sensitization in SERT-/- mice, whereas ketanserin was ineffective. METH-induced increases in extracellular 5-HT (5-HTex) levels were substantially reduced in SERT-/- mice, although SERT genotype had no effect on METH-induced increases in extracellular dopamine. These experiments demonstrate that 5-HT actions, including those at 5-HT1B receptors, contribute to METH-induced locomotor sensitization. Modulation of 5-HT1B receptors might aid therapeutic approaches to the sequelae of chronic METH use.
authors.affiliation: Departments of aBiological Psychiatry bGynecology and Obstetrics, Tohoku University Graduate School of Medicine, Sendai cDepartment of Molecular Psychiatry, Tokyo Institute of Psychiatry, Tokyo, Japan dDepartment of Psychiatry und Psychotherapy, University of Wurzburg, Wurzburg, Germany eClinical Neuropharmacology Section, Laboratory of Clinical Science, National Institute on Mental Health, Intramural Research Program, Bethesda fMolecular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, USA.
authors.forename: Moe
authors.initials: M
authors.lastname: Igari
authors.forename: Hao-Wei
authors.initials: HW
authors.lastname: Shen
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hagino
authors.forename: Setsu
authors.initials: S
authors.lastname: Fukushima
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Murphy
authors.forename: Frank Scott
authors.initials: FS
authors.lastname: Hall
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
chemical_list: D001549:Benzamides; D000697:Central Nervous System Stimulants; C108531:N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; D010069:Oxadiazoles; D044302:Receptor, Serotonin, 5-HT1B; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D008694:Methamphetamine; D007650:Ketanserin; D004298:Dopamine