Attenuated methamphetamine-induced locomotor sensitization in serotonin transporter knockout mice is restored by serotonin 1B receptor antagonist treatment

Moe Igari, Hao Wei Shen, Yoko Hagino, Setsu Fukushima, Yoshiyuki Kasahara, Klaus Peter Lesch, Dennis L. Murphy, Frank Scott Hall, George R. Uhl, Kazutaka Ikeda, Nobuo Yaegashi, Ichiro Sora

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)167-179
Number of pages13
JournalBehavioural Pharmacology
Volume26
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • 5-HT<inf>1B</inf> receptor
  • addiction
  • in-vivo microdialysis
  • knockout
  • locomotion
  • methamphetamine
  • mouse
  • SB 216641
  • sensitization
  • serotonin transporter

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Medicine(all)

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  • Cite this

    Igari, M., Shen, H. W., Hagino, Y., Fukushima, S., Kasahara, Y., Lesch, K. P., Murphy, D. L., Hall, F. S., Uhl, G. R., Ikeda, K., Yaegashi, N., & Sora, I. (2015). Attenuated methamphetamine-induced locomotor sensitization in serotonin transporter knockout mice is restored by serotonin 1B receptor antagonist treatment. Behavioural Pharmacology, 26, 167-179. https://doi.org/10.1097/FBP.0000000000000120