Serotonin reuptake transporter deficiency modulates the acute thermoregulatory and locomotor activity response to 3,4-(±)-methylenedioxymethamphetamine, and attenuates depletions in serotonin levels in SERT-KO rats

Lucina E. Lizarraga, Andy V. Phan, Aram B. Cholanians, Joseph M. Herndon, Serrine S. Lau, Terrence J. Monks

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

3,4-(±)-Methylenedioxymethamphetamine (MDMA) is a ringsubstituted amphetamine derivative with potent psychostimulant properties. The neuropharmacological effects of MDMA are biphasic in nature, initially causing synaptic monoamine release, primarily of serotonin (5-HT), inducing thermogenesis and hyperactivity (5-HT syndrome). The long-term effects of MDMA manifest as a prolonged depletion in 5-HT, and structural damage to 5-HT nerve terminals. MDMA toxicity is in part mediated by an ability to inhibit the presynaptic 5-HT reuptake transporter (SERT). Using a SERT-knockout (SERT-KO) rat model, we determined the impact of SERT deficiency on thermoregulation, locomotor activity, and neurotoxicity in SERT-KO or Wistar-based wild-type (WT) rats exposed to MDMA. WT and SERT-KO animals exhibited the highest thermogenic responses to MDMA (four times 10 mg/kg, sc at 12 h intervals) during the diurnal (first and third) doses according to peak body temperature and area under the curve (Σ°C × h) analysis. Although no differences in peak body temperature were observed between MDMA-treated WT and SERT-KO animals, Σ°C × h following the first MDMA dose was reduced in SERT-KO rats. Exposure to a single dose of MDMA stimulated horizontal velocity in both WT and SERTKO rats, however, this effect was delayed and attenuated in the KO animals. Finally, SERT-KO rats were insensitive to MDMAinduced long-term (7 days) depletions in 5-HT and its metabolite, 5-hydroxyindole acetic acid, in both cortex and striatum. In conclusion, SERT deficiencymodulated MDMA-mediated thermogenesis, hyperactivity and neurotoxicity in KO rats. The data confirm that the SERT is essential for the manifestation of the acute and long-term toxicities of MDMA.

Original languageEnglish (US)
Article numberkfu039
Pages (from-to)421-431
Number of pages11
JournalToxicological Sciences
Volume139
Issue number2
DOIs
StatePublished - 2014

Keywords

  • Locomotor activity
  • MDMA
  • Neurotoxicity
  • SERT
  • Thermoregulation

ASJC Scopus subject areas

  • Toxicology

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