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Publication Detail

Title: 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.

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

Published In Toxicol Sci, (2014 Jun)

Abstract: 3,4-(±)-Methylenedioxymethamphetamine (MDMA) is a ring-substituted 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 (∑°C × h) analysis. Although no differences in peak body temperature were observed between MDMA-treated WT and SERT-KO animals, ∑°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 SERT-KO rats, however, this effect was delayed and attenuated in the KO animals. Finally, SERT-KO rats were insensitive to MDMA-induced long-term (7 days) depletions in 5-HT and its metabolite, 5-hydroxyindole acetic acid, in both cortex and striatum. In conclusion, SERT deficiency modulated 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.

PubMed ID: 24595820 Exiting the NIEHS site

MeSH Terms: Animals; Body Temperature Regulation/drug effects*; Body Temperature/drug effects; Brain/drug effects; Brain/metabolism; Gene Knockdown Techniques; Hydroxyindoleacetic Acid/metabolism; Male; Motor Activity/drug effects*; N-Methyl-3,4-methylenedioxyamphetamine/toxicity*; Neurotoxicity Syndromes/etiology*; Neurotoxicity Syndromes/metabolism; Neurotoxicity Syndromes/physiopathology; Rats, Wistar; Serotonin Plasma Membrane Transport Proteins/deficiency*; Serotonin Plasma Membrane Transport Proteins/genetics; Serotonin/metabolism*; Time Factors

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