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.
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.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.
authors.forename: Lucina E
authors.initials: LE
authors.lastname: Lizarraga
authors.forename: Andy V
authors.initials: AV
authors.lastname: Phan
authors.forename: Aram B
authors.initials: AB
authors.lastname: Cholanians
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Herndon
authors.forename: Serrine S
authors.initials: SS
authors.lastname: Lau
authors.forename: Terrence J
authors.initials: TJ
authors.lastname: Monks
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: MDMA; SERT; locomotor activity; neurotoxicity; thermoregulation