PMID- 24595820
OWN - NLM
STAT- MEDLINE
DCOM- 20141229
LR  - 20211021
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 139
IP  - 2
DP  - 2014 Jun
TI  - 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.
PG  - 421-31
LID - 10.1093/toxsci/kfu039 [doi]
AB  - 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 ( summation operator degrees C x h) analysis. Although no 
      differences in peak body temperature were observed between MDMA-treated WT and 
      SERT-KO animals,  summation operator degrees C x 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.
FAU - Lizarraga, Lucina E
AU  - Lizarraga LE
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, Arizona 85721.
FAU - Phan, Andy V
AU  - Phan AV
FAU - Cholanians, Aram B
AU  - Cholanians AB
FAU - Herndon, Joseph M
AU  - Herndon JM
FAU - Lau, Serrine S
AU  - Lau SS
FAU - Monks, Terrence J
AU  - Monks TJ
LA  - eng
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - DA023525/DA/NIDA NIH HHS/United States
GR  - T32 ES007091/ES/NIEHS NIH HHS/United States
GR  - 5T32ES007091/ES/NIEHS NIH HHS/United States
GR  - R01 DA023525/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140304
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 0 (Slc6a4 protein, rat)
RN  - 333DO1RDJY (Serotonin)
RN  - 54-16-0 (Hydroxyindoleacetic Acid)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Body Temperature/drug effects
MH  - Body Temperature Regulation/*drug effects
MH  - Brain/drug effects/metabolism
MH  - Gene Knockdown Techniques
MH  - Hydroxyindoleacetic Acid/metabolism
MH  - Male
MH  - Motor Activity/*drug effects
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neurotoxicity Syndromes/*etiology/metabolism/physiopathology
MH  - Rats, Wistar
MH  - Serotonin/*metabolism
MH  - Serotonin Plasma Membrane Transport Proteins/*deficiency/genetics
MH  - Time Factors
PMC - PMC4031621
OTO - NOTNLM
OT  - MDMA
OT  - SERT
OT  - locomotor activity
OT  - neurotoxicity
OT  - thermoregulation
EDAT- 2014/03/07 06:00
MHDA- 2014/12/30 06:00
PMCR- 2015/06/01
CRDT- 2014/03/06 06:00
PHST- 2014/03/06 06:00 [entrez]
PHST- 2014/03/07 06:00 [pubmed]
PHST- 2014/12/30 06:00 [medline]
PHST- 2015/06/01 00:00 [pmc-release]
AID - kfu039 [pii]
AID - 10.1093/toxsci/kfu039 [doi]
PST - ppublish
SO  - Toxicol Sci. 2014 Jun;139(2):421-31. doi: 10.1093/toxsci/kfu039. Epub 2014 Mar 4.