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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.
Toxicol Sci. 2014 Jun; 139(2):421-31.TS

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+Show Affiliations

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24595820

Citation

Lizarraga, Lucina E., et al. "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." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 139, no. 2, 2014, pp. 421-31.
Lizarraga LE, Phan AV, Cholanians AB, et al. 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. Toxicol Sci. 2014;139(2):421-31.
Lizarraga, L. E., Phan, A. V., Cholanians, A. B., Herndon, J. M., Lau, S. S., & Monks, T. J. (2014). 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. Toxicological Sciences : an Official Journal of the Society of Toxicology, 139(2), 421-31. https://doi.org/10.1093/toxsci/kfu039
Lizarraga LE, et al. 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. Toxicol Sci. 2014;139(2):421-31. PubMed PMID: 24595820.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Lizarraga,Lucina E, AU - Phan,Andy V, AU - Cholanians,Aram B, AU - Herndon,Joseph M, AU - Lau,Serrine S, AU - Monks,Terrence J, Y1 - 2014/03/04/ PY - 2014/3/6/entrez PY - 2014/3/7/pubmed PY - 2014/12/30/medline KW - MDMA KW - SERT KW - locomotor activity KW - neurotoxicity KW - thermoregulation SP - 421 EP - 31 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol. Sci. VL - 139 IS - 2 N2 - 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. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/24595820/Serotonin_reuptake_transporter_deficiency_modulates_the_acute_thermoregulatory_and_locomotor_activity_response_to_34__±__methylenedioxymethamphetamine_and_attenuates_depletions_in_serotonin_levels_in_SERT_KO_rats_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfu039 DB - PRIME DP - Unbound Medicine ER -