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Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug. Despite an increase in the number of fatalities related to its use, no definite therapeutic method has been established thus far. In the present study, risperidone's ability to attenuate MDMA-induced hyperthermia and its mechanism of action were investigated in rats. The pharmacological effect of MDMA was evaluated using microdialysis. In the body temperature experiment, administration of risperidone before and after MDMA administration significantly suppressed MDMA-induced hyperthermia in a dose-dependent fashion. Furthermore, risperidone completely inhibited MDMA-induced hyperthermia at a low ambient temperature. Moreover, pretreatment with ritanserin, ketanserin, or R-96544, all of which are 5-HT(2A)-receptor antagonists, significantly prevented MDMA-induced hyperthermia. On the other hand, pretreatment with WAY-100635 (a 5-HT(1A) receptor antagonist), SB 206553 (a 5-HT(2B/2C) receptor antagonist), or SB 242084 (a 5-HT(2C) receptor antagonist) did not prevent MDMA-induced hyperthermia. Pretreatment with haloperidol, which blocks the dopamine (DA) receptors D(2) and D(1), significantly prevented MDMA-induced hyperthermia. However, sulpiride and L-741626, which are D(2) receptor blockers, did not prevent MDMA-induced hyperthermia. Pretreatment with SCH 23390 (a D(1) receptor antagonist) significantly prevented MDMA-induced hyperthermia. Furthermore, postadministration of ritanserin, haloperidol, and SCH23390 reversed MDMA-induced hyperthermia. These results demonstrate that the mechanism underlying the suppression of MDMA-induced hyperthermia by risperidone is primarily based on the drug's potent 5-HT(2A) receptor blocking effect, and to a lesser extent, on its D(1) receptor blocking effect. A microdialysis study showed that when MDMA (10mg/kg) was subcutaneously (s.c.) injected into the rats, the DA and serotonin (5-HT) levels in the anterior hypothalamus of the rats increased approximately 10- and 50-fold, respectively, as compared to their preadministration levels. These increases in the DA and 5-HT levels after MDMA injection were significantly suppressed by pretreatment with risperidone (0.5mg/kg). This suggested that both the DA and 5-HT systems were involved in the induction of hyperthermia by MDMA. Taken together, the present study's results indicate that risperidone may be an effective drug for the treatment of MDMA-induced hyperthermia in humans.

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  • Authors+Show Affiliations

    ,

    Department of Psychiatry, Jichi Medical University, Tochigi, Japan; Tamura city Miyakozi Clinic, Japan. kazs@jichi.ac.jp

    , , , , ,

    Source

    Neurotoxicology 29:6 2008 Nov pg 1030-6

    MeSH

    Analysis of Variance
    Animals
    Body Temperature
    Disease Models, Animal
    Dopamine
    Dopamine Antagonists
    Dose-Response Relationship, Drug
    Drug Interactions
    Fever
    Hallucinogens
    Male
    N-Methyl-3,4-methylenedioxyamphetamine
    Rats
    Rats, Wistar
    Risperidone
    Serotonin
    Serotonin Antagonists
    Time Factors

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    18722468

    Citation

    Shioda, Katsutoshi, et al. "Risperidone Attenuates and Reverses Hyperthermia Induced By 3,4-methylenedioxymethamphetamine (MDMA) in Rats." Neurotoxicology, vol. 29, no. 6, 2008, pp. 1030-6.
    Shioda K, Nisijima K, Yoshino T, et al. Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats. Neurotoxicology. 2008;29(6):1030-6.
    Shioda, K., Nisijima, K., Yoshino, T., Kuboshima, K., Iwamura, T., Yui, K., & Kato, S. (2008). Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats. Neurotoxicology, 29(6), pp. 1030-6. doi:10.1016/j.neuro.2008.07.005.
    Shioda K, et al. Risperidone Attenuates and Reverses Hyperthermia Induced By 3,4-methylenedioxymethamphetamine (MDMA) in Rats. Neurotoxicology. 2008;29(6):1030-6. PubMed PMID: 18722468.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats. AU - Shioda,Katsutoshi, AU - Nisijima,Koichi, AU - Yoshino,Tatsuki, AU - Kuboshima,Kyoko, AU - Iwamura,Tatsunori, AU - Yui,Kunio, AU - Kato,Satoshi, Y1 - 2008/08/05/ PY - 2007/11/06/received PY - 2008/07/22/revised PY - 2008/07/22/accepted PY - 2008/8/30/pubmed PY - 2009/3/27/medline PY - 2008/8/30/entrez SP - 1030 EP - 6 JF - Neurotoxicology JO - Neurotoxicology VL - 29 IS - 6 N2 - 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug. Despite an increase in the number of fatalities related to its use, no definite therapeutic method has been established thus far. In the present study, risperidone's ability to attenuate MDMA-induced hyperthermia and its mechanism of action were investigated in rats. The pharmacological effect of MDMA was evaluated using microdialysis. In the body temperature experiment, administration of risperidone before and after MDMA administration significantly suppressed MDMA-induced hyperthermia in a dose-dependent fashion. Furthermore, risperidone completely inhibited MDMA-induced hyperthermia at a low ambient temperature. Moreover, pretreatment with ritanserin, ketanserin, or R-96544, all of which are 5-HT(2A)-receptor antagonists, significantly prevented MDMA-induced hyperthermia. On the other hand, pretreatment with WAY-100635 (a 5-HT(1A) receptor antagonist), SB 206553 (a 5-HT(2B/2C) receptor antagonist), or SB 242084 (a 5-HT(2C) receptor antagonist) did not prevent MDMA-induced hyperthermia. Pretreatment with haloperidol, which blocks the dopamine (DA) receptors D(2) and D(1), significantly prevented MDMA-induced hyperthermia. However, sulpiride and L-741626, which are D(2) receptor blockers, did not prevent MDMA-induced hyperthermia. Pretreatment with SCH 23390 (a D(1) receptor antagonist) significantly prevented MDMA-induced hyperthermia. Furthermore, postadministration of ritanserin, haloperidol, and SCH23390 reversed MDMA-induced hyperthermia. These results demonstrate that the mechanism underlying the suppression of MDMA-induced hyperthermia by risperidone is primarily based on the drug's potent 5-HT(2A) receptor blocking effect, and to a lesser extent, on its D(1) receptor blocking effect. A microdialysis study showed that when MDMA (10mg/kg) was subcutaneously (s.c.) injected into the rats, the DA and serotonin (5-HT) levels in the anterior hypothalamus of the rats increased approximately 10- and 50-fold, respectively, as compared to their preadministration levels. These increases in the DA and 5-HT levels after MDMA injection were significantly suppressed by pretreatment with risperidone (0.5mg/kg). This suggested that both the DA and 5-HT systems were involved in the induction of hyperthermia by MDMA. Taken together, the present study's results indicate that risperidone may be an effective drug for the treatment of MDMA-induced hyperthermia in humans. SN - 0161-813X UR - https://www.unboundmedicine.com/medline/citation/18722468/Risperidone_attenuates_and_reverses_hyperthermia_induced_by_34_methylenedioxymethamphetamine__MDMA__in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-813X(08)00139-3 DB - PRIME DP - Unbound Medicine ER -