Abstract
The popular drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has complex interactions with thermoregulatory systems, resulting in either hyperthermia or hypothermia. MDMA induces hypothermia when given to animals housed at a low ambient temperature. In this study we report that MDMA (7.5 mg/kg i.p.) given at normal ambient temperatures of 24 to 25°C caused, in conscious freely moving rats, hypothermia (mean decrease from baseline of 1.1 ± 0.06°C at 40 min). Pretreating animals with a 0.5 mg/kg i.p. dose of the 5-hydroxytryptamine 1A (5-HT1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635) not only prevented MDMA-induced hypothermia, but resulted in the development of hyperthermia (mean temperature increase from baseline of 0.74 ± 0.2°C at 120 min). After treatment with WAY 100635, MDMA also elicited an enhanced tachycardia (mean increases in heart rate from baseline of 110 ± 16 beats/min at 90 min). To identify the location of 5-HT1A receptors responsible for hypothermia induced by MDMA, we first investigated the role of 5-HT1A receptors in the rostral raphe pallidus (rRP) in decreases in temperature evoked by the known 5-HT1A agonist 8-hydroxy-2-di-n-propylamino-tetralin (DPAT). Microinjections of 0.5 nmol of WAY 100635 into the rRP significantly attenuated DPAT (0.2 mg/kg i.p.)-elicited hypothermia. In parallel experiments, we found that microinjections of WAY 100635 into the rRP, while significantly augmenting MDMA-mediated tachycardia, did not alter body temperature. These results demonstrate that although hypothermia mediated by both MDMA and DPAT shares a common dependence on the activation of 5-HT1A receptors, the location of these receptors is different for each drug.
Footnotes
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This work was supported by United States Public Health Service Grants DA20484 and NS19883.
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Part of this work was presented in abstract form: Rusyniak DE, Zaretsky DV, Zaretskaia MV, and DiMicco JA (2005) WAY 100635 reverses the initial hypothermia from MDMA in rats, in Neuroscience 2005; 2005 Nov 12–16; Washington, DC. Society for Neuroscience, Washington DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.126169.
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ABBREVIATIONS: MDMA, 3,4-methylenedioxymethamphetamine; 5HT, 5-hydroxytryptamine, serotonin; IBAT, interscapular brown adipose tissue; DPAT, 8-hydroxy-2-di-n-propylamino-tetralin; WAY 100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide, WAY; rRP, rostral raphe pallidus; PBS, phosphate-buffered saline; ANOVA, analysis of variance; LSD, least significant difference; au, units of activity; OR, outside the region; SR 46349B, 1(Z)-[2-(dimethylamino) ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene.
- Received May 24, 2007.
- Accepted August 15, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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