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NEUROPHARMACOLOGY

3,4-Methylenedioxymethamphetamine- and 8-Hydroxy-2-di-n-propylamino-tetralin-Induced Hypothermia: Role and Location of 5-Hydroxytryptamine 1A Receptors

Departments of Emergency Medicine (D.E.R., M.V.Z.) and Pharmacology and Toxicology (D.E.R., D.V.Z., M.V.Z., J.A.D.), Indiana University School of Medicine, Indianapolis, Indiana

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-HT_1A) 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-HT_1A receptors responsible for hypothermia induced by MDMA, we first investigated the role of 5-HT_1A receptors in the rostral raphe pallidus (rRP) in decreases in temperature evoked by the known 5-HT_1A 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-HT_1A receptors, the location of these receptors is different for each drug.

Address correspondence to: Dr. Daniel E. Rusyniak, Regenstrief Health Center, Suite R2200, 1050 Wishard Blvd., Indianapolis, IN 46202-2859. E-mail: drusynia{at}iupui.edu

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