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Role of the serotonin 5-HT2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethamphetamine

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Abstract

Rationale

Contradictory evidence exists regarding the role of the 5-HT2A receptor (5-HT2AR) in hyperactivity and hyperthermia elicited by the substituted amphetamine (+)-3,4-methylenedioxymethamphetamine.

Objectives

The present studies examined the ability of the selective 5-HT2AR antagonist M100907 to block hyperactivity and hyperthermia produced across the (+)-MDMA dose-effect curve.

Methods

Male rats were pretreated with M100907 (0, 0.25, 0.5, 1, and 2 mg/kg) followed by treatment with (+)-MDMA (0–12 mg/kg); activity was recorded for 90 min followed by determination of rectal temperature. Additionally, we investigated the ability of M100907 (0 and 0.5 mg/kg) to reverse hyperthermia elicited by (+)-MDMA (12 mg/kg).

Results

The first study demonstrated that M100907 attenuated hyperactivity in the periphery of the monitor and eliminated rearing induced by (+)-MDMA (3 mg/kg) with no effect on basal activity. In two subsequent studies, (+)-MDMA (0–12 mg/kg) dose-dependently increased peripheral activity and rearing and produced hyperthermia. Pretreatment with M100907 decreased peripheral activity evoked by (+)-MDMA, right-shifted the dose-effect curve for rearing, and blocked (+)-MDMA-induced hyperthermia, while having no effect when administered alone. A final study demonstrated the ability of M100907 (0.5 mg/kg) to reverse hyperthermia produced by (+)-MDMA (12 mg/kg).

Conclusions

These results suggest that the 5-HT2AR contributes to the generation of peripheral hyperactivity and rearing and, especially, the hyperthermia evoked by (+)-MDMA and that 5-HT2AR antagonists should be further investigated as treatments for the psychological and hyperthermic effects of (±)-MDMA.

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Acknowledgements

This research was supported by National Institute on Drug Abuse grants DA 00260, DA 13595, DA 07287, and DA 15272. Portions of these data were presented at the 64th annual meeting of the College on Problems of Drug Dependence (Quebec City, Canada, 2002) and the biannual meeting of the European Behavioral Pharmacology Society (Antwerp, Belgium, 2003). We gratefully thank Teri Tarrant for secretarial assistance and Marcy J. Bubar, Jeff J. Burmeister, Julie D. Ross, and Regina P. Szucs for their comments and suggestions. We would also like to thank the National Institute on Drug Abuse for providing us with (+)-MDMA.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Center for Addiction Research, University of Texas Medical Branch, Galveston, TX 77555-1031, USA

    David V. Herin, Shijing Liu & Kathryn A. Cunningham

  2. Laboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Building 8, Room B1-21, Bethesda, MD 20892, USA

    Thomas Ullrich & Kenner C. Rice

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  1. David V. Herin
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  2. Shijing Liu
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  5. Kathryn A. Cunningham
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Correspondence to Kathryn A. Cunningham.

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Herin, D.V., Liu, S., Ullrich, T. et al. Role of the serotonin 5-HT2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethamphetamine. Psychopharmacology 178, 505–513 (2005). https://doi.org/10.1007/s00213-004-2030-4

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