Abstract
The 5-hydroxytryptamine1B/1D(5-HT1B/1D) antagonist 2′-methyl-4′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127935) and 5-HT1A antagonistN-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635) were used to assess whether hyperactivity induced by 3 mg/kg (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA] is mediated by 5-HT1B/1D and/or 5-HT1A receptors. Activity in the periphery and center of an open field as well as rearing activity were measured in photobeam monitors. (+)-MDMA-induced peripheral and central activities were blocked by GR 127935 (0.3, 0.625, 1.25, and 2.5 mg/kg); central hyperactivity was blocked by 0.1, 0.3, and 0.625 mg/kg GR 127935. WAY 100635 (0.5–2 mg/kg) had little effect on (+)-MDMA-induced activity except for an enhancement of central activity at one dose (0.5 mg/kg). Central activity induced by (+)-MDMA increased from day 1 to day 5 of treatment with (+)-MDMA (3 mg/kg), whereas peripheral, central, and rearing activity significantly increased in (+)-MDMA-treated rats pretreated daily with GR 127935 (2.5 mg/kg). Withdrawal from (+)-MDMA, but not GR 127935 + (+)-MDMA, pretreatment was associated with heightened hyperactivity induced by the 5-HT1B/1A agonist RU 24969 (2 mg/kg i.p.); treatments were not associated with alterations in 5-HT and 5-hydroxyindoleacetic acid content or turnover in frontal cortex. These data support a role for 5-HT1B/1D in mediating the acute hyperactivity evoked by (+)-MDMA. The development of sensitization to (+)-MDMA was associated with supersensitivity to a 5-HT1B/1A agonist, suggesting that these receptors may contribute to sensitization. However, sensitization to (+)-MDMA developed even under conditions of 5-HT1B/1D receptor blockade, which is somewhat counter to this speculation. Perhaps, under circumstances of continued 5-HT1B/1D blockade, other mechanisms (e.g., dopamine) predominate in the progressive enhancement of behavior with repeated (+)-MDMA treatment.
Footnotes
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Send reprint requests to: Dr. Kathryn A. Cunningham, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031. E-mail: cunningham{at}utmb.edu
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↵1 Support for this research was provided by the National Institute on Drug Abuse Grants DA 06511, DA 00260, and DA 07287.
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↵2 Present address: Eli Lilly and Company Limited, Lilly Research Center, Erl Wood Manor, Sunninghill Rd., Windlesham, Surrey, U.K., GU20 6PH.
- Abbreviations:
- (+)-MDMA
- (+)-3,4-methylenedioxymethamphetamine
- 5-HT
- 5-hydroxytryptamine
- DA
- dopamine
- GR 127935
- 2′-methyl-4′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide)
- WAY 100635
- N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
- 5-HIAA
- 5-hydroxyindole acetic acid
- VTA
- ventral tegmental area
- NAc
- nucleus accumbens
- Received December 3, 1998.
- Accepted April 22, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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