Vol. 290, Issue 3, 965-973, September 1999

Pharmacological Studies of the Acute and Chronic Effects of (+)-3,4-Methylenedioxymethamphetamine on Locomotor Activity: Role of 5-Hydroxytryptamine_1A and 5-Hydroxytryptamine_1B/1D Receptors¹

Andrew C. McCreary², Michael G. Bankson and Kathryn A. Cunningham

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas

The 5-hydroxytryptamine_1B/1D (5-HT_1B/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-HT_1A antagonist N-(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-HT_1B/1D and/or 5-HT_1A 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-HT_1B/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-HT_1B/1D in mediating the acute hyperactivity evoked by (+)-MDMA. The development of sensitization to (+)-MDMA was associated with supersensitivity to a 5-HT_1B/1A agonist, suggesting that these receptors may contribute to sensitization. However, sensitization to (+)-MDMA developed even under conditions of 5-HT_1B/1D receptor blockade, which is somewhat counter to this speculation. Perhaps, under circumstances of continued 5-HT_1B/1D blockade, other mechanisms (e.g., dopamine) predominate in the progressive enhancement of behavior with repeated (+)-MDMA treatment.