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) Receptors

J Pharmacol Exp Ther. 1999 Sep;290(3):965-73.

Abstract

The 5-hydroxytryptamine(1B/1D) (5-HT(1B/1D)) antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c 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)cyclohe xanecarboxamide (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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3,4-Methylenedioxyamphetamine / pharmacology*
  • Animals
  • Behavior, Animal / drug effects*
  • Drug Administration Schedule
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • Indoles / pharmacology
  • Male
  • Motor Activity / drug effects*
  • Oxadiazoles / pharmacology
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT1D
  • Receptors, Serotonin / classification
  • Receptors, Serotonin / physiology*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Agents / pharmacology*
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Sodium Chloride / pharmacology

Substances

  • Indoles
  • Oxadiazoles
  • Piperazines
  • Pyridines
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT1D
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Agents
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • 5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole
  • GR 127935
  • Sodium Chloride
  • 3,4-Methylenedioxyamphetamine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide