Pharmacological studies of the acute and chronic effects of (+)-3,4- methylenedioxymethamphetamine on locomotor activity

Role of 5- hydroxytryptaminela and 5-hydroxytryptamine(1B/1D) receptors

Andrew C. McCreary, Michael G. Bankson, Kathryn Cunningham

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)965-973
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume290
Issue number3
StatePublished - Sep 1999

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Receptor, Serotonin, 5-HT1B
N-Methyl-3,4-methylenedioxyamphetamine
Locomotion
Pharmacology
Serotonin
Receptor, Serotonin, 5-HT1D
Serotonin Antagonists
Hydroxyindoleacetic Acid
Receptor, Serotonin, 5-HT1A
Frontal Lobe
Carboxylic Acids
Amides
Dopamine

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{788035b918a24eccb6134dd28c196a0a,
title = "Pharmacological studies of the acute and chronic effects of (+)-3,4- methylenedioxymethamphetamine on locomotor activity: Role of 5- hydroxytryptaminela and 5-hydroxytryptamine(1B/1D) receptors",
abstract = "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.",
author = "McCreary, {Andrew C.} and Bankson, {Michael G.} and Kathryn Cunningham",
year = "1999",
month = "9",
language = "English (US)",
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pages = "965--973",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
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T1 - Pharmacological studies of the acute and chronic effects of (+)-3,4- methylenedioxymethamphetamine on locomotor activity

T2 - Role of 5- hydroxytryptaminela and 5-hydroxytryptamine(1B/1D) receptors

AU - McCreary, Andrew C.

AU - Bankson, Michael G.

AU - Cunningham, Kathryn

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N2 - 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.

AB - 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.

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