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PRECLINICAL STUDY: FULL ARTICLE: Tolerance to 3,4‐methylenedioxymethamphetamine is associated with impaired serotonin release
Author(s) -
Jones Karen,
Brennan Katharine A.,
ColussiMas Joyce,
Schenk Susan
Publication year - 2010
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1111/j.1369-1600.2010.00217.x
Subject(s) - mdma , agonist , serotonergic , fenfluramine , serotonin , pharmacology , stimulant , 5 ht receptor , receptor antagonist , receptor , antagonist , chemistry , 8 oh dpat , medicine
Tolerance to the behavioural effects of 3,4‐methylenedioxymethamphetamine (MDMA) following high dose exposure has been attributed to alterations in serotonergic systems. The present study aimed to determine whether decreased 5‐HT release and/or 5‐HT 2A/C receptor desensitization might play a role in tolerance by measuring the response to selective ligands following MDMA exposure. To this end, the latency to nose poke and emerge from a hide box to an open field arena following administration of various ligands to MDMA pre‐treated and control rats was measured. Acute exposure to MDMA (0.0–3.3 mg/kg), the 5‐HT releasing stimulant fenfluramine (0.0–2.0 mg/kg) and the 5‐HT 2 receptor agonist m‐CPP (0.0–1.25 mg/kg) increased nose poke and emergence latency. Following administration of doses that produce 5‐HT 2A receptor‐mediated behaviours, the 5‐HT 2 receptor agonist (±)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane failed to alter nose poke and emergence latency, suggesting a limited role of this receptor subtype in these behaviours. Activation of 5‐HT 2C receptors was implicated in the behavioural response to both MDMA and m‐CPP since the increased emergence latency was dose‐dependently attenuated by pre‐treatment with the selective 5‐HT 2C receptor antagonist RS102221 (0.0–1.0 mg/kg). Tolerance to the behavioural effect of MDMA and fenfluramine but not m‐CPP was produced by prior exposure to MDMA (10 mg/kg administered at two‐hour intervals, total 40 mg/kg), and tissue levels of 5‐HT and 5‐HIAA were decreased. These findings suggest that tolerance to the increased nose poke and emergence latency produced by MDMA is due to impaired 5‐HT release.