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Modulation of the Neurotoxic Effects of Methamphetamine by the Selective κ‐Opioid Receptor Agonist U69593
Author(s) -
Daly E. El,
Chefer V.,
Sandill S.,
Shippenberg T. S.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0741553.x
Subject(s) - methamphetamine , agonist , pharmacology , opioid receptor , neuroscience , chemistry , opioid , receptor , medicine , psychology , biochemistry
κ‐Opioid receptor agonists prevent alterations indopamine neurotransmission that occur in response to repeated cocaineadministration. The present microdialysis study examined whetheradministration of the selective κ‐opioid receptor agonist U69593 withmethamphetamine prevents alterations in dopamine levels produced by neurotoxicdoses of methamphetamine. Swiss Webster mice were injected intraperitoneallywith methamphetamine (10.0 mg/kg) or saline, four times in 1 day, at 2‐hintervals. Prior to the first and third injection, they received U69593 (0.32mg/kg s.c.) or vehicle. Microdialysis was conducted 3, 7, or 21 days later.Basal and K + ‐evoked (60 and 100 m M ) dopamine overflow werereduced 3 days after methamphetamine administration. These effects werelong‐lasting in that they were still apparent 7 and 21 days aftermethamphetamine treatment. Intrastriatal (5.0 and 50 μ M ) orsystemic (1.0‐10.0 mg/kg) administration of methamphetamine increased dopamineconcentrations in control animals. In mice preexposed to methamphetamine,methamphetamine‐evoked dopamine overflow was reduced. In animals that hadreceived methamphetamine with U69593, basal dopamine levels did not differfrom those of vehicle‐treated controls. U69593 treatment attenuated thedecrease in K + ‐evoked dopamine produced by prior methamphetamine exposure. The reduction in methamphetamine‐evoked dopamine levels was also attenuated. The administration of U69593 alone did not modify basal or stimulus‐evoked dopamine levels. These data demonstrate that repeated methamphetamine administration reduces presynaptic dopamine neuronal function in mouse striatum and that co‐administration of a selective κ‐opioid receptor agonist with methamphetamine attenuates these effects. U69593 treatment did not modify the hyperthermic effects of methamphetamine, indicating that this κ‐opioid receptor agonist selectively attenuates methamphetamine‐induced alterations in dopamine neurotransmission.