title: Modulation of the neurotoxic effects of methamphetamine by the selective kappa-opioid receptor agonist U69593.
abstract: Kappa-opioid receptor agonists prevent alterations in dopamine neurotransmission that occur in response to repeated cocaine administration. The present microdialysis study examined whether administration of the selective kappa-opioid receptor agonist U69593 with methamphetamine prevents alterations in dopamine levels produced by neurotoxic doses of methamphetamine. Swiss Webster mice were injected intraperitoneally with methamphetamine (10.0 mg/kg) or saline, four times in 1 day, at 2-h intervals. Prior to the first and third injection, they received U69593 (0.32 mg/kg s.c.) or vehicle. Microdialysis was conducted 3, 7, or 21 days later. Basal and K+-evoked (60 and 100 mM) dopamine overflow were reduced 3 days after methamphetamine administration. These effects were long-lasting in that they were still apparent 7 and 21 days after methamphetamine treatment. Intrastriatal (5.0 and 50 microM) or systemic (1.0-10.0 mg/kg) administration of methamphetamine increased dopamine concentrations in control animals. In mice preexposed to methamphetamine, methamphetamine-evoked dopamine overflow was reduced. In animals that had received methamphetamine with U69593, basal dopamine levels did not differ from those of vehicle-treated controls. U69593 treatment attenuated the decrease 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 kappa-opioid receptor agonist with methamphetamine attenuates these effects. U69593 treatment did not modify the hyperthermic effects of methamphetamine, indicating that this kappa-opioid receptor agonist selectively attenuates methamphetamine-induced alterations in dopamine neurotransmission.
authors.affiliation: Integrative Neuroscience Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224, USA.
authors.forename: E
authors.initials: E
authors.lastname: El Daly
authors.forename: V
authors.initials: V
authors.lastname: Chefer
authors.forename: S
authors.initials: S
authors.lastname: Sandill
authors.forename: T S
authors.initials: TS
authors.lastname: Shippenberg
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D044482:Benzeneacetamides; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D004347:Drug Interactions; D005334:Fever / Q000139:chemically induced; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D017551:Microdialysis; D011188:Potassium / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D000700:Analgesics; D044482:Benzeneacetamides; D015259:Dopamine Agents; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D008694:Methamphetamine; C045444:U 69593; D011188:Potassium; D004298:Dopamine