title: Lack of effect of kappa-opioid receptor agonism on long-term methamphetamine-induced neurotoxicity in rats.
abstract: High-dose methamphetamine treatment induces long-term deficits in central monoamine systems. However, the mechanisms underlying these effects are unknown. Previous work has shown that the Kappa-opioid receptor agonist U-69593 [(+)-(5alpha,7alpha,8b)-(+)-N-methyl-N[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl] benzeneacetamide] attenuates the neurotoxic effects of methamphetamine on extracellular dopamine levels in mice, suggesting that endogenous Kappa-opioid receptor ligands, such as dynorphin, may protect against methamphetamine-induced toxicity and play a role in mediating the long-term consequences of methamphetamine. To further examine the role that dynorphin systems play in methamphetamine-induced neurotoxicity, we administered to male rats a total of four injections of methamphetamine (7.5 mg/kg, s.c.), with a 2-h interval between each dose. Rats were pretreated with either the Kappa-agonist U-69593 (0.32 mg/kg, s.c.) or vehicle, 15 min prior to the first and third methamphetamine injection. Furthermore, cages containing the U-69593 + methamphetamine-treated rats were placed on heating pads for 30 min after the first U-69593 injection to prevent the drug from blocking methamphetamine-induced hyperthermia. Rats were sacrificed 7 days after treatment. Striatal dopamine and serotonin contents were decreased approximately 75% and 55%, respectively, in the methamphetamine-treated rats and approximately 88% and 65%, respectively, in rats receiving the U-69593 + methamphetamine combination. There was a approximately 20% mortality rate in the rats treated with methamphetamine compared to approximately 75% mortality rate in rats treated with both U-69593 and methamphetamine. A similar rate of mortality was observed when combining a different Kappa-agonist, U-50488 [trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamine], with methamphetamine. These data suggest that Kappa-agonists do not protect against methamphetamine-induced toxicity to monoamines in rats, and may potentiate mortality when co-administered with methamphetamine.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East, Rm. 201, Salt Lake City, UT 84112, USA. K.Keefe@m.cc.utah.edu
authors.forename: Kamisha L
authors.initials: KL
authors.lastname: Johnson-Davis
authors.forename: Glen R
authors.initials: GR
authors.lastname: Hanson
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Keefe
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D019969:Amphetamine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000700:Analgesics / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D001923:Brain Chemistry / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004298:Dopamine / Q000032:analysis; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012701:Serotonin / Q000032:analysis
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D044482:Benzeneacetamides; D000697:Central Nervous System Stimulants; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D012701:Serotonin; D008694:Methamphetamine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C045444:U 69593; D004298:Dopamine