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Lack of effect of κ-opioid receptor agonism on long-term methamphetamine-induced neurotoxicity in rats

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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 κ-opioid receptor agonist U-69593 [(+)-(5α, 7α, 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 k-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 metham-phetamine (7.5 mg/kg, s.c.), with a 2-h interval between each dose. Rats were pretreated with either the κ-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 ≈75% and 55%, respectively, in the methamphetamine-treated rats and ≈88% and 65%, respectively, in rats receiving the U-69593+methamphetamine combination. There was a ≈20% mortality rate in the rats treated with methamphetamine compared to ≈75% mortality rate in rats treated with both U-69593 and methamphetamine. A similar rate of mortality was observed when combining a different κ-agonist, U-50488 [trans-(−)-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamine], with methamphetamine. These data suggest that κ-agonists do not protect against methamphetamine-induced toxicity to monoamines in rats, and may potentiate mortality when co-administered with methamphetamine.

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Johnson-Davis, K.L., Hanson, G.R. & Keefe, K.A. Lack of effect of κ-opioid receptor agonism on long-term methamphetamine-induced neurotoxicity in rats. neurotox res 5, 273–281 (2003). https://doi.org/10.1007/BF03033385

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