Methamphetamine-induced changes in the striatal dopamine pathway in μ-opioid receptor knockout mice

Background: Repeated exposure to methamphetamine (METH) can cause not only neurotoxicity but also addiction. Behavioral sensitization is widely used as an animal model for the study of drug addiction. We previously reported that the mu-opioid receptor knockout mice were resistant to METH-induced behavioral sensitization but the mechanism is unknown. Methods: The present study determined whether resistance of the mu-opioid receptor (mu-OR) knockout mice to behavioral sensitization is due to differential expression of the stimulatory G protein alpha subunit (G alpha s) or regulators of G-protein signaling (RGS) coupled to the dopamine D1 receptor. Mice received daily intraperitoneal injections of saline or METH (10 mg/kg) for 7 consecutive days to induce sensitization. On day 11(following 4 abstinent days), mice were either given a test dose of METH (10 mg/kg) for behavioral testing or sacrificed for neurochemical assays without additional METH treatment. Results: METH challenge-induced stereotyped behaviors were significantly reduced in the mu-opioid receptor knockout mice when compared with those in wild-type mice. Neurochemical assays indicated that there is a decrease in dopamine D1 receptor ligand binding and an increase in the expression of RGS4 mRNA in the striatum of METH-treated mu-opioid receptor knockout mice but not of METH-treated wild-type mice. METH treatment had no effect on the expression of G alpha s and RGS2 mRNA in the striatum of either strain of mice. Conclusions: These results indicate that down-regulation of the expression of the dopamine D1 receptor and up-regulation of RGS4 mRNA expression in the striatum may contribute to the reduced response to METH-induced stereotypy behavior in mu-opioid receptor knockout mice. Our results highlight the interactions of the mu-opioid receptor system to METH-induced behavioral responses by influencing the expression of RGS of dopamine D1 receptors.