A Dopamine D1 Receptor-Dependent [beta]-Arrestin Signaling Complex Potentially Regulates Morphine-Induced Psychomotor Activation but not Reward in Mice

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2011-02, Vol.36 (3), p.551
• Main Authors: Urs, Nikhil M, Daigle, Tanya L, Caron, Marc G
• Format: Article
• Language: English
• Subjects: Analgesics; Behavior; Dopamine; Drug dosages; Kinases; Morphine; Narcotics; Neurosciences; Proteins
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2010.186

Morphine is a widely used analgesic in humans that is associated with multiple untoward effects, such as addiction and physical dependence. In rodent models, morphine also induces locomotor activity. These effects likely involve functionally selective mechanisms. Indeed, G protein-coupled receptor desensitization and adaptor protein [beta]-arrestin 2 ([beta]arr2) through its interaction with the μ-opioid receptor regulates the analgesic but not the rewarding properties of morphine. However, [beta]arr2 is also required for morphine-induced locomotor activity in mice, but the exact cellular and molecular mechanisms that mediate this arrestin-dependent behavior are not understood. In this study, we show that [beta]arr2 is required for morphine-induced locomotor activity in a dopamine D1 receptor (D1R)-dependent manner and that a [beta]arr2/phospho-ERK ([beta]arr2/pERK) signaling complex may mediate this behavior. Systemic administration of SL327, an MEK inhibitor, inhibits morphine-induced locomotion in wild-type mice in a dose-dependent manner. Acute morphine administration to mice promotes the formation of a [beta]arr2/pERK signaling complex. Morphine-induced locomotor activity and formation of the [beta]arr2/pERK signaling complex is blunted in D1R knockout (D1-KO) mice and is presumably independent of D2 dopamine receptors. However, D1Rs are not required for morphine-induced reward as D1-KO mice show the same conditioned place preference for morphine as do control mice. Taken together, these results suggest a potential role for a D1R-dependent [beta]arr2/pERK signaling complex in selectively mediating the locomotor-stimulating but not the rewarding properties of morphine.