A dopamine D1 receptor-dependent β-arrestin signaling complex potentially regulates morphine-induced psychomotor activation but not reward in mice.
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 β-arrestin 2 (βarr2) through its interaction with the μ-opioid receptor regulates the analgesic but not the rewarding properties of morphine. However, βarr2 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 βarr2 is required for morphine-induced locomotor activity in a dopamine D1 receptor (D1R)-dependent manner and that a βarr2/phospho-ERK (βarr2/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 βarr2/pERK signaling complex. Morphine-induced locomotor activity and formation of the βarr2/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 βarr2/pERK signaling complex in selectively mediating the locomotor-stimulating but not the rewarding properties of morphine.
Urs
Nikhil M
NM
Department of Cell Biology, Duke University, Durham, NC 27710, USA.
Daigle
Tanya L
TL
Caron
Marc G
MG
D000704:Analysis of Variance; D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009294:Narcotics / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000172:deficiency / Q000378:metabolism*; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D009294:Narcotics; D017447:Receptors, Dopamine D1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009020:Morphine; D048049:Extracellular Signal-Regulated MAP Kinases