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The Journal of Neuroscience, November 12, 2003, 23(32):10265-10273

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Behavioral/Systems/Cognitive
Enhanced Rewarding Properties of Morphine, but not Cocaine, in arrestin-2 Knock-Out Mice

Laura M. Bohn,¹ Raul R. Gainetdinov,² Tatyana D. Sotnikova,² Ivan O. Medvedev,² Robert J. Lefkowitz,³ Linda A. Dykstra,⁴ and Marc G. Caron²

¹Department of Pharmacology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210, Departments of ²Cell Biology and ³Biochemistry and Medicine, Duke University Medical Center, Howard Hughes Medical Institute Laboratories, Durham, North Carolina 27710, and ⁴University of North Carolina at Chapel Hill, Department of Psychology, Chapel Hill, North Carolina 27599

The reinforcing and psychomotor effects of morphine involve opiate stimulation of the dopaminergic system via activation of µ-opioid receptors (µOR). Both µ-opioid and dopamine receptors are members of the G-protein-coupled receptor (GPCR) family of proteins. GPCRs are known to undergo desensitization involving phosphorylation of the receptor and the subsequent binding of arrestins, which prevents further receptor-G-protein coupling. Mice lacking arrestin-2 (arr2) display enhanced sensitivity to morphine in tests of pain perception attributable to impaired desensitization of µOR. However, whether abrogating µOR desensitization affects the reinforcing and psychomotor properties of morphine has remained unexplored. In the present study, we examined this question by assessing the effects of morphine and cocaine on locomotor activity, behavioral sensitization, conditioned place preference, and striatal dopamine release in arr2 knock-out (arr2-KO) mice and their wild-type (WT) controls. Cocaine treatment resulted in very similar neurochemical and behavioral responses between the genotypes. However, in the arr2-KO mice, morphine induced more pronounced increases in striatal extracellular dopamine than in WT mice. Moreover, the rewarding properties of morphine in the conditioned place preference test were greater in the arr2-KO mice when compared with the WT mice. Thus, arr2 appears to play a more important role in the dopaminergic effects mediated by morphine than those induced by cocaine.

Key words: morphine; cocaine; dopamine; arrestin; knock-out mice; locomotor activity; sensitization; microdialysis; conditioned place preference

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Received June 30, 2003; revised September 11, 2003; accepted September 17, 2003.

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