Enhanced Rewarding Properties of Morphine, but not Cocaine, in βarrestin-2 Knock-Out Mice

Abstract

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 βarrestins, which prevents further receptor-G-protein coupling. Mice lacking βarrestin-2 (βarr2) 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 βarr2 knock-out (βarr2-KO) mice and their wild-type (WT) controls. Cocaine treatment resulted in very similar neurochemical and behavioral responses between the genotypes. However, in the βarr2-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 βarr2-KO mice when compared with the WT mice. Thus, βarr2 appears to play a more important role in the dopaminergic effects mediated by morphine than those induced by cocaine.