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The Journal of Neuroscience, February 1, 2003, 23(3):1006

Molecular Evidence for the Functional Role of Dopamine D3 Receptor in the Morphine-Induced Rewarding Effect and Hyperlocomotion

Minoru Narita1, Keisuke Mizuo1, Hirokazu Mizoguchi2, Mamoru Sakata1, Michiko Narita1, Leon F. Tseng2, and Tsutomu Suzuki1

1 Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo 142-8501, Japan, and 2 Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-0509

The aim of the present study was to investigate the role of dopamine D3 receptors in the rewarding effect and hyperlocomotion induced by a prototypical µ-opioid receptor agonist morphine using dopamine D3 receptor knock-out mice. The µ-opioid receptor in the brain determined by the [tylosil-3,5-3H(N)]-[D-Ala2,N-MePhe4,Gly-ol5]enkephalin binding assay was not significantly changed by a deletion of the dopamine D3 receptor gene. Furthermore, we found that no significant differences in G-protein activation by morphine in the limbic forebrain and lower midbrain were noted between the two genotypes. These results suggest that the function of the µ-opioid receptor itself was not affected by a deletion of the dopamine D3 receptor gene. To ascertain the morphine-induced rewarding effect in both genotypes, the conditioned place preference paradigm was performed. Deletion of the dopamine D3 receptor gene resulted in a remarkable enhancement of the morphine-induced rewarding effect. Furthermore, knock-out mice with deletions of the dopamine D3 receptor revealed a dramatic potentiation of morphine-induced hyperlocomotion. Under these conditions, a loss of the dopamine D3 receptor gene had no effect on the basal levels of dopamine and the increased dopamine turnover by morphine in the limbic forebrain. These findings provide further evidence that dopamine D3 receptor contributes to the postsynaptically negative modulation of the mesolimbic dopaminergic pathway that is associated with the rewarding effect and hyperlocomotion through the stimulation of µ-opioid receptors induced by morphine in the mouse.

Key words: dopamine D3 receptor; morphine; rewarding effect; hyperlocomotion; negative feedback system

Copyright © 2003 Society for Neuroscience  0270-6474/03/2331006-07$05.00/0




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