Molecular evidence for the functional role of dopamine D3 receptor in the morphine-induced rewarding effect and hyperlocomotion

The aim of the present study was to investigate the role of dopamine D-3 receptors in the rewarding effect and hyperlocomotion induced by a prototypical mu-opioid receptor agonist morphine using dopamine D-3 receptor knock-out mice. The mu-opioid receptor in the brain determined by the [tylosil-3,5-H-3(N)]-[D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin binding assay was not significantly changed by a deletion of the dopamine D-3 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 mu-opioid receptor itself was not affected by a deletion of the dopamine D-3 receptor gene. To ascertain the morphine-induced rewarding effect in both genotypes, the conditioned place preference paradigm was performed. Deletion of the dopamine D-3 receptor gene resulted in a remarkable enhancement of the morphine-induced rewarding effect. Furthermore, knock-out mice with deletions of the dopamine D-3 receptor revealed a dramatic potentiation of morphine-induced hyperlocomotion. Under these conditions, a loss of the dopamine D-3 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 D-3 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 mu-opioid receptors induced by morphine in the mouse.