The Physiological Role of Dopamine D2 Receptors

Abstract

Interest lies in the study of the physiological activity of D2 receptors that are abundantly expressed in the striatum, substantia nigra, and hypophysis. Two isoforms of this receptor have been described that differ by their coupling characteristics to G-proteins in vitro . D2 and D1 receptors are the most abundant dopaminergic receptors expressed in the brain. The parallel activation by dopamine of these two receptors in the basal ganglia leads to the activation of two pathways whose synergistic action controls coordinated movements. Unexpectedly, the elimination of D1 receptor expression by homologous recombination, which would be predicted to affect the locomotion-enhancing direct pathway, leads instead of hyperlocomotion in homozygous mice. These results contradict pharmacological studies in which the use of D1 receptor antagonists results in a cataleptic response of treated animals. To study the physiology of the D2 receptor in vivo , mutant mice lacking a functional D2 receptor gene have been generated by homologous recombination. In contrast to D1R, D2R-deficient animals display a phenotype that broadly resembles D2 antagonist treatment, indicating that the effect observed by antagonist treatment is because of the blocking of D2 receptors and not to other members of the dopamine receptor family. The knockout of the D2R gene has evidenced the pleiotropic role of this receptor in the control of physiological functions. The most evident phenotypes are a serious locomotor impairment and abnormal hormonal function. Interestingly, in the D2R knockout animals, there is an increase in enkephalin (ENK) mRNA expression, which could be responsible for the decreased movement of these animals. It is interesting to note that the phenotype exhibited by D2R-deficient mice, at the level of expression of striatal specific peptides, resembles the findings obtained by treatment of 6-OHDA-lesioned animals. This might indicate that the primary target of dopamine depletion in this model is the D2 receptor.