Dopamine D(1A) receptor-deficient mice: An examinaton of D(1)-like receptors in rodent brain.

摘要

D₁-like receptors are thought to play a major role in cellular and behavioral functions. As a result, the present study utilized D_1A receptor knockout mice to further clarify the functional role of D₁-like receptors in rodent brain. The goal of the project was to examine three factors possibly affected by the D_1A gene mutation: D₁-like receptor expression, D₁-like receptor-mediated function and aspects of the dopaminergic system that may have compensated for the loss of the D_1A receptor. While a 60–77% decrease in D₁-like receptor expression was observed in the heterozygous genotype (via receptor autoradiography), only a slight D₁-like receptor labeling was found in the homozygous mice (exclusively in the hippocampus). This labeling is proposed to be the D_1B receptor, providing the first quantification of this receptor in rodent brain. The decreased D ₁-like receptor expression in the heterozygous mice provides a unique investigation of the effects of receptor reserve on drug activity. In contrast to the original prediction for D₁-like receptor full agonist activity in the heterozygous mice (no change in the maximal adenylate cyclase activity, i.e., V_max, but a decrease in potency), a decrease in V_max with no change in potency was seen with both full and partial agonists in the heterozygote and EEDQ-treated tissues. In addition, the D₁-like receptor full agonists displayed a higher intrinsic activity than dopamine in all tissues analyzed. These functional results demonstrate that D ₁-like receptors in this mouse strain behave differently than that of rats or primates with regards to receptor reserve and response to agonists. Several aspects of the dopaminergic system possibly compensating for the loss of the D_1A receptor were examined via receptor autoradiography and high performance liquid chromatography (i.e., D₂ receptor expression, the number of D₂ receptors in the high affinity state, and dopamine metabolite concentrations). No significant differences, however, were observed in any component analyzed. The studies presented in this dissertation provide important information pertaining to the role of the D₁-like receptors in rodent brain and further support the utility of D_1A receptor knockout mice as a tool for D₁ receptor research.