The indirect basal ganglia pathway in dopamine D-2 receptor-deficient mice

Recent pathophysiological models of basal ganglia function in Parkinson's d isease predict that specific neurochemical changes in the indirect pathway would follow the lack of stimulation of D-2 dopamine receptors. Post mortem studies of the basal ganglia in genetically modified mice lacking function al copies of the D-2 dopamine receptor gene allowed us to test these predic tions. When compared with their congenic Ng wild-type siblings, mice lackin g D-2 receptors show an increased expression of enkephalin messenger RNA in the striatum, and an increased activity and expression of cytochrome oxida se I in the subthalamic nucleus, as expected. In addition, D-2 receptor-def icient mice display a reduced expression of glutamate decarboxylase-67 mess enger RNA in the globus pallidus, as the basal ganglia model predicts. This reduction contrasts with the lack of change or increase in glutamate decar boxylase-67 messenger RNA expression found in animals depleted of dopamine after lesions of the mesostriatal dopaminergic system. Furthermore, D-2 rec eptor-deficient mice show a significant decrease in substance P messenger R NA expression in the striatonigral neurons which form the direct pathway. F inally, glutamate decarboxylase-67 messenger RNA expression in the basal ga nglia output nuclei was not affected by mutations in the D-2 receptor gene, a fact that could probably be related to the absence of a parkinsonian loc omotor phenotype in D-2 receptor-deficient mice. In summary, these findings provide compelling evidence demonstrating that t he lack of endogenous stimulation of D-2 receptors is sufficient to produce subthalamic nucleus hyperactivity, as assessed by cytochrome oxidase I his tochemistry and messenger RNA expression, and strongly suggest the existenc e of interactions between the basal ganglia direct and indirect pathways. ( C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.