The indirect basal ganglia pathway in dopamine D2 receptor-deficient mice

M. G. Murer, G. Dziewczapolski, P. Salin, M. Vila, K. Y. Tseng, M. Ruberg, M. Rubinstein, M. A. Kelly, D. K. Grandy, M. J. Low, E. Hirsch, R. Raisman-Vozari, O. Gershanik

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Recent pathophysiological models of basal ganglia function in Parkinson's disease predict that specific neurochemical changes in the indirect pathway would follow the lack of stimulation of D2 dopamine receptors. Post mortem studies of the basal ganglia in genetically modified mice lacking functional copies of the D2 dopamine receptor gene allowed us to test these predictions. When compared with their congenic N5 wild-type siblings, mice lacking D2 receptors show an increased expression of enkephalin messenger RNA in the striatum, and an increased activity and expression of cytochrome oxidase I in the subthalamic nucleus, as expected. In addition, D2 receptor-deficient mice display a reduced expression of glutamate decarboxylase-67 messenger RNA in the globus pallidus, as the basal ganglia model predicts. This reduction contrasts with the lack of change or increase in glutamate decarboxylase-67 messenger RNA expression found in animals depleted of dopamine after lesions of the mesostriatal dopaminergic system. Furthermore, D2 receptor-deficient mice show a significant decrease in substance P messenger RNA expression in the striatonigral neurons which form the direct pathway. Finally, glutamate decarboxylase-67 messenger RNA expression in the basal ganglia output nuclei was not affected by mutations in the D2 receptor gene, a fact that could probably be related to the absence of a parkinsonian locomotor phenotype in D2 receptor-deficient mice. In summary, these findings provide compelling evidence demonstrating that the lack of endogenous stimulation of D2 receptors is sufficient to produce subthalamic nucleus hyperactivity, as assessed by cytochrome oxidase I histochemistry and messenger RNA expression, and strongly suggest the existence of interactions between the basal ganglia direct and indirect pathways. (C) 2000 IBRO.

Original languageEnglish (US)
Pages (from-to)643-650
Number of pages8
Issue number4
StatePublished - Aug 23 2000
Externally publishedYes


  • Globus pallidus
  • Parkinson's disease
  • Striatum
  • Substantia nigra
  • Subthalamic nucleus

ASJC Scopus subject areas

  • General Neuroscience


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