The levels of glutamic acid decarboxylase (GAD) were strongly increased in the cortex and the striatum in dopamine D2 receptors null (D2R-/-) mice, which show a significant locomotor impairment. In this study, the effects of different GABAergic drugs on locomotor activity were analyzed in D2R-/- mice. After administering muscimol (1 mg/kg), a GABAA receptor agonist, the D2R-/- mice showed increased locomotor activity up to 200%. When the muscimol dose was increased (4-6 mg/kg), the D2R-/- mice exhibited seizure-like behavior, and the electroencephalographic (EEG) recordings during these behaviors showed a high amplitude rhythmic epileptiform activity in these mice. In situ hybridization showed that after injecting muscimol in the D2R-/- mice, the expression of enkephalin and immediate early gene, NGFI-A, was closely regulated with the locomotor activity regulated by GABAergic stimulation. These results suggest that the absence of D2R alters the GABAergic neurotransmission, specifically on GABAA-receptor mediated signaling, and stimulating the GABAA receptor can reverse the dysfunction of GABAergic inhibition in the motor circuits in the basal ganglia.
Bibliographical noteFunding Information:
The authors wish to acknowledge Dr. D.G. Kim, Dr. M.K. Joo, and Dr. K.H. Kim (College of Medicine, Yonsei University) and also Dr. D. Kim (KIST), Dr. K. Joo (College of Medicine, Seoul National University), and as well as all the members of Department of Neurology in College of Medicine, Seoul National University, for their help and useful discussions. We also thank Dr. J.K. Seong (Seoul National University) for his collaboration and the staff of the animal facilities for technical assistance and W.S. Yang and R.J. Hwang for technical assistance. We also thank Dr. J.B. Park (Sungkunkwan University, South Korea) and Dr. H. Herschman (UCLA School of Medicine, USA) for providing the NGFI-A cDNA, and Dr. M.O. Lee (Sejong University, Seoul, South Korea) for the NGFI-B cDNA. J.J. An, and Y.N. Kim are the recipient of a grant from the Brain Korea 21 program for medical science from Korea Ministry of Education. This work was supported by National Brain Research Program (grant No. 98-J04-02-01-A-01 and No. M1-0108-00-0063) and the Molecular and Cellular BioDiscovery Research Program (grant No. M1-0311-00-0069) of Korean Ministry of Science and Technology, by Korea Research Foundation (No. 2000-015-DP0327) and by the Brain Korea 21 Project.
ASJC Scopus subject areas
- Molecular Biology
- Cellular and Molecular Neuroscience
- Cell Biology