Altered GABAergic neurotransmission in mice lacking dopamine D2 receptors.
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 GABA(A) 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 GABA(A)-receptor mediated signaling, and stimulating the GABA(A) receptor can reverse the dysfunction of GABAergic inhibition in the motor circuits in the basal ganglia.
An
Juan Ji
JJ
Laboratory of Electrophysiology, Medical Research Center, College of Medicine, Yonsei University, Seoul 120-752, South Korea.
Bae
Mi-Hyun
MH
Cho
Sang Rae
SR
Lee
Soo-Hyun
SH
Choi
Seong-Hoon
SH
Lee
Bae Hwan
BH
Shin
Hee-Sup
HS
Kim
Yong Nyun
YN
Park
Kye Won
KW
Borrelli
Emiliana
E
Baik
Ja-Hyun
JH
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D004745:Enkephalins / Q000378:metabolism; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics*; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000201:enzymology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D004745:Enkephalins; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; D004298:Dopamine