Effect of GABA(A) receptor stimulation in the subthalamic nucleus on motor deficits induced by nigrostriatal lesions in the rat.
Inhibition of the subthalamic nucleus by lesions or GABAergic agonists improves motor symptoms in monkeys or humans with a loss of nigrostriatal dopaminergic neurons, a characteristic of Parkinson's disease. In rats, nigrostriatal lesions induce deficits in a variety of motor tests that are ameliorated by dopaminergic agonists. However, the validity of these tests to predict the beneficial effects of subthalamic inhibition is not known. We have examined the effects of an intrasubthalamic injection of the GABA(A) receptor agonist muscimol (0.1 microg/0.1 microL) in intact rats and in rats with a unilateral nigrostriatal lesion. Muscimol induced a mild ipsiversive rotation in sham-operated (control) rats and blocked contraversive rotations induced by apomorphine in lesioned rats. In addition, in the cylinder test of limb use asymmetry, muscimol decreased the ipsilateral bias after lesion without inducing any significant effect in sham-operated controls. In the forced-step test, however, 0.1 microg (but not 0.01 microg) of muscimol into the subthalamic nucleus induced a behavioral bias by markedly decreasing the number of adjusting steps of the contralateral limb in control rats, similar to the effect of a nigrostriatal lesion. Neither dose improved performance in this test in rats with lesions, and the higher dose exacerbated the deficit. The data support a beneficial role of stimulating subthalamic GABA(A) receptors for akinesia but also reveal negative behavioral effects of this treatment and suggest that the cylinder and forced-step tests measure different aspects of behavioral deficits after dopaminergic lesions.
Mehta
Arpesh
A
Department of Neurology and Neurobiology, David Geffen School of Medicine at UCLA, B114, Reed Neurological Research Center, 710 Westwood Plaza, Los Angeles, CA 90095, USA.
Chesselet
Marie-Françoise
MF
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D058785:GABA-A Receptor Agonists; D007276:Injections, Intraventricular; D008297:Male; D019957:Motor Skills Disorders / Q000188:drug therapy / Q000378:metabolism*; D009118:Muscimol / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000378:metabolism*
D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D009118:Muscimol