title: GABAA-receptor activation in the subthalamic nucleus compensates behavioral asymmetries in the hemiparkinsonian rat.
abstract: The subthalamic nucleus (STN) has a pivotal role in the pathophysiology of Parkinson's disease (PD). Modulation of STN activity (by lesions, pharmacological or electrical stimulation) has been shown to improve motor parameters in PD patients and in animal models of PD. In an attempt to characterize the neurochemical bases for such antiparkinsonian action, we address specific neurotransmitter systems via local pharmacological manipulation of the STN in hemiparkinsonian rats. Here, we have focused on the GABAergic and glutamatergic receptors in the STN. In animals with unilateral 6-hydroxydopamine lesions of the nigro-striatal tract, we administered either the selective GABAA-agonist muscimol (0.5 μg and 1.0 μg), the non-competitive N-methyl-d-aspartate (NMDA)-antagonist MK-801 (dizocilpine; 2.5 μg), or vehicle (0.25 μl) into the STN. The effects of GABAergic and glutamatergic modulation of the STN on motor parameters were assessed by gauging rotational behavior and locomotion. Application of muscimol ipsilateral to the side of dopamine-depletion influenced turning behavior in a dose-dependent fashion, with the low dose re-adjusting turning behavior to a non-biased distribution, and the high dose evoking contraversive turning. The administration of MK-801 did not have such effects. These findings give evidence for the involvement of GABAergic activation in the STN in the compensation of motor asymmetries in the hemiparkinsonian rat, whereas N-methyl-d-aspartate (NMDA)-antagonism was ineffective in this model of PD.
authors.affiliation: Center for Behavioral Neuroscience, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Petri
authors.forename: Martin
authors.initials: M
authors.lastname: Pum
authors.forename: Jan
authors.initials: J
authors.lastname: Vesper
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Huston
authors.forename: Alfons
authors.initials: A
authors.lastname: Schnitzler
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018663:Adrenergic Agents / Q000633:toxicity; D000661:Amphetamine; D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000502:physiology; D001523:Mental Disorders / Q000188:drug therapy / Q000209:etiology*; D009118:Muscimol / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications* / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D018709:Statistics, Nonparametric; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018663:Adrenergic Agents; D058785:GABA-A Receptor Agonists; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D015102:3,4-Dihydroxyphenylacetic Acid; D009118:Muscimol; D016291:Dizocilpine Maleate; D016627:Oxidopamine; D000661:Amphetamine; D004298:Dopamine; D006719:Homovanillic Acid
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-dihydroxyphenylacetic acid; 6-OHDA; 6-hydroxydopamine; DA; DBS; DOPAC; GABA; GPe; GPi; HPLC-EC; HVA; M1; MFB; MK-801; MPTP; MRBD; Muscimol; N-methyl-d-aspartate; NMDA; PD; Parkinson's disease; SNr; STN; Turning behavior; deep brain stimulation; dopamine; globus pallidus externa; globus pallidus interna; high performance liqiuid chromatography with coupled electrochemical detection; homovanillic acid; i.p.; intraperitoneal; l-3,4-dihydroxyphenylalanine; l-DOPA; medial forebrain bundle; movement related beta desynchronisation; primary motor area; substantia nigra pars reticulata; subthalamic nucleus; γ-aminobutyric acid