Intrasubthalamic nucleus metabotropic glutamate receptor activation: a behavioral, Fos immunohistochemical and [14C]2-deoxyglucose autoradiographic study.
Metabotropic glutamate receptors are a major class of excitatory amino acid receptors. Eight metabotropic glutamate receptor subtypes have been cloned, and are classified into three groups (I, II and III) based on amino acid sequence identity, effector systems and pharmacological profile. Previous results have shown that unilateral stimulation of metabotropic glutamate receptors in the subthalamic nucleus with the non-subtype-selective metabotropic glutamate receptor agonist 1S,3R-1-amino-1,3-cyclopentane dicarboxylate results in contralateral rotation in rats and Fos expression in the subthalamic nucleus. This suggests that metabotropic glutamate receptor stimulation results in altered subthalamic nucleus activity with consequent altered basal ganglia activity on the injected side. We sought to determine the metabotropic glutamate receptor subtype(s) involved and the functional neuroanatomy underlying the rotational behavior. Unilateral intrasubthalamic nucleus injection of group II or group III metabotropic glutamate receptor agonists induced contralateral rotation. In addition to producing rotation, group II and group III metabotropic glutamate receptor agonists induce toxicity in the subthalamic nucleus and overlying thalamus. Following group II or group III subthalamic nucleus metabotropic glutamate receptor stimulation, there is Fos-like immunoreactivity in the globus pallidus, subthalamic nucleus, substantia nigra pars reticulata and entopeduncular nucleus, suggesting altered activity in subthalamic nucleus target regions. However, examination of [14C]2-deoxyglucose uptake suggests that the alterations in basal ganglia activity are different following group II versus group III metabotropic glutamate receptor stimulation, suggesting that rotation is occurring via different mechanisms. It appears that stimulation of subthalamic nucleus group II metabotropic glutamate receptors induces rotation by increasing subthalamic nucleus activity. These results suggest that group II metabotropic glutamate receptor antagonists may be useful for alleviating subthalamic nucleus overactivity in Parkinson's disease.
Kearney
J A
JA
Department of Neurology, The University of Michigan, Ann Arbor, MI 48109, USA.
Albin
R L
RL
D015761:4-Aminopyridine / Q000494:pharmacology; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites; D001345:Autoradiography; D001522:Behavior, Animal; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D003847:Deoxyglucose; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D010302:Parkinson Disease, Secondary / Q000378:metabolism / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D012399:Rotation; D013378:Substantia Nigra / Q000737:chemistry / Q000378:metabolism; D020531:Subthalamic Nucleus / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*
D000600:Amino Acids, Dicarboxylic; D000963:Antimetabolites; D002250:Carbon Radioisotopes; D018690:Excitatory Amino Acid Agonists; D016760:Proto-Oncogene Proteins c-fos; D018094:Receptors, Metabotropic Glutamate; C035261:(alpha-carboxycyclopropyl)glycine; D003847:Deoxyglucose; D015761:4-Aminopyridine; D005947:Glucose