Intrasubthalamic nucleus metabotropic glutamate receptor activation: A behavioral, Fos immunohistochemical and [C-14]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 r esults have shown that unilateral stimulation of metabotropic glutamate rec eptors in the subthalamic nucleus with the non-subtype-selective metabotrop ic glutamate receptor agonist 1S,3R-1-amino-1,3-cyclopentane dicarboxylate results in contralateral rotation in rats and Fos expression in the subthal amic nucleus. This suggests that metabotropic glutamate receptor stimulatio n results in altered subthalamic nucleus activity with consequent altered b asal ganglia activity on the injected side. We sought to determine the meta botropic glutamate receptor subtype(s) involved and the functional neuroana tomy underlying the rotational behavior. Unilateral intrasubthalamic nucleu s injection of group II or group III metabotropic glutamate receptor agonis ts 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 gr oup III subthalamic nucleus metabotropic glutamate receptor stimulation, th ere is Fos-like immunoreactivity in the globus pallidus, subthalamic nucleu s, substantia nigra pars reticulata and entopeduncular nucleus, suggesting altered activity in subthalamic nucleus target regions. However, examinatio n of [C-14]2-deoxyglucose uptake suggests that the alterations in basal gan glia activity are different following group II versus group III metabotropi c glutamate receptor stimulation, suggesting that rotation is occurring via different mechanisms. It appears that stimulation of subthalamic nucleus group II metabotropic gl utamate receptors induces rotation by increasing subthalamic nucleus activi ty. These results suggest that group II metabotropic glutamate receptor ant agonists may be useful for alleviating subthalamic nucleus overactivity in Parkinson's disease. Published by Elsevier Science Ltd.