Functional analysis of the effects of striatal metabotropic glutamate receptor stimulation

Excitatory amino acids are important neurotransmitters in the basal ganglia. The metabotropic glutamate receptors (mGluRs) are a major class of excitatory amino acid receptors. Eight mGluR subtypes have been cloned and have been classified into three groups based on their amino acid sequence homology, pharamacological profile and effector systems. The striatum has a high density of mGluR binding sites and several mGluR mRNAs and proteins are expressed by striatal neurons. This suggests that mGluRs may play an important role in striatal function. Supportive of this, unilateral striatal injection of a non-subtype selective mGluR agonist results in vigorous contralateral rotation in rats. This dissertation examines the role of mGluRs in basal ganglia function by examining the phenomenon of mGluR agonist-induced rotation in detail, examining the pharmacology and underlying neuroanatomical correlates of this behavior.; Pharmacological studies suggest that mGluR agonist-induced rotation is mediated by group I mGluRs. Additionally, mGluR agonist-induced rotation can be modulated by other important basal ganglia neurotransmitter systems, including dopamine, adenosine and acetylcholine. Immediate early gene expression and cerebral glucose metabolism mapping studies suggest that activation of striatal mGluRs results in increased activity of the striatopallidal pathway, leading to disinhibition of the subthalamic nucleus (STN) and increased activity in the entopeduncular nucleus and substantia nigra. The STN hyperactivity is reminiscent of STN overactivity seen in Parkinson's disease, suggesting that group I mGluR antagonists may be useful for its symptomatic treatment.; It is well documented in animal models of Parkinson's disease that chronic dopamine depletion leads to many changes in the striatum. Therefore, any changes in the effects of striatal mGluR activation on rotational behavior, immediate early gene expression and local cerebral glucose metabolism were examined under conditions of chronic dopamine denervation in unilateral 6-hydroxydopamine lesioned rats. The effects of striatal group I and group II mGluR stimulation appear to be unchanged. However, there are changes in the effects of striatal group III mGluR stimulation.; The studies presented in this dissertation support an important role for group I mGluRs in modulating striatal function under normal and pathological conditions and suggest that mGluRs may be useful targets for pharmacotherapy of Parkinson's disease.