Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Abstract

Loss of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) leads to increased activity of glutamatergic neurons in the subthalamic nucleus (STN). Recent studies reveal that the resultant increase in STN-induced excitation of basal ganglia output nuclei is responsible for the disabling motor impairment characteristic of PD. On the basis of this, it is possible that any manipulation that reduces activity at excitatory STN synapses onto basal ganglia output nuclei could be useful in the treatment of PD. We now report that group II metabotropic glutamate receptors (mGluRs) are presynaptically localized on STN terminals and that activation of these receptors inhibits excitatory transmission at STN synapses. In agreement with the hypothesis that this could provide a therapeutic benefit in PD, a selective agonist of group II mGluRs induces a dramatic reversal of catalepsy in a rat model of PD. These results raise the exciting possibility that selective agonists of group II mGluRs could provide an entirely new approach to the treatment of PD. These novel therapeutic agents would provide a noninvasive pharmacological treatment that does not involve the manipulation of dopaminergic systems, thus avoiding the problems associated with current therapies. Key words: substantia nigra pars reticulata; subthalamic nucleus; group II metabotropic glutamate receptors; Parkinson's disease; catalepsy; presynaptic inhibitionParkinson's disease (PD) is a common neurodegenerative disorder characterized by disabling motor impairments including tremor, rigidity, and bradykinesia. The primary pathological change giving rise to the symptoms of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta that modulate the function of neurons in the striatum and other nuclei in the basal ganglia (BG) motor circuit. Currently, the most effective pharmacological agents for the treatment of PD include levodopa (L-DOPA), the immediate precursor of dopamine, and other drugs that replace the lost dopaminergic modulation of BG function (Poewe and Granata, 1997). Unfortunately, dopamine replacement therapy ultimately fails in most patients because of loss of efficacy with progression of the disease and severe motor and psychiatric side effects (Poewe et al., 1986). Because of this, a great deal of effort has been focused on developing new approaches for the treatment of PD.Recent studies reveal that loss of nigrostriatal dopamine neurons results in a series of neurophysiological changes that lead to overactivity of a critical nucleus in the BG motor circuit termed the subthalamic nucleus (STN). The STN contains glutamatergic projection neurons that provide the major excitatory input to the globus pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr), the major output nuclei of the basal ganglia. Increased activity of STN neurons leads to an increase in glutamate release at STN synapses onto GABAergic projection neurons in the output nuclei. This glutamate-mediated overexcitation of BG output ultima...

Distinct Functional Roles of the Metabotropic Glutamate Receptors 1 and 5 in the Rat Globus Pallidus

“…All whole-cell patch-clamp recordings were obtained as described previously (Marino et al, 1998;Bradley et al, 2000). Fourteen-to 18-d-old Sprague Dawley rats were used in all experiments.…”

Anxiolytic Activity of the MGLU2/3 Receptor Agonist LY354740 on the Elevated Plus Maze is Associated with the Suppression of Stress-Induced c-Fos in the Hippocampus and Increases in c-Fos Induction in Several Other Stress-Sensitive Brain Regions

“…In brain synapses such as the central nucleus of the amygdala (Neugebauer et al, 2000), hippocampal perforant path (Kilbride et al, 1998(Kilbride et al, , 2001, medial prefrontal cortex (mPFC) (Marek et al, 2000), nucleus accumbens (Robbe et al, 2002), and substantia nigra (Bradley et al, 2000), LY354740 has been shown to suppress evoked glutamate excitatory synaptic potentials/ currents (reviewed by Schoepp et al, 2003). In particular, the intra-amygdalar injection of LY354740 disrupted fearpotentiated startle (Walker et al, 2002), and intrahippocampal injection of LY354740 produced an anticonflict effect in the Vogel drinking test (Tatarczynska et al, 2001), suggesting that these regions may be involved in the anxiolytic actions of LY354740 when it is administered systemically.…”

Kainate Receptors in the Striatum: Implications for Excitoxicity in Huntington's Disease

“…Whether this indicates a true species difference between rodents and primates regarding the presynaptic localization of mGluR2 in the pallidal complex or relies upon technical differences in the sensitivity of the different antibodies used in these studies remains to be established. It is worth noting that functional group II mGluRs were found to be expressed on putative STN glutamatergic terminals in the rat SNr (Bradley et al, 2000). If the intense mGluR2 immunolabeling seen in the human pallidum corresponds to presynaptic STN terminals, the group II mGluRs become a very promising target to reduce the release of glutamate from hyperactive subthalamopallidal terminals in PD.…”

“…Another mGluR subtype of interest for PD therapy is mGluR2, which was found to be expressed on subthalamonigral terminals in rats (Bradley et al, 2000). Furthermore, activation of these receptors in brain slices reduces glutamatergic transmission at subthalamonigral synapses (Bradley et al, 2000) and systemic administration of group II agonist reverses haloperidolinduced catalepsy (Bradley et al, 2000).…”