Activation of group II metabotropic glutamate receptors inhibits synaptic excitation of the substantia Nigra pars reticulata.
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.
Bradley
S R
SR
Department of Pharmacology, Emory University, Atlanta, Georgia 30322, USA.
Marino
M J
MJ
Wittmann
M
M
Rouse
S T
ST
Awad
H
H
Levey
A I
AI
Conn
P J
PJ
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D018492:Dopamine Antagonists; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology / Q000502:physiology; D006220:Haloperidol; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000502:physiology; D017661:Receptors, Presynaptic / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000502:physiology
D001643:Bridged Bicyclo Compounds; D018492:Dopamine Antagonists; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D017661:Receptors, Presynaptic; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid; D006220:Haloperidol; C104753:eglumetad