Dopamine modulates the function of group II and group III metabotropic glutamate receptors in the substantia nigra pars reticulata.
Recent findings have shown that dendritically released dopamine (DA) plays an important modulatory role in the substantia nigra pars reticulata (SNr). It is therefore possible that the loss of DA observed in Parkinson's disease (PD) could hold important consequences for nigral function. Previously, we have shown that activation of presynaptically localized group II metabotropic glutamate receptors (mGluRs) inhibits excitatory transmission at the subthalamic nucleus (STN)-SNr synapse and that activation of presynaptically localized group III mGluRs decreases excitatory and inhibitory transmission in the SNr. To test the hypothesis that nigral DA can modulate mGluR function in the SNr, we performed whole-cell patch-clamp recordings from gamma-aminobutyric acidergic SNr neurons in slices obtained from rats that were acutely reserpinized. In slices obtained from reserpinized animals, the effect of group II mGluR activation by the selective agonist (+)-2-aminobicyclo[3.1.0]-hexane-2,6-dicarboxylate monohydrate (LY354740) (100 nM), but not group III mGluR activation [L-(+)-2-amino-4-phosphonobutyric acid, L-AP4, 500 microM], at STN-SNr synapses is significantly decreased. This effect could be mimicked in control slices by prior bath application of haloperidol (20 microM) and R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) (20 microM) but not sulpiride (50 microM). Furthermore, application of dopamine (100 microM) and (+/-)-6-chloro-7,8-dyhydroxy-3allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine (SKF82958) (1 microM) but not quinpirole (10 microM) could rescue the group II mGluR effect in reserpinized slices. The effect of group III mGluR activation (L-AP4, 100 microM) on inhibitory synaptic transmission was also significantly reduced in slices from reserpine-treated animals. This effect was mimicked by haloperidol (20 microM), SCH23390 (20 microM), and sulpiride (50 microM) in control slices. Thus, in a Parkinsonian state, the loss of nigral DA may add to the overall pathophysiological changes in basal ganglia output.
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia.
Marion
M
Wittmann
Michael J
MJ
Marino
P Jeffrey
PJ
Conn
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*; D013469:Sulpiride / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D001552:Benzazepines; D001643:Bridged Bicyclo Compounds; D018491:Dopamine Agonists; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D013469:Sulpiride; C071262:SK&F 82958; D006220:Haloperidol; C104753:eglumetad; D004298:Dopamine