Metabotropic glutamate receptors depress glutamate-mediated synaptic input to rat midbrain dopamine neurones in vitro

1 Glutamate (AMPA receptor-mediated) excitatory postsynaptic potentials (e.p.s.ps.), evoked by electrical stimulation rostral to the recording site, were examined by intracellular microelectrode recording from dopamine neurones in parasagittal slices of rat ventral midbrain. 2 The e.p.s.p. was depressed by the group III metabotropic glutamate (mGlu) receptor agonist L-2-amino-4-phosphonobutyric acid (L-AP4; 0.01-30 mu M) by up to 60% with an EC50 of 0.82 mu M. The depression induced by L-AP4 (3 mu M) was reversed by the group III preferring mGlu receptor antagonist, alpha-methyl-4-phosphonophenylglycine (MPPG; 250 mu M). 3 The group I and II mGlu agonist, 1S,3R-aminocyclopentanedicarboxylic acid (ACPD; 3-30 mu M) also depressed the e.p.s.p. in a concentration-dependent manner. The effect of ACPD (10 mu M) was reversed by (+)-alpha-methyl-4-carboxyphenylglycine (MCPG; 1 mM; 4 cells). This effect of ACPD was also partially antagonized (by 50.3+/-15.7%, 4 cells) by MPPG (250 mu M). 4 The selective agonist at group I mGlu receptors, dihydroxyphenylglycine (DHPG; 100 mu M), decreased e.p.s.p. amplitude by 27.1+/-8.2% (7 cells), as did the group II mGlu receptor-selective agonist (1S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 1 mu M) by 26.7+/-4.3% (5 cells). 5 DHPG (10-100 mu M) caused a depolarization of the recorded cell, as did ACPD (3-30 mu M), whereas no such postsynaptic effect of either L-AP4 or DCG-IV was observed. 6 These results provide evidence for the presence of presynaptic inhibitory metabotropic glutamate autoreceptors from the mGlu receptor groups II and III on descending glutamatergic inputs to midbrain dopamine neurones. Group I mGlu receptors mediate a postsynaptic depolarization, and can also depress glutamatergic transmission, but may not necessarily be localized presynaptically. These sites represent novel drug targets for treatment of schizophrenia and movement disorders of basal ganglia origin.