Metabotropic glutamate and muscarinic cholinergic receptor-mediated preferential inhibition of N-methyl-D-aspartate component of transmissions in rat ventral tegmental area

Presynaptic inhibition is one of the major control mechanisms in the CNS. Our laboratory recently reported that presynaptic GABA_B and adenosine A₁ receptors mediate a preferential inhibition on N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents recorded in rat midbrain dopamine neurons. Here we extended these findings to metabotropic glutamate and muscarinic cholinergic receptors. Intracellular voltage clamp recordings were made from dopamine neurons in rat ventral tegmental area in slice preparations. (±)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (agonist for groups I and II metabotropic glutamate receptors) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4; agonist for group III metabotropic glutamate receptors) were significantly more potent for inhibiting N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents, as compared with inhibition of excitatory postsynaptic currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Such preferential inhibition of the N-methyl-D-aspartate component was also observed for muscarine (agonist for muscarinic cholinergic receptors). Inhibitory effects of (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, L-AP4, and muscarine were blocked reversibly by their respective antagonists [(RS)-α-methyl-4-carboxyphenylglycine, (RS)-α-methyl-4-phosphonophenylglycine, and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide]. In addition, all three agonists increased the ratio of excitatory postsynaptic currents in paired-pulse studies and did not reduce currents induced by exogenous N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Interestingly, the glutamate release stimulator 4-aminopyridine (30 μM) and the glutamate uptake inhibitor L-anti-endo-3,4-methanopyrrolidine dicarboxylate (300 μM) preferentially increased the amplitude of N-methyl-D-aspartate excitatory postsynaptic currents. Thus, agonists for metabotropic glutamate and muscarinic cholinergic receptors act presynaptically to cause a preferential reduction in the N-methyl-D-aspartate component of excitatory synaptic transmissions. Together with the evidence for GABA_B and adenosine A₁ receptor-mediated preferential inhibition of the N-methyl-D-aspartate component, the present results suggest that limiting glutamate spillover onto postsynaptic N-methyl-D-aspartate receptors may be a general rule for presynaptic modulation in midbrain dopamine neurons.