A slow excitatory postsynaptic current mediated by G-protein-coupled metabotropic glutamate receptors in rat ventral tegmental dopamine neurons

Dopamine neurons in the substantia nigra and ventral tegmental area express metabotropic glutamate receptors, but activation of these receptors by synaptic release of neurotransmitter has not been demonstrated thus far. Patch pipettes were used to record membrane currents under voltage clamp from presumed dopamine-containing neurons in the whole-cell configuration in the rat brain slice. A short train of electrical stimuli delivered to bipolar electrodes placed in the slice evoked a slow excitatory postsynaptic current (EPSC; 50-300 pA at -70 mV) which peaked 560 ms after onset and lasted several seconds, with a decay time-constant of 630 ms. This slow EPSC was voltage-dependent, and was abolished by tetrodotoxin (0.5 mu M) or by perfusate containing low calcium (0.5 mM) and high magnesium (10 mM). The metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG; 300 mu M) blocked the slow EPSC, but L(+)-2-amino-3-phosphonopropionic acid (AP3; 300 mu M) had no effect. The slow EPSC was largely occluded by inward current produced by the metabotropic receptor agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD; 300 mu M), and the EPSC was reduced >90% during acute desensitization produced by prolonged perfusion with t-ACPD. (+/-)-2-Amino-4-phosphonobutyric acid (AP4; 300 mu M), another metabotropic receptor agonist, reduced the slow EPSC but had no effect on currents evoked by t-ACPD applied by pressure-ejection from micropipettes. The slow EPSC was progressively reduced in amplitude when pipettes contained the G-protein inhibitor GDP-beta-S (0.5 mM). When pipettes contained GTP-gamma-S (0.5 mM), a non-hydrolysable analogue of GTP, onset of the slow EPSC was more rapid and its decay was significantly prolonged. These results demonstrate that a slow EPSC mediated by G-protein-coupled metabotropic glutamate receptors can be evoked in dopamine neurons.