Presynaptic inhibition preferentially reduces the NMDA receptor-mediated component of transmission in rat midbrain dopamine neurons

1 We used patch pipettes to record whole-cell currents from single dopamine neurons in slices of rat midbrain. Pharmacological methods were used to is olate EPSCs evoked by focal electrical stimulation. 2 Baclofen was significantly more potent for inhibiting NMDA receptor-media ted EPSCs (IC50 = 0.24 mu M) compared with inhibition of EPSCs mediated by AMPA receptors (IC50 = 1.72 mu M). The increased potency of baclofen for in hibiting the NMDA component persisted in superfusate that contained zero Mg 2+ and when postsynaptic K+ conductances were reduced by Cs+ and QX-314. Ef fects of baclofen on EPSCs were blocked by the GABA(B) receptor antagonist CGP-35348. 3 Adenosine was 20 fold more potent for reducing the NMDA component of tran smission (IC50 = 31 mu M) compared with inhibition of AMPA receptor-mediate d EPSCs (IC50 = 654 mu M). Effects of adenosine on EPSCs were blocked by th e A(1) receptor antagonist DPCPX. 4 Both baclofen and adenosine significantly increased the ratio of EPSCs in paired-pulse studies, suggesting presynaptic sites of action. Although ade nosine (1 mM) did not reduce currents evoked by exogenous NMDA (10 mu M), b aclofen (1 mu M) reduced NMDA currents by 29%. Neither baclofen nor adenosi ne altered currents evoked by exogenous AMPA (1 mu M). 5 We conclude that adenosine acts at presynaptic A(1) receptors to cause a preferential reduction in the NMDA component of synaptic transmission. In c ontrast, baclofen preferentially reduces NMDA EPSCs by acting at both pre- and postsynaptic GABA(B) receptors. By regulating NMDA receptor function, A (1) and GABA(B) receptors may play important roles in regulating the excita bility of dopamine neurons.