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

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Abstract

1. We used patch pipettes to record whole-cell currents from single dopamine neurons in slices of rat midbrain. Pharmacological methods were used to isolate EPSCs evoked by focal electrical stimulation. 2. Baclofen was significantly more potent for inhibiting NMDA receptor-mediated EPSCs (IC50 = 0.24 μM) compared with inhibition of EPSCs mediated by AMPA receptors (IC50 = 1.72 μM). The increased potency of baclofen for inhibiting the NMDA component persisted in superfusate that contained zero Mg2+ and when postsynaptic K+ conductances were reduced by Cs+ and QX-314. Effects 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 transmission (IC50 = 31 μM) compared with inhibition of AMPA receptor-mediated EPSCs (IC50 = 654 μM). Effects of adenosine on EPSCs were blocked by the A1 receptor antagonist DPCPX. 4. Both baclofen and adenosine significantly increased the ratio of EPSCs in paired-pulse studies, suggesting presynaptic sites of action. Although adenosine (1 mM ) did not reduce currents evoked by exogenous NMDA (10 μM), baclofen (1 μM) reduced NMDA currents by 29%. Neither baclofen nor adenosine altered currents evoked by exogenous AMPA (1 μM). 5. We conclude that adenosine acts at presynaptic A1 receptors to cause a preferential reduction in the NMDA component of synaptic transmission. In contrast, baclofen preferentially reduces NMDA EPSCs by acting at both pre- and postsynaptic GABA(B) receptors. By regulating NMDA receptor function, A1 and GABA(B) receptors may play important roles in regulating the excitability of dopamine neurons.

Original languageEnglish (US)
Pages (from-to)1422-1430
Number of pages9
JournalBritish Journal of Pharmacology
Volume127
Issue number6
DOIs
StatePublished - 1999

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Baclofen
Dopaminergic Neurons
Mesencephalon
N-Methyl-D-Aspartate Receptors
N-Methylaspartate
Adenosine
Inhibitory Concentration 50
GABA-B Receptors
AMPA Receptors
GABA-B Receptor Antagonists
Presynaptic Receptors
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Synaptic Transmission
Electric Stimulation
Pharmacology

Keywords

  • Adenosine
  • Baclofen
  • EPSC
  • GABA(B)
  • N-methyl-D-aspartate
  • Presynaptic inhibition
  • Substantia nigra
  • Synaptic transmission
  • Ventral tegmental area
  • Voltage-clamp

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Presynaptic inhibition preferentially reduces the NMDA receptor-mediated component of transmission in rat midbrain dopamine neurons",
abstract = "1. We used patch pipettes to record whole-cell currents from single dopamine neurons in slices of rat midbrain. Pharmacological methods were used to isolate EPSCs evoked by focal electrical stimulation. 2. Baclofen was significantly more potent for inhibiting NMDA receptor-mediated EPSCs (IC50 = 0.24 μM) compared with inhibition of EPSCs mediated by AMPA receptors (IC50 = 1.72 μM). The increased potency of baclofen for inhibiting the NMDA component persisted in superfusate that contained zero Mg2+ and when postsynaptic K+ conductances were reduced by Cs+ and QX-314. Effects 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 transmission (IC50 = 31 μM) compared with inhibition of AMPA receptor-mediated EPSCs (IC50 = 654 μM). Effects of adenosine on EPSCs were blocked by the A1 receptor antagonist DPCPX. 4. Both baclofen and adenosine significantly increased the ratio of EPSCs in paired-pulse studies, suggesting presynaptic sites of action. Although adenosine (1 mM ) did not reduce currents evoked by exogenous NMDA (10 μM), baclofen (1 μM) reduced NMDA currents by 29{\%}. Neither baclofen nor adenosine altered currents evoked by exogenous AMPA (1 μM). 5. We conclude that adenosine acts at presynaptic A1 receptors to cause a preferential reduction in the NMDA component of synaptic transmission. In contrast, baclofen preferentially reduces NMDA EPSCs by acting at both pre- and postsynaptic GABA(B) receptors. By regulating NMDA receptor function, A1 and GABA(B) receptors may play important roles in regulating the excitability of dopamine neurons.",
keywords = "Adenosine, Baclofen, EPSC, GABA(B), N-methyl-D-aspartate, Presynaptic inhibition, Substantia nigra, Synaptic transmission, Ventral tegmental area, Voltage-clamp",
author = "Wu, {Yan Na} and Ke-Zhong Shen and Steven Johnson",
year = "1999",
doi = "10.1038/sj.bjp.0702680",
language = "English (US)",
volume = "127",
pages = "1422--1430",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
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TY - JOUR

T1 - Presynaptic inhibition preferentially reduces the NMDA receptor-mediated component of transmission in rat midbrain dopamine neurons

AU - Wu, Yan Na

AU - Shen, Ke-Zhong

AU - Johnson, Steven

PY - 1999

Y1 - 1999

N2 - 1. We used patch pipettes to record whole-cell currents from single dopamine neurons in slices of rat midbrain. Pharmacological methods were used to isolate EPSCs evoked by focal electrical stimulation. 2. Baclofen was significantly more potent for inhibiting NMDA receptor-mediated EPSCs (IC50 = 0.24 μM) compared with inhibition of EPSCs mediated by AMPA receptors (IC50 = 1.72 μM). The increased potency of baclofen for inhibiting the NMDA component persisted in superfusate that contained zero Mg2+ and when postsynaptic K+ conductances were reduced by Cs+ and QX-314. Effects 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 transmission (IC50 = 31 μM) compared with inhibition of AMPA receptor-mediated EPSCs (IC50 = 654 μM). Effects of adenosine on EPSCs were blocked by the A1 receptor antagonist DPCPX. 4. Both baclofen and adenosine significantly increased the ratio of EPSCs in paired-pulse studies, suggesting presynaptic sites of action. Although adenosine (1 mM ) did not reduce currents evoked by exogenous NMDA (10 μM), baclofen (1 μM) reduced NMDA currents by 29%. Neither baclofen nor adenosine altered currents evoked by exogenous AMPA (1 μM). 5. We conclude that adenosine acts at presynaptic A1 receptors to cause a preferential reduction in the NMDA component of synaptic transmission. In contrast, baclofen preferentially reduces NMDA EPSCs by acting at both pre- and postsynaptic GABA(B) receptors. By regulating NMDA receptor function, A1 and GABA(B) receptors may play important roles in regulating the excitability of dopamine neurons.

AB - 1. We used patch pipettes to record whole-cell currents from single dopamine neurons in slices of rat midbrain. Pharmacological methods were used to isolate EPSCs evoked by focal electrical stimulation. 2. Baclofen was significantly more potent for inhibiting NMDA receptor-mediated EPSCs (IC50 = 0.24 μM) compared with inhibition of EPSCs mediated by AMPA receptors (IC50 = 1.72 μM). The increased potency of baclofen for inhibiting the NMDA component persisted in superfusate that contained zero Mg2+ and when postsynaptic K+ conductances were reduced by Cs+ and QX-314. Effects 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 transmission (IC50 = 31 μM) compared with inhibition of AMPA receptor-mediated EPSCs (IC50 = 654 μM). Effects of adenosine on EPSCs were blocked by the A1 receptor antagonist DPCPX. 4. Both baclofen and adenosine significantly increased the ratio of EPSCs in paired-pulse studies, suggesting presynaptic sites of action. Although adenosine (1 mM ) did not reduce currents evoked by exogenous NMDA (10 μM), baclofen (1 μM) reduced NMDA currents by 29%. Neither baclofen nor adenosine altered currents evoked by exogenous AMPA (1 μM). 5. We conclude that adenosine acts at presynaptic A1 receptors to cause a preferential reduction in the NMDA component of synaptic transmission. In contrast, baclofen preferentially reduces NMDA EPSCs by acting at both pre- and postsynaptic GABA(B) receptors. By regulating NMDA receptor function, A1 and GABA(B) receptors may play important roles in regulating the excitability of dopamine neurons.

KW - Adenosine

KW - Baclofen

KW - EPSC

KW - GABA(B)

KW - N-methyl-D-aspartate

KW - Presynaptic inhibition

KW - Substantia nigra

KW - Synaptic transmission

KW - Ventral tegmental area

KW - Voltage-clamp

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U2 - 10.1038/sj.bjp.0702680

DO - 10.1038/sj.bjp.0702680

M3 - Article

C2 - 10455292

AN - SCOPUS:0032788201

VL - 127

SP - 1422

EP - 1430

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

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