Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro

Mark O. Cunningham, Gavin L. Woodhall, Sarah E. Thompson, David J. Dooley, Roland S G Jones*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

We have recently shown that the anticonvulsant drugs phenytoin, lamotrigine and sodium valproate all reduce the release of glutamate at synapses in the entorhinal cortex in vitro. In the present investigation we determined whether this property was shared by gabapentin and pregabalin, using whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) in layer V neurons in slices of rat entorhinal cortex. Both drugs reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation of afferent inputs, suggesting a presynaptic effect to reduce glutamate release. The frequency of spontaneous EPSCs (sEPSCs) was concurrently reduced by GBP, further supporting a presynaptic action. There was no significant change in amplitude although a slight reduction was seen, particularly with gabapentin, which may reflect a reduction in the number of larger amplitude sEPSCs. When activity-independent miniature EPSCs were recorded in the presence of tetrodotoxin, both drugs continued to reduce the frequency of events with no change in amplitude. The reduction in frequency induced by gabapentin or pregabalin was blocked by application of the L-amino acid transporter substrate L-isoleucine. The results show that gabapentin and pregabalin, like other anticonvulsants, reduce glutamate release at cortical synapses. It is possible that this reduction is a combination of two effects: a reduction of activity-dependent release possibly via interaction with P/Q-type voltage-gated Ca channels, and a second action, as yet unidentified, occurring downstream of Ca influx into the presynaptic terminals.

Original languageEnglish
Pages (from-to)1566-1576
Number of pages11
JournalEuropean Journal of Neuroscience
Volume20
Issue number6
DOIs
Publication statusPublished - 6 Sep 2004

Fingerprint

Excitatory Postsynaptic Potentials
Synapses
Glutamic Acid
Entorhinal Cortex
Anticonvulsants
Amino Acid Transport Systems
Isoleucine
Tetrodotoxin
Presynaptic Terminals
Valproic Acid
Phenytoin
Pharmaceutical Preparations
Electric Stimulation
Neurons
In Vitro Techniques
Pregabalin
gabapentin

Keywords

  • Ca channels
  • evoked currents
  • spontaneous currents

Cite this

Cunningham, Mark O. ; Woodhall, Gavin L. ; Thompson, Sarah E. ; Dooley, David J. ; Jones, Roland S G. / Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. In: European Journal of Neuroscience. 2004 ; Vol. 20, No. 6. pp. 1566-1576.
@article{96fabfdd5e6849ff8bb8eeb7590e19f8,
title = "Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro",
abstract = "We have recently shown that the anticonvulsant drugs phenytoin, lamotrigine and sodium valproate all reduce the release of glutamate at synapses in the entorhinal cortex in vitro. In the present investigation we determined whether this property was shared by gabapentin and pregabalin, using whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) in layer V neurons in slices of rat entorhinal cortex. Both drugs reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation of afferent inputs, suggesting a presynaptic effect to reduce glutamate release. The frequency of spontaneous EPSCs (sEPSCs) was concurrently reduced by GBP, further supporting a presynaptic action. There was no significant change in amplitude although a slight reduction was seen, particularly with gabapentin, which may reflect a reduction in the number of larger amplitude sEPSCs. When activity-independent miniature EPSCs were recorded in the presence of tetrodotoxin, both drugs continued to reduce the frequency of events with no change in amplitude. The reduction in frequency induced by gabapentin or pregabalin was blocked by application of the L-amino acid transporter substrate L-isoleucine. The results show that gabapentin and pregabalin, like other anticonvulsants, reduce glutamate release at cortical synapses. It is possible that this reduction is a combination of two effects: a reduction of activity-dependent release possibly via interaction with P/Q-type voltage-gated Ca channels, and a second action, as yet unidentified, occurring downstream of Ca influx into the presynaptic terminals.",
keywords = "Ca channels, evoked currents, spontaneous currents",
author = "Cunningham, {Mark O.} and Woodhall, {Gavin L.} and Thompson, {Sarah E.} and Dooley, {David J.} and Jones, {Roland S G}",
year = "2004",
month = "9",
day = "6",
doi = "10.1111/j.1460-9568.2004.03625.x",
language = "English",
volume = "20",
pages = "1566--1576",
journal = "European Journal of Neuroscience",
issn = "0953-816X",
publisher = "Wiley-Blackwell",
number = "6",

}

Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. / Cunningham, Mark O.; Woodhall, Gavin L.; Thompson, Sarah E.; Dooley, David J.; Jones, Roland S G.

In: European Journal of Neuroscience, Vol. 20, No. 6, 06.09.2004, p. 1566-1576.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro

AU - Cunningham, Mark O.

AU - Woodhall, Gavin L.

AU - Thompson, Sarah E.

AU - Dooley, David J.

AU - Jones, Roland S G

PY - 2004/9/6

Y1 - 2004/9/6

N2 - We have recently shown that the anticonvulsant drugs phenytoin, lamotrigine and sodium valproate all reduce the release of glutamate at synapses in the entorhinal cortex in vitro. In the present investigation we determined whether this property was shared by gabapentin and pregabalin, using whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) in layer V neurons in slices of rat entorhinal cortex. Both drugs reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation of afferent inputs, suggesting a presynaptic effect to reduce glutamate release. The frequency of spontaneous EPSCs (sEPSCs) was concurrently reduced by GBP, further supporting a presynaptic action. There was no significant change in amplitude although a slight reduction was seen, particularly with gabapentin, which may reflect a reduction in the number of larger amplitude sEPSCs. When activity-independent miniature EPSCs were recorded in the presence of tetrodotoxin, both drugs continued to reduce the frequency of events with no change in amplitude. The reduction in frequency induced by gabapentin or pregabalin was blocked by application of the L-amino acid transporter substrate L-isoleucine. The results show that gabapentin and pregabalin, like other anticonvulsants, reduce glutamate release at cortical synapses. It is possible that this reduction is a combination of two effects: a reduction of activity-dependent release possibly via interaction with P/Q-type voltage-gated Ca channels, and a second action, as yet unidentified, occurring downstream of Ca influx into the presynaptic terminals.

AB - We have recently shown that the anticonvulsant drugs phenytoin, lamotrigine and sodium valproate all reduce the release of glutamate at synapses in the entorhinal cortex in vitro. In the present investigation we determined whether this property was shared by gabapentin and pregabalin, using whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) in layer V neurons in slices of rat entorhinal cortex. Both drugs reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation of afferent inputs, suggesting a presynaptic effect to reduce glutamate release. The frequency of spontaneous EPSCs (sEPSCs) was concurrently reduced by GBP, further supporting a presynaptic action. There was no significant change in amplitude although a slight reduction was seen, particularly with gabapentin, which may reflect a reduction in the number of larger amplitude sEPSCs. When activity-independent miniature EPSCs were recorded in the presence of tetrodotoxin, both drugs continued to reduce the frequency of events with no change in amplitude. The reduction in frequency induced by gabapentin or pregabalin was blocked by application of the L-amino acid transporter substrate L-isoleucine. The results show that gabapentin and pregabalin, like other anticonvulsants, reduce glutamate release at cortical synapses. It is possible that this reduction is a combination of two effects: a reduction of activity-dependent release possibly via interaction with P/Q-type voltage-gated Ca channels, and a second action, as yet unidentified, occurring downstream of Ca influx into the presynaptic terminals.

KW - Ca channels

KW - evoked currents

KW - spontaneous currents

UR - http://www.scopus.com/inward/record.url?scp=4644259036&partnerID=8YFLogxK

UR - http://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.2004.03625.x/abstract

U2 - 10.1111/j.1460-9568.2004.03625.x

DO - 10.1111/j.1460-9568.2004.03625.x

M3 - Article

C2 - 15355323

AN - SCOPUS:4644259036

VL - 20

SP - 1566

EP - 1576

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 6

ER -