TY - JOUR
T1 - Pyridostigmine enhances glutamatergic transmission in hippocampal CA1 neurons
AU - Pavlovsky, Lev
AU - Browne, R. Orie
AU - Friedman, Alon
N1 - Funding Information:
Supported by grants from the US-Israeli Binational Science Foundation Grant 9700174, Grant 4536 from the Chief’s Scientist’s Office of the Ministry of Health, Israel, and the U.S. Army Medical Research and Materiel Command (DAMD 17-99-1-9547).
PY - 2003/2/1
Y1 - 2003/2/1
N2 - Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Due to its positively charged ammonium group, under normal conditions pyridostigmine cannot cross the blood-brain barrier (BBB) and penetrate the brain. However, several studies have suggested that under conditions in which the BBB is disrupted, pyridostigmine enters the brain, changes cortical excitability, and leads to long-lasting alterations in gene expression. The aim of this study was to characterize the mechanisms underlying pyridostigmine-induced changes in the excitability of central neurons. Using whole cell intracellular recordings in hippocampal neurons we show that pyridostigmine decreases repetitive firing adaptation and increases the appearance of excitatory postsynaptic potentials. In voltage clamp recordings, both pyridostigmine and acetylcholine (ACh) increased the frequency but not the amplitude of excitatory postsynaptic currents. These effects were reversible upon the administration of the muscarinic receptor antagonist, atropine, and were not blocked by tetrodotoxin. We conclude that pyridostigmine, by increasing free ACh levels, causes muscarinic-dependent enhancement of excitatory transmission. This mechanism may explain central side effects previously attributed to this drug as well as the potency of AChE inhibitors, including nerve-gas agents and organophosphate pesticides, in the initiation of cortical synchronization, epileptic discharge, and excitotoxic damage.
AB - Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Due to its positively charged ammonium group, under normal conditions pyridostigmine cannot cross the blood-brain barrier (BBB) and penetrate the brain. However, several studies have suggested that under conditions in which the BBB is disrupted, pyridostigmine enters the brain, changes cortical excitability, and leads to long-lasting alterations in gene expression. The aim of this study was to characterize the mechanisms underlying pyridostigmine-induced changes in the excitability of central neurons. Using whole cell intracellular recordings in hippocampal neurons we show that pyridostigmine decreases repetitive firing adaptation and increases the appearance of excitatory postsynaptic potentials. In voltage clamp recordings, both pyridostigmine and acetylcholine (ACh) increased the frequency but not the amplitude of excitatory postsynaptic currents. These effects were reversible upon the administration of the muscarinic receptor antagonist, atropine, and were not blocked by tetrodotoxin. We conclude that pyridostigmine, by increasing free ACh levels, causes muscarinic-dependent enhancement of excitatory transmission. This mechanism may explain central side effects previously attributed to this drug as well as the potency of AChE inhibitors, including nerve-gas agents and organophosphate pesticides, in the initiation of cortical synchronization, epileptic discharge, and excitotoxic damage.
KW - Acetylcholine
KW - Acetylcholinesterase inhibitors
KW - Glutamate
KW - Muscarinic receptors
KW - Presynaptic modulation
KW - Synaptic transmission
UR - http://www.scopus.com/inward/record.url?scp=0037331337&partnerID=8YFLogxK
U2 - 10.1016/S0014-4886(02)00016-X
DO - 10.1016/S0014-4886(02)00016-X
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C2 - 12618125
AN - SCOPUS:0037331337
SN - 0014-4886
VL - 179
SP - 181
EP - 187
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -