Pyridostigmine enhances glutamatergic transmission in hippocampal CA1 neurons.
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.
Pavlovsky
Lev
L
Department of Physiology, Soroka University Medical Center, Ben-Gurion University and Zlotowski Center of Neuroscience, Beersheva, Israel.
Browne
R Orie
RO
Friedman
Alon
A
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011729:Pyridostigmine Bromide / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D018698:Glutamic Acid; D013779:Tetrodotoxin; D001285:Atropine; D011729:Pyridostigmine Bromide; D000109:Acetylcholine