Acetylcholinesterase inhibition reveals endogenous nicotinic modulation of glutamate inputs to CA1 stratum radiatum interneurons in hippocampal slices

• Published in: Neurotoxicology (Park Forest South) Vol. 36; pp. 72 - 81
• Main Authors: Alkondon, Manickavasagom, Albuquerque, Edson X., Pereira, Edna F.R.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.05.2013; Elsevier
• Subjects: 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; Acetylcholine - pharmacology; Acetylcholinesterase; Age Factors; Animals; Animals, Newborn; Biological and medical sciences; CA1 Region, Hippocampal - cytology; Chemical and industrial products toxicology. Toxic occupational diseases; Cholinesterase Inhibitors - pharmacology; Donepezil; Electric Stimulation; EPSC; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Gas, fumes; Glutamic Acid - metabolism; Guinea Pigs; Hippocampus; In Vitro Techniques; Indans - pharmacology; Interneuron; Interneurons - drug effects; Lethal Dose 50; Male; Mecamylamine - pharmacology; Medical sciences; Neuropharmacology; Nicotine - metabolism; Nicotinic Antagonists - pharmacology; Patch-Clamp Techniques; Pharmacology. Drug treatments; Piperidines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Soman; Soman - pharmacology; Toxicology; AChE; MLA; ACh; LTP; MEC; ACSF; SRI; Acetylcholinesterase; CNQX; Interneuron; LD50; Donepezil; nAChR; NMDA; EC50; TTX; Soman; EPSC; Hippocampus; Psychotropic; Central nervous system; Esterases; Encephalon; Chemical warfare agent; Endogenous; Modulation; Piperidine derivatives; Anticholinesterase agent; Inhibition; Toxic gas; Enzyme; Enzyme inhibitor; Antialzheimer agent; Glutamate; Histological section; Carboxylic ester hydrolases; Nootropic agent; Excitatory aminoacid; Neurotransmitter; Hydrolases; Organophosphorus compounds
• DOI: 10.1016/j.neuro.2013.02.005
• ISSN: 0161-813X

► Soman, an irreversible AChE inhibitor is a potent neurotoxicant. ► Soman-induced seizures have been associated with increased brain glutamate levels. ► AChE inhibition in hippocampal slices increased frequency of spontaneous EPSCs in stratum radiatum interneurons. ► Both α7 and non-α7 nACRs were involved in the modulation of EPSCs. The involvement of brain nicotinic acetylcholine receptors (nAChRs) in the neurotoxicological effects of soman, a potent acetylcholinesterase (AChE) inhibitor and a chemical warfare agent, is not clear. This is partly due to a poor understanding of the role of AChE in brain nAChR-mediated functions. To test the hypothesis that AChE inhibition builds sufficient acetylcholine (ACh) in the brain and facilitates nAChR-dependent glutamate transmission, we used whole-cell patch-clamp technique to record spontaneous glutamate excitatory postsynaptic currents (EPSCs) from CA1 stratum radiatum interneurons (SRI) in hippocampal slices. First, the frequency, amplitude and kinetics of EPSCs recorded from slices of control guinea pigs were compared to those recorded from slices of guinea pigs after a single injection of the irreversible AChE inhibitor soman (25.2μg/kg, s.c.). Second, EPSCs were recorded from rat hippocampal slices before and after their superfusion with the reversible AChE inhibitor donepezil (100nM). The frequency of EPSCs was significantly higher in slices taken from guinea pigs 24h but not 7 days after the soman injection than in slices from control animals. In 52% of the rat hippocampal slices tested, bath application of donepezil increased the frequency of EPSCs. Further, exposure to donepezil increased both burst-like and large-amplitude EPSCs, and increased the proportion of short (20–100ms) inter-event intervals. Donepezil's effects were suppressed significantly in presence of 10μM mecamylamine or 10nM methyllycaconitine. These results support the concept that AChE inhibition is able to recruit nAChR-dependent glutamate transmission in the hippocampus and such a mechanism can contribute to the acute neurotoxicological actions of soman.