Vol. 304, Issue 1, 254-265, January 2003

Low Concentrations of Pyridostigmine Prevent Soman-Induced Inhibition of GABAergic Transmission in the Central Nervous System: Involvement of Muscarinic Receptors

Máriton D. Santos , Edna F. R. Pereira, Yasco Aracava , Newton G. Castro, William P. Fawcett, William R. Randall and Edson X. Albuquerque

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine (M.D.S., E.F.R.P., Y.A., W.P.F., W.R.R., E.X.A.), Baltimore, Maryland; Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas (Y.A., N.G.C., E.X.A.), and Instituto de Biofísica Carlos Chagas Filho (M.D.S.), Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

This study was designed to investigate the effects of the cholinesterase inhibitors soman and pyridostigmine bromide (PB) on synaptic transmission in the CA1 field of rat hippocampal slices. Soman (1-100 nM, 10-15 min) decreased the amplitude of GABAergic postsynaptic currents (IPSCs) evoked by stimulation of Schaffer collaterals and recorded from CA1 pyramidal neurons. It also decreased the amplitude and frequency of spontaneous IPSCs recorded from pyramidal neurons. Whereas the maximal effect of soman on evoked GABAergic transmission was observed at 10 nM, full cholinesterase inhibition was induced by 1 nM soman. After 10-15-min exposure of hippocampal slices to 100 nM PB, GABAergic transmission was facilitated and cholinesterase activity was not significantly affected. At nanomolar concentrations, soman and PB have no direct effect on GABA_A receptors. The effects of soman and PB on GABAergic transmission were inhibited by the m2 receptor antagonist 11-[[[2-diethylamino-O-methyl]-1-piperidinyl] acetyl]-5,11-dihydrol-6H-pyridol[2,3-b][1,4]benzodiazepine-6- one (1 nM) and the m3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine (100 nM), respectively, and by the nonselective muscarinic receptor antagonist atropine (1 µM). Thus, changes in GABAergic transmission are likely to result from direct interactions of soman and PB with m2 and m3 receptors, respectively, located on GABAergic fibers/neurons synapsing onto the neurons under study. Although the effects of 1 nM soman and 100 nM PB were diametrically opposed, they only canceled one another when PB was applied to the neurons before soman. Therefore, PB, acting via m3 receptors, can effectively counteract effects arising from the interactions of soman with m2 receptors in the brain.