Abstract
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 GABAA 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.
Footnotes
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This work was supported by the U.S. Army Medical and Research Development Command contract DAMD-17-95-C-5063, a grant from the Janssen Research Foundation, U.S. Public Health Service Grant NS41671, and Conselho Nacional de Pesquisa e Desenvolvimento, Brazil. A preliminary account of this study was presented at the 1999 Annual Meetings of the Society for Neurosciences (Abstr Soc Neurosci25:1972, 1999; program no. 836.5, 2002 CD-ROM).
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DOI: 10.1124/jpet.102.043109
- Abbreviations:
- ACh
- acetylcholine
- CNS
- central nervous system
- PB
- pyridostigmine bromide
- AFDX-116
- 11-[[[2-diethylamino-O-methyl]-1-piperidinyl]acetyl]-5,11-dihydrol-6H-pyridol[2,3-b][1,4]benzodiazepine-6-one
- ACSF
- artificial cerebrospinal fluid
- PSC
- postsynaptic current
- ANOVA
- analysis of variance
- CNQX
- 6-cyano-7-nitroquinoxaline-2,3-dione
- APV
- 2-amino-5-phosphonovaleric acid
- 4-DAMP
- 4-diphenylacetoxy-N-methylpiperidine
- MLA
- methyllycaconitine
- DHβE
- dihydro-β-erythroidine
- EPSC
- excitatory postsynaptic current
- IPSC
- inhibitory postsynaptic current
- nAChR
- nicotinic acetylcholine receptor
- VX
- O-ethylS-[2(diisopropylamino)ethyl]methylphosphonothioate
- QX-314
- N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide
- Received August 16, 2002.
- Accepted September 11, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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