Abstract
The present study was designed to test the hypothesis that an acute in vivo treatment with reversible or irreversible acetylcholinesterase (AChE) inhibitors modifies the activities of nicotinic receptors (nAChRs) in hippocampal neurons. Here, whole-cell nicotinic responses were recorded from CA1 interneurons in hippocampal slices obtained from male guinea pigs at 1, 7, or 14 days after treatment with the irreversible AChE inhibitor, soman (1× LD50 s.c.), and/or the reversible AChE inhibitor, galantamine (8 mg/kg i.m.). Naive animals were used as controls. Three types of nAChR responses, namely types IA, II, and III, which were mediated by α7, α4β2, and α3β2β4 nAChRs, respectively, could be recorded from the interneurons. The magnitude of α7 nAChR currents was neuron-type dependent. Stratum radiatum interneurons (SRIs) with thick initial dendrites had the largest α7 nAChR currents. Acute challenge with soman caused sustained reduction of type IA current amplitudes recorded from stratum oriens interneurons and increased the ratio of acetylcholine- to choline-evoked current amplitudes recorded from SRIs. In guinea pigs that developed long-lasting convulsions after the soman challenge, there was a sustained reduction of α3β2β4 nAChR responses. Acute treatment with galantamine had no effect on type IA or III responses, whereas it decreased the incidence of type II currents. Pretreatment of the guinea pigs with galantamine prevented the suppressive effect of soman on type III responses. The neuron type-specific changes in nAChR activity induced by soman, some of which could be prevented by galantamine, may contribute to the maintenance of pathological rhythms in the hippocampal neuronal network.
Footnotes
-
This study was supported by the National Institutes of Health CounterACT Program through the National Institute of Neurological Disorders and Stroke [Award UO1NS059344] and by the Army Research Office [Contract W911NF-06-1-0098].
-
Patents are pending for the method of prophylactically treating organophosphorus poisoning.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.146068.
-
ABBREVIATIONS: OP, organophosphorus; AChE, acetylcholinesterase; ACh, acetylcholine; nAChR, nicotinic acetylcholine receptor; EPSC, excitatory postsynaptic current; SRI, stratum radiatum interneuron; ACSF, artificial cerebrospinal fluid; QX-314, lidocaine N-ethyl bromide; NMDA, N-methyl-d-aspartate; SOI, stratum oriens interneuron; SPI, stratum pyramidal interneuron; SO, stratum oriens; SR, stratum radiatum; SLM, stratum lacunosum moleculare; MLA, methyllycaconitine; α-BGT, α-bungarotoxin.
- Received September 12, 2008.
- Accepted October 7, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|