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NEUROPHARMACOLOGY

A Single in Vivo Application of Cholinesterase Inhibitors Has Neuron Type-Specific Effects on Nicotinic Receptor Activity in Guinea Pig Hippocampus

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland

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 (1x 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 7, 4β2, and 3β2β4 nAChRs, respectively, could be recorded from the interneurons. The magnitude of 7 nAChR currents was neuron-type dependent. Stratum radiatum interneurons (SRIs) with thick initial dendrites had the largest 7 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 3β2β4 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.

Address correspondence to: Dr. Edson X. Albuquerque, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201. E-mail: ealbuque{at}umaryland.edu