Vol. 290, Issue 2, 901-907, August 1999

Muscarinic Receptor Agonists, Like Dopamine Receptor Antagonist Antipsychotics, Inhibit Conditioned Avoidance Response in Rats

Harlan E. Shannon, John C. Hart, Frank P. Bymaster, David O. Calligaro, Neil W. DeLapp, Charles H. Mitch, John S. Ward, Anders Fink-Jensen, Per Sauerberg, Lone Jeppesen, Malcolm J. Sheardown and Michael D.B. Swedberg

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (H.E.S, J.C.H., F.P.B., D.O.C., N.W.D, C.H.M., J.S.W.); and Novo Nordisk A/S, Health Care Discovery, Måløv, Denmark (A.F.J., P.S., L.J., M.J.S., M.D.B.S)

The purpose of our studies was to determine the effects of muscarinic receptor agonists on conditioned avoidance responding in the rat. Rats were trained to avoid or escape an electric shock delivered to the feet in a discrete trial procedure. The muscarinic receptor agonists pilocarpine and [2-ethyl-8-methyl-2,8-diazaspiro(4.5)decane-1,3-dione] hydrochloride (RS86) and the cholinesterase inhibitor physostigmine all decreased the percentage of avoidance responses at doses that produced less than approximately 30% response failures. Similar results were obtained with the antipsychotic drugs haloperidol, trifluoperazine, chlorpromazine, and clozapine. However, the benzodiazepine anxiolytic diazepam did not decrease avoidance responding up to doses that produced ataxia. On the other hand, oxotremorine and arecoline decreased avoidance responding only by producing response failures, whereas aceclidine produced intermediate changes. The muscarinic receptor antagonists scopolamine, trihexyphenidyl, and benztropine were without effect when administered alone but antagonized the decreases in avoidance responding produced by pilocarpine and RS86. Scopolamine had little effect on the decreases in avoidance responding produced by haloperidol. The newer muscarinic receptor partial agonists or agonist/antagonists [R-(Z)-(+)--(methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile] hydrochloride, talsaclidine, milameline, and xanomeline also produced dose-related decreases in avoidance responding. Our results demonstrate that muscarinic receptor agonists can decrease avoidance responding in a manner similar to dopamine-receptor antipsychotic drugs, suggesting that muscarinic receptor agonists may provide an alternative approach to the treatment of psychosis.