Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats

The purpose of our studies was to determine the effects of muscarinic recep tor agonists on conditioned avoidance responding in the rat. Rats were trai ned to avoid or escape an electric shock delivered to the feet in a discret e trial procedure. The muscarinic receptor agonists pilocarpine and [2-ethy l-8-methyl-2,8-diazaspiro(4.5)decane-1,3-dione] hydrochloride (RS86) and th e cholinesterase inhibitor physostigmine all decreased the percentage of av oidance responses at doses that produced less than approximately 30% respon se failures. Similar results were obtained with the antipsychotic drugs hal operidol, trifluoperazine, chlorpromazine, and clozapine. However, the benz odiazepine anxiolytic diazepam did not decrease avoidance responding up to doses that produced ataxia. On the other hand, oxotremorine and arecoline d ecreased avoidance responding only by producing response failures, whereas aceclidine produced intermediate changes. The muscarinic receptor antagonis ts scopolamine, trihexyphenidyl, and benztropine were without effect when a dministered alone but antagonized the decreases in avoidance responding pro duced by pilocarpine and RS86. Scopolamine had little effect on the decreas es in avoidance responding produced by haloperidol. The newer muscarinic re ceptor partial agonists or agonist/antagonists [R-(Z)-(+)-alpha-(methoxyimi no)-1-azabicyclo[2.2.2]octane-3-acetonitrile] hydrochloride, talsaclidine, milameline, and xanomeline also produced dose-related decreases in avoidanc e responding. Our results demonstrate that muscarinic receptor agonists can decrease avoidance responding in a manner similar to dopamine-receptor ant ipsychotic drugs, suggesting that muscarinic receptor agonists may provide an alternative approach to the treatment of psychosis.