Rapid induction of supersensitivity to muscarinic antagonists-induced motor excitation by continuous stimulation of cholinergic receptors.

Following single or repeated treatment with the irreversible anticholinesterase, DFP or, during infusion of the muscarinic receptor agonist, oxotremorine, and the reversible anticholinesterase physostigmine, effects of challenges with muscarinic antagonists were studied in rats. The antagonists, atropine, scopolamine, benztropine, orphenadrine and trihexyphenidyl induced, to a low degree, limb-shakes (myoclonus) and stereotyped behaviors in normal rats. However, within 24-72 hr after the above pretreatments, this myoclonus was significantly enhanced. The anticholinergic-stereotypies were also increased but only by severe cholinergic pretreatment and at a time later than that for the myoclonus. Myoclonus and stereotypies are known to be produced by treatments which directly enhance serotonergic and dopaminergic activities, respectively. It is suggested that during prolonged cholinergic stimulation, the cholinergic-monoaminergic balance in the brain can be altered depending upon the degree of stimulation. This could be responsible for the observed differential onset of changes in the anticholinergic-behavioral responses, which could, in turn, be mediated by different monoaminergic (serotonin and dopamine) systems.