Tolerance to an anticholinergic agent is paralleled by increased binding to muscarinic receptors in rat brain and increased behavioral response to a centrally active cholinomimetic.

Pretreatment of rats with agents with strong antimuscarinic activity in the CNS (scopolamine, benztropine, trihexyphenidyl, amitriptyline, and thioridazine) but not their inactive congeners (desipramine, fluphenazine, or haloperidol) led to significant increases in the maximum apparent density of binding sites for 3H-QNB in cerebral cortical or striatal membranes. The dopamine agonist bromocriptine induced a similar effect that was blocked by haloperidol in striatum. None of these treatments altered the apparent affinity of the test ligand. Tolerance to the behavioral activating action of scopolamine developed over two weeks of daily treatment. This change was paralleled by an increase in 3H-QNB binding in cerebral cortex which was dependent on the dose and duration of treatment with scopolamine and persisted for a week following two weeks of treatment. Scopolamine pretreatment led to a significant increase in basal, spontaneous motor activity in the rat, but also to a marked increase in the motor-inhibitory actions of the centrally active muscarinic agonist pilocarpine. These results add to the impression that decreased availability of ACh agonists can significantly increase the availability and functional activity of central muscarinic ACh receptors to reflect "disuse supersensitivity."