The withdrawal of tricyclic antidepressants produces symptoms characteristic of cholinergic overdrive states. The authors previously proposed that these states are the consequence of the pharmacological induction of cholinergic system supersensitivity by chronic treatment with antidepressants, combined with a reduction in the plasma level of a competitive muscarinic receptor antagonist when the dose of a tricyclic is decreased. This is consistent with the facts that all tricyclic antidepressants are antimuscarinic agents and that classical antimuscarinic compounds, such as scopolamine, up-regulate and supersensitize muscarinic cholinergic systems. The authors present evidence that chronic treatment with amitriptyline supersensitizes a central cholinergic mechanism. Core body temperature is subject to influence by a central (hypothalamic) muscarinic mechanism, which is rendered supersensitive to cholinomimetic challenge by treatment with scopolamine. The authors telemetrically measured the hypothermic responses of adult male rats to various doses of the muscarinic agonist oxotremorine before and in the course of chronic treatment with amitriptyline. Treatment with amitriptyline resulted in marked enhancement of the cholinomimetic-induced hypothermia. Methylscopolamine nitrate, a peripherally active antimuscarinic agent, did not block the hypothermic response to oxotremorine, whereas scopolamine, a centrally active antimuscarinic compound, did. This study indicates that the chronic administration of amitriptyline can produce supersensitivity of a central muscarinic cholinergic mechanism. Clinical and theoretical implications of this finding are discussed.