Squirrel monkeys responded under fixed-interval schedules in which the first response after a fixed time period resulted either in the delivery of a food pellet or in the termination of stimuli associated with impending electric shock delivery. tricyclic antidepressant drugs markedly increased responding in 3 of 10 monkeys studied; less marked but reliable increases in responding were seen with 3 others, whereas the remaining 4 monkeys showed no increases in responding. Increases in responding were observed with amitriptyline HCl (0.1-17 mg/kg), imipramine HCl (0.3-17 mg/kg), chlorimipramine HCl (0.3-17 mg/kg), nortriptyline HCl (1-17 mg/kg) and desmethylimipramine HCl (1-17 mg/kg). Amitriptyline was most potent and desmethylimipramine least potent. The pattern of individual differences in the effects of the antidepressants was matched by a similar pattern of differences in the effects of atropine sulfate (0.03-1.7 mg/kg) and scopolamine HBr (0.003-0.3 mg/kg). That is, atropine and scopolamine increased responding only in those monkey showing increases in responding with the antidepressant drugs. In contrast, all monkeys showed increases in responding with the histamine H1 antagonist diphenhydramine HCl (0.3-17 mg/kg). The order of potency of the antidepressant drugs for producing response rate increases (i.e., amitriptyline greater than imipramine greater than desmethylimipramine) is the same as that reported by others for the affinity of these drugs for muscarinic binding sites in rat brain. This correspondence in relative potencies in addition to the similar pattern of individual differences produced by the antimuscarinic and antidepressant drugs suggests that the increases in responding observed were mediated by antimuscarinic properties of the antidepressant drugs.