Stimulant actions of histamine H1 antagonists on operant behavior in the squirrel monkey

Squirrel monkeys were studied under fixed-interval schedules of reinforcement in which the first response (lever press) after a fixed period of time resulted either in the delivery of a food pellet or in the termination of stimuli associated with impending electric shock delivery. Benztropine mesylate (0.03–1.7 mg/kg), promethazine HCl (0.3–10 mg/kg), and diphenhydramine HCl (0.3–17 mg/kg) all produced marked increases in responding at intermediate doses. The increases in responding were at least as great as those observed with psychomotor stimulants, such as amphetamine, in this species under similar behavioral conditions. Benztropine was most potent and diphenhydramine was least potent in most monkeys and, in some, promethazine and diphenhydramine were about equipotent. The order of potency and the magnitude of potency differences among the drugs suggest that the behavioral effects were due to antagonist actions at histamine H₁ receptors, rather than to effects on dopamine uptake or on muscarinic receptors.