Several dopamine agonists, administered i.m., produced persistent, excessive and non-localized scratching in squirrel monkeys (Saimiri sciureus). Studies were conducted with a series of drugs to determine the pharmacological mechanisms responsible for this effect. All of the dopamine D2 agonists studied produced dose-related increases in scratching, whereas several dopamine D1 receptor agonists, indirect dopamine agonists and drugs acting on other receptors failed to produce dose-related increases in scratching. The scratching produced by D2 agonists was stereospecific; (-)-NPA produced scratching whereas its (+)-enantiomer was inactive up to doses 300-fold higher. Scratching induced by quinpirole was attenuated by both D2 and D1 antagonists, and this antagonism was stereospecific, with the D2 antagonist (-)-eticlopride, but not its enantiomer, active. Sensitivity developed to the effects of D2 agonists with the quinpirole dose-effect curve shifting to the left by a factor of approximately 64. Two partial D2 receptor agonists (SDZ 208-911 and SDZ 208-912) had limited efficacy in producing scratching, however, one partial D2 receptor agonist (terguride) was fully efficacious, suggesting that there are spare receptors for this effect. The peripherally active dopamine antagonist domperidone and the histamine antagonist diphenhydramine also reduced the scratching induced by D2 agonists, but not to the same extent as centrally acting D2 antagonists. Scratching in squirrel monkeys is an effect that appears to be due to agonist actions at D2 receptors, and may be mediated by a release of histamine. This behavioral activity may be useful as an in vivo indication of D2 receptor activity in primates.