Suppression of cocaine self-administration in monkeys: Effects of delayed punishment

Rationale Delaying presentation of a drug can decrease its effectiveness as a reinforcer, but the effect of delaying punishment of drug self-administration is unknown. Objective This study examined whether a histamine injection could punish cocaine self-administration in a drug- drug choice, whether delaying histamine would decrease its effectiveness, and whether the effects of delay could be described within a delay discounting framework. Methods Monkeys were implanted with double-lumen catheters to allow separate injection of cocaine and histamine. In discrete trials, subjects first chose between cocaine (50 or 100 μg/kg/inj) alone and an injection of the same dose of cocaine followed immediately by an injection of histamine (0.37-50 μg/kg). Next, they chose between cocaine followed immediately by histamine and cocaine followed by an equal but delayed dose of histamine. Results When choosing between cocaine alone and cocaine followed immediately by histamine, preference increased with histamine dose from indifference to >80% choice of cocaine alone. When choosing between cocaine followed by immediate histamine and cocaine followed by delayed histamine, monkeys showed strong position preferences. When delayed histamine was associated with the non-preferred position, preference for that option increased with delay from ≤30% to >85%. The corresponding decrease in choice of the preferred position was well described by a hyperboloid discounting function. Conclusions Histamine can function as a punisher in the choice between injections of cocaine and delay can decrease its effectiveness as a punisher. The effects of delaying punishment of drug self-administration can be conceptualized within the delay discounting framework.