Behavioral contingencies, not pharmacological exposure, determine the development, loss and retention of tolerance to amphetamine hypophagia

The purpose of this study was to determine whether behavioral contingencies or pharmacological exposure governs the development, loss and retention of tolerance to amphetamine-induced hypophagia in rats. In Experiment 1, rats that had developed tolerance by learning to suppress stereotypy that interfered with feeding from a bottle were divided into three groups to test the retention of tolerance. The Before group received injections of amphetamine (2.0 mg/kg) before access to milk, the After group received injections of amphetamine after access to milk, and the Saline group received injections of saline before access to milk. Both the After and Saline groups lost tolerance when later tested with amphetamine before milk tests. Thus, the loss of tolerance was not a function of drug withdrawal, because drug exposure remained constant in the After group. When milk reward was obtained noncontingently, tolerance was lost even though pharmacological exposure was maintained. Behavioral strategies that were learned while intoxicated were replaced with new learning when the contingencies were changed. Experiment 2 determined that tolerance loss was a function of new learning and not simply ingesting milk in the unintoxicated state. Bottle-fed tolerant rats were given amphetamine prior to intraoral feeding of milk during a retention interval. Subsequent testing with amphetamine in the bottle condition revealed that tolerance was lost. Because the cannula feeding condition does not require suppression of stereotypy, milk reward was available noncontingently in the intoxicated state and tolerance was lost even though drug exposure was maintained. In Experiment 3 rats were given chronic amphetamine injections and intraoral feeding. Subsequent tests with amphetamine and bottle feeding revealed that no tolerance developed. These results demonstrate that even when ingestion occurs in the intoxicated state, no tolerance develops if milk reward is available noncontingently. Animals that drank intraorally were not tolerant when tested in the bottle condition.