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J Pharmacol Exp Ther. 1987 Jan;240(1):65-73.

Stimulus control and the development of behavioral tolerance to daily injections of d-amphetamine in the rat.


We examined whether daily d-amphetamine administration affected behavior under the control of external stimuli differently than behavior not under such control. Two variants of a fixed-consecutive-number reinforcement schedule were combined in a multiple schedule. An external discriminative stimulus indicated when the schedule requirement for reinforcement had been satisfied in one component, no such stimulus was used in the other component. Reinforcement frequency was roughly equated between the components by reducing the probability of reinforcement in the added stimulus component. Two groups of animals were given daily i.p. injections with equivalent doses of drug. Tolerance to the drug's behavioral effects developed when injections occurred before behavioral evaluation but did so only to a limited extent when injections were given only after the sessions. This indicated that behaving in the presence of the drug facilitated the development of such tolerance. It developed under both stimulus control conditions at both doses; at 3.0 mg/kg, it developed predominantly in those aspects of behavior that were under the control of external discriminative stimuli. Although drug-related decreases in reinforcement frequency in some animals were correlated with behavioral tolerance development, differential tolerance development was not associated consistently with such reductions. Establishing discriminative control of behavior by external stimuli can both reduce sensitivity to repeated d-amphetamine administration and facilitate the development of tolerance to its behavioral effects.

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