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Behavioral Tolerance. Fig. 1. Hypothetical data, based on Chen (1968) and Carlton and Wolgin (1971) showing how behavioral tolerance can be measured using one group of animals that initially receives a drug (in this example amphetamine) that disrupts reinforcement (milk drinking in this example) before daily access to the reinforcer, and a second group of animals that initially receives a drug that disrupts reinforcement after daily access to the reinforcer. The appetitive behavior decreases in the group that received drug before the session, but tolerance develops over time with performance returning to baseline levels. If behavioral factors were not involved then when the animals in the after group were given drug before the session they too should also show tolerance, i.e., intake would be at baseline levels. If experience with the behavior and reinforcement while under the influence of drug were necessary then behavior would be disrupted as if they had not received any drug yet. Furthermore, if behavior recovers at the same rate as it did in the group first exposed to drug before the session then this indicates that the prior pharmacological drug experience produced no savings or increase in the rate of tolerance development.

with milk drinking that only requires swallowing milk that is delivered intraorally. One approach for testing the learning hypothesis of behavioral tolerance is to compare the effects of an anorectic stimulant drug on milk swallowing versus milk drinking, e.g., Wolgin and Munoz (2006). You would hypothesize that stereotypy induced by a stimulant would disrupt milk drinking, but not milk swallowing such that tolerance would only be observed in the rats that must learn to approach and lick the fluid spout in the presence of drug-induced stereotypy. This is indeed the case. When the animals that received drug and drank milk intraorally were switched to licking the fluid spout, the previous exposure to the stimulant did not provide savings in the rate of tolerance development. Thus, tolerance development required the contingency between licking and fluid delivery to suppress stereotypic movements.

These data are exciting in that they clearly showed a role for environmental contingencies in modulating the response to long-term drug administration. The development of tolerance only in the animals drinking milk after drug administration strongly argues that dispositional and pharmacodynamic factors alone cannot account for tolerance development, and also strongly supports the reinforcement-loss hypothesis to account for behavioral tolerance. The demonstration of behavioral tolerance does not rule out a contribution for dispositional tolerance or some other factor related to the environment modulating tolerance development. For example, the increase in food deprivation due to reinforcement loss or some motor component of behaving could alter the physiological response to a drug, and in turn alter drug disposition.

An ideal study on behavioral tolerance would determine complete dose-response functions for a drug effect on behavior before, during, and after a period of repeated administration in one group of animals receiving drug prior to the session, and another group of animals receiving drug post session. In this way tolerance development could be clearly quantified and defined as a shift to the right in the dose-response function during the period of repeated administration (see Fig. 2). Behavioral tolerance would be defined as a shift to the right in the dose-response function during the period of repeated administration only in those animals receiving drug prior to the session. Although ideal, many studies do not determine dose-response function during the period of repeated administration. In the absence of a shift to the right in the dose-response function one must be cautious in assuming tolerance development. It is possible that the animals may have learned the compensatory behavior only under the influence of the dose given repeatedly. In that case, the repeated drug dose may be functioning as a discriminative stimulus for responding.

Behavioral tolerance, i.e., tolerance to a behavioral effect of a drug that is dependent upon experience with

Behavioral Tolerance. Fig. 2. Hypothetical data showing how complete dose-response functions are used to demonstrate the development of tolerance. During repeated administration the effect of each dose is less than observed before the period of repeated administration, i.e., there is a shift to the right in the dose-response function. After repeated administration the effect of each dose is similar to what was observed before the period of repeated administration, i.e., the dose-response function has shifted back to baseline.

reinforcement while intoxicated, has been well documented. Although the reinforcement-loss hypothesis that requires instrumental responding for tolerance to develop has received much support, the exact biological mechanisms accounting for the drug-environment interaction have not been identified. Future work in neuroscience may wish to take advantage of the specificity of behavioral tolerance development to examine the central nervous system changes associated with learning including analysis of neural pathways and cellular mechanisms. Such work will not only provide valuable insight into the central mechanisms underlying behavioral tolerance, but also elucidate mechanisms associated with learning in general.

Cross-References

► Appetite Suppressants

► Instrumental Conditioning

► Operant Behavior in Animals

► Rate-Dependency Theory

► Schedule of Reinforcement

► Sensitization to Drugs

References

Carlton PL, Wolgin DL (1971) Contingent tolerance to the anorexigenic effects of amphetamine. Physiol Behav 7:221-223 Chen CS (1968) A study of the alcohol-tolerance effect and an introduction of a new behavioral technique. Psychopharmacologia 12:433-440

Schuster CR, Dockens WS, Woods JH (1966) Behavioral variables affecting the development of amphetamine tolerance. Psychophar-macology 9:170-182 Wolgin DL, Munoz JR (2006) Role of instrumental learning in tolerance to cathinone hypophagia. Behav Neurosci 120:362-370

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