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Sensitization and Tolerance in Psychostimulant Self-Administration

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Abstract

Under some conditions, stimulant preexposure sensitizes rats to the reinforcing effects of cocaine and other stimulants, whereas under other conditions exposure decreases the reinforcing efficacy of cocaine. This paper reviews the literature on the effects of stimulant preexposure on self-administration, focusing on methodological and interpretative issues. It is concluded that both sensitization and tolerance occur following stimulant preexposure but that these two effects can be dissociated temporally, with sensitization occurring during the development of drug self-administration and tolerance occurring in response to high doses of stimulants administered to experienced self-administering rats. The relative contribution of both of these effects to compulsive drug-taking is discussed, with emphasis on the development of cocaine as a reinforcer, maintenance of self-administration, and relapse to drug-taking.

Section snippets

Acquisition of cocaine self-administration

When animals are given limited access to psychostimulant self-administration (2–3 h daily), there is large across-subject variability in the latency to acquisition of an operant for this behavior. Deneau, Yanagita, and Seevers [7]originally described some monkeys as “resistant” and others as “susceptible” based on their propensity to acquire self-administration. In our laboratory, we routinely observe that some rats acquire self-administration within just a few days of testing (susceptible),

Maintenance of self-administration

Once acquisition occurs, the minimum dose that will maintain self-administration remains fairly stable over long periods of daily testing. This stability is depicted in Fig. 2. These data were derived using a within-session dose–effect curve determination procedure modeled after Winger et al. [38]. For these tests, self-administration of each dose of cocaine was obtained during 30-min bins with cocaine being delivered on an FR 5 schedule of reinforcement. After each 30-min bin, there was a

Sensitization to the reinforcing effects of stimulants

A small number of investigators have noted that after experience with cocaine or other stimulants, lower doses than would initially maintain self-administration become effective reinforcers. For example, Woolverton et al. [40]found that the reinforcing effects of methamphetamine were enhanced following preexposure. Doses that were initially subthreshold for self-administration became capable of maintaining responding in two out of three monkeys following a period of intermittent methamphetamine

Predisposition to Cocaine Abuse

In a study on humans by Davidson et al. [6], many of the participants reported that the first several exposures to cocaine were not positive, and these same individuals reported lower cocaine use than subjects who reported that the initial cocaine experiences were very positive. Thus, individuals who experienced cocaine as more positive on initial use tended to use the drug a second time more quickly and to use it more frequently than subjects who did not experience these positive effects of

Tolerance to the reinforcing effects of stimulants

In a series of papers, Emmett-Oglesby and his group 12, 13have studied the effect of more stringent preexposure regimens on the subsequent self-administration of cocaine. In these studies, experienced cocaine self-administering rats were administered cocaine (20.0 mg/kg IV every 8 h for 7 days), d-amphetamine, or methamphetamine (0.32, 1.0, or 3.2 mg/kg every 12 h for 7 days). Both prior to and following the chronic dosing, a multidosing and progressive ratio method were used to determine the

Role of tolerance in drug self-administration

It is hard to imagine how tolerance to the reinforcing effects of cocaine might play a role in the acquisition of cocaine self-administration. It is also difficult to incorporate tolerance to the reinforcing effects of drugs into a model where this phenomenon maintains drug-taking. Thus, although tolerance to cocaine’s reinforcing effects appears to occur following exposure, it does not seem that this phenomenon plays a role in drug self-administration. Rather, tolerance to cocaine’s

Summary

Sensitization and tolerance are both produced following preexposure. We have demonstrated sensitization to the positively reinforcing properties of cocaine by showing a reduced latency to acquisition of self-administration following intermittent exposures to low doses of cocaine. Tolerance to the positively reinforcing properties of cocaine is produced by higher dose preexposures to experienced rats. Thus, sensitization and tolerance are behavioral effects of repeated psychostimulant

Acknowledgements

This work was supported by grants DA 06825 and NO1 DA 3-8201. We gratefully acknowledge the technical help of Deborah Cullen and Brian Harwell. Helpful discussions with the Psychology 649 graduate class are also acknowledged.

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