Explaining the escalation of drug use in substance dependence: models and appropriate animal laboratory tests.
Pharmacology. 2007-01-01; 80(2-3): 65-119
DOI: 10.1159/000103923
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1. Pharmacology. 2007;80(2-3):65-119. Epub 2007 Jun 14.
Explaining the escalation of drug use in substance dependence: models and
appropriate animal laboratory tests.
Zernig G(1), Ahmed SH, Cardinal RN, Morgan D, Acquas E, Foltin RW, Vezina P,
Negus SS, Crespo JA, Stöckl P, Grubinger P, Madlung E, Haring C, Kurz M, Saria A.
Author information:
(1)Experimental Psychiatry Unit, Department of Psychiatry, Medical University
Innsbruck, Innsbruck, Austria.
Escalation of drug use, a hallmark of drug dependence, has traditionally been
interpreted as reflecting the development of tolerance to the drug’s effects.
However, on the basis of animal behavioral data, several groups have recently
proposed alternative explanations, i.e. that such an escalation of drug use might
not be based on (1) tolerance, but rather be indicative of (2) sensitization to
the drug’s reinforcing effect, (3) reward allostasis, (4) an increase in the
incentive salience of drug-associated stimuli, (5) an increase in the reinforcing
strength of the drug reinforcer relative to alternative reinforcers, or (6) habit
formation. From the pharmacological perspective, models 1-3 allow predictions
about the change in the shape of drug dose-effect curves that are based on
mathematically defined models governing receptor-ligand interaction and signal
transduction. These predictions are tested in the present review, which also
describes the other currently championed models for drug use escalation and other
components of apparent ‘reinforcement’ (in its original meaning, like ‘tolerance’
or ‘sensitization’, a purely descriptive term). It evaluates the animal
experimental approaches employed to support or prove the existence of each of the
models and reinforcement components, and recapitulates the clinical evidence,
which strongly suggests that escalation of drug use is predominantly based on an
increase in the frequency of intoxication events rather than an increase in the
dose taken at each intoxication event. Two apparent discrepancies in animal
experiments are that (a) sensitization to overall reinforcement has been found
more often for psychostimulants than for opioids, and that (b) tolerance to the
reinforcing and other effects has been observed more often for opioids than for
cocaine. These discrepancies are resolved by the finding that cocaine levels seem
to be more tightly regulated at submaximum reinforcing levels than opioid levels
are. Consequently, animals self-administering opioids are more likely to expose
themselves to higher above-threshold doses than animals self-administering
psychostimulants, rendering the development of tolerance to opioids more likely
than tolerance to psychostimulants. The review concludes by making suggestions on
how to improve the current behavioral experimental approaches.
Copyright (c) 2007 S. Karger AG, Basel.
DOI: 10.1159/000103923
PMID: 17570954 [Indexed for MEDLINE]