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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.)

Escalation of drug use by addicts has traditionally been interpreted as tolerance to the drug's effects. On the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e., that such an escalation of drug dose might not be based on tolerance but rather be indicative of (i) sensitization to the reinforcing effect or the incentive salience of the drug of abuse or (ii) shifts in baseline mood, i.e., allostasis. In the present study, the emergence of opioid tolerance or sensitization during the progression of opioid dependence was assessed by comparing the methadone doses that were initially required to alleviate the opioid withdrawal symptoms of intravenous opioid users who presented for detoxification upon 3-7 consecutive admissions over the course of up to 84 months. Upon the second admission, the 48 surveyed male patients needed 115 +/- 6% (p = 0.012) and the 32 female patients needed 121 +/- 12% (p = 0.01) of the methadone dose required upon the first admission. Upon the third admission, the respective values were 121 +/- 8% (males; p = 0.013) and 111 +/- 12% (females; n.s.), and upon the fourth admission, 125 +/- 14% (males; p = 0.026) and 131 +/- 14 (females; p = 0.01). Inter-admission intervals averaged 14 +/- 1 months (n = 135) for males and 13 +/- 1 months (n = 91) for females and were not significantly different across consecutive admissions, suggesting that tolerance did not develop faster upon repetition of abuse-withdrawal cycles. In conclusion, the intravenous opioid users surveyed in the present study developed only very moderate tolerance during the repeated abuse-detoxification cycles that were typical for their disease progression. The present data do not support the notion that sensitization to the opioids' reinforcing effects occurred in this naturalistic clinical sample., (Copyright 2006 S. Karger AG, Basel.)