Pavlovian psychopharmacology: The associative basis of tolerance.

Abstract

The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRs) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. If the usual predrug cues are presented in the absence the drug, the unopposed CCRs are evident as withdrawal symptoms. Recent findings elucidate intercellular and intracellular events mediating CCRs and indicate the importance of internal stimuli (pharmacological cues and interoceptive cues inherent in self-administration) to the acquisition of drug tolerance and the expression of withdrawal symptoms. Early chroniclers of drug effects noted that responsivity to drugs often decreased as a function of experience with the drug. For example, in 1612, Jean Mousin, physician to the King of France, wondered why individuals sometimes became progressively more sober while they were continuing to drink alcoholic beverages. Although the term tolerance was not used until some years later, it appears that Mousin observed the phenomenon now termed acute tolerance-decreased responsiveness to a drug within the course of a single administration (Kalant, 1998). Acute Tolerance and Withdrawal Acute tolerance has been investigated extensively with respect to ethanol (e.g., see LeBlanc, Kalant, & Gibbins, 1975) as well as other drugs, such as opiates. For example, over the course of a single, long administration of morphine, accomplished by gradual infusion via an implanted morphine pellet, the analgesic effect of the drug decreases (e.g., see Tilson, Rech, & Stolman, 1973; Wei & Way, 1975). The existence of acute tolerance is evidence that pharmacological stimulation initiates adaptive responses that compensate for the primary drug effect (

Disrupting the memory of places induced by drugs of abuse weakens motivational withdrawal in a context-dependent manner

“…In fact, disrupting the former also weakens the latter. This outcome has important implications for developing therapeutic strategies to treat or prevent addiction, and in line with previous literature, underscores the importance of context and cue-dependent conditioning in eliciting morphine dependence and motivational withdrawal (24)(25)(26)(27).…”

Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

“…Core body temperature was selected as the dependent variable because it can be measured accurately, continuously and non-invasively and because it reflects the operation of a well studied, centrally regulated control system. This is important because regulatory principles are at the foundation of numerous influential theories relevant to drug addiction (e.g., Solomon 1980;Poulos and Cappell 1991;Koob and LeMoal 1997;Siegel et al 2000). Our drug choice was influenced by the ease, speed and accuracy with which steadystate drug concentrations could be achieved and maintained.…”

The role of injection cues in the production of the morphine preexposure effect in taste aversion learning

“…Specifically, morphine was administered subcutaneously in the present studies and is assumed to have a gradual, slow onset of effect, which would overshadow the drug injection cues, subsequently producing the preexposure effect via a pharmacological mechanism (i.e., see Kim et al, 1999;Siegel et al, 2000). If this is the case, degrading the association of the injection cues with morphine's effects by administering extinction injections would not be expected to alter the preexposure effect.…”