Marvin D. Krank

The role of predrug signals in morphine analgesic tolerance: support for a Pavlovian conditioning model of tolerance.

According to a model of morphine tolerance, which emphasizes Pavlovian conditioning principles, tolerance results from an association between predrug environmental cues and the systemic effects of the drug. To assess this model, groups of rats were administered morphine on either three or nine occasions, with a complex environmental stimulus either paired or not paired with each injection. Control groups had equivalent experience with the environmental cue and injection procedure, but the injected substance was physiological saline. Subsequently, the analgesic effect of the opiate was tested in all subjects following administration of the drug in conjunction with the environmental cue. As expected on the basis of the conditioning model of tolerance, subjects with a pretest history of paired morphine administrations displayed analgesic tolerance, but subjects with a pretest history of unpaired administration displayed no evidence of such tolerance. The results suggest that prior demonstrations that the display of morphine tolerance is specific to the drug administration environment may be readily interpreted by a conditioning analysis of tolerance.

Structural, concurrent, and predictive validity of the Substance Use Risk Profile Scale in early adolescence

A brief personality risk profile (23 items), the Substance Use Risk Profile Scale was tested for concurrent and predictive validity for substance use in 1139 adolescents (grades 8-10) from a mid-sized city in western Canada. The SURPS was administered in two waves of a longitudinal study separated by 12 months (2003-04). As expected, four subscales were supported by confirmatory factor and metric invariance analysis. In regression analysis, three subscales, hopelessness, impulsivity, and sensation seeking, were positively related to current and future use; while one, anxiety sensitivity, was negatively related. Findings suggest clinical utility for screening adolescents at risk for substance use.

Anticipation of Pharmacological and Nonpharmacological Events: Classical Conditioning and Addictive Behavior

Typically, pharmacological phenomena such as tolerance, sensitization, and dependence have been viewed as resulting from the operation of feedback mechanisms: pharmacologically disturbed homeostatic functioning is countered by compensatory responses that restore physiological equilibrium. We summarize the results of research indicating that feedforward mechanisms (i.e., regulatory responses made in anticipation of a drug) also importantly contribute to drug effects. Such feedforward mechanisms operate on the basis of Pavlovian conditioning principles. We also discuss the role of such physiological feedforward mechanisms in areas that are not primarily pharmacological: immunology, exercise physiology, and stress.

Conditional hyperalgesia is elicited by environmental signals of morphine.

Groups of rats were administered a placebo and tested for sensitivity to “hot plate” stimulation in the presence of an environmental stimulus which had, in the past, either been paired or unpaired with either morphine or saline injections. Paired morphine groups showed significantly more reactivity to the aversive stimulation than the unpaired morphine groups and the saline control groups. Unpaired morphine groups did not differ from saline control groups. This conditional hyperalgesia elicited by a cue paired with morphine cannot be interpreted as the result of differential pretest assessment experience or novelty.

Pavlovian conditioning with ethanol: sign-tracking (autoshaping), conditioned incentive, and ethanol self-administration.

BACKGROUND Conditioned incentive theories of addictive behavior propose that cues signaling a drugs reinforcing effects activate a central motivational state. Incentive motivation enhances drug-taking and drug-seeking behavior. We investigated the behavioral response to cues associated with ethanol and their interaction with operant self-administration of ethanol. METHODS In two experiments, rats received operant training to press a lever for a sweetened ethanol solution. After operant training, the animals were given Pavlovian pairings of a brief and localized cue light with the sweetened ethanol solution (no lever present). Lever pressing for ethanol was then re-established, and the behavioral effects of the cue light were tested during an ethanol self-administration session. RESULTS The conditioned responses resulting from pairing cue lights with the opportunity to ingest ethanol had three main effects: (1) induction of operant behavior reinforced by ethanol, (2) stimulation of ethanol-seeking behavior (magazine entries), and (3) signal-directed behavior (i.e., autoshaping, or sign-tracking). Signal-directed behavior interacted with the other two effects in a manner predicted by the location of the cue light. These conditioned responses interact with operant responding for ethanol reinforcement. CONCLUSIONS These findings demonstrate the importance of Pavlovian conditioning effects on ethanol self-administration and are consistent with conditioned incentive theories of addictive behavior.

Impulsivity, impulsive and reflective processes and the development of alcohol use and misuse in adolescents and young adults

This paper contrasts dual-process and personality approaches in the prediction of addictive behaviors and related risk behaviors. In dual-process models, behavior is described as the joint outcome of qualitatively different “impulsive” (or associative) and “reflective” processes. There are important individual differences regarding both types of processes, and the relative strength of both in a specific situation is influenced by prior behavior and state variables (e.g., fatigue, alcohol use). From this perspective, a specific behavior (e.g., alcohol misuse) can be predicted by the combined indices of the behavior-related impulsive processes (e.g., associations with alcohol), and reflective processes, including the ability to refrain from a motivationally salient action. Personality approaches have reported that general traits such as impulsivity predict addictive behaviors. Here we contrast these two approaches, with supplementary analyses on four datasets. We hypothesized that trait impulsivity can predict specific risky behaviors, but that its predictive power disappears once specific behavior-related associations, indicators of executive functioning, and their interaction are entered into the equation. In all four studies the observed interaction between specific associations and executive control (EC) was robust: trait impulsivity did not diminish the prediction of alcohol use by the interaction. Trait impulsivity was not always related to alcohol use, and when it was, the predictive power disappeared after entering the interaction between behavior-specific associations and EC in one study, but not in the other. These findings are interpreted in relation to the validity of the measurements used, which leads to a more refined hypothesis.

Effect of partial reinforcement on tolerance to morphine-induced analgesia and weight loss in the rat

The effect of partial reinforcement on the development of tolerance to morphine-induced analgesia and weight loss was examined. Groups of rats were presented a distinctive set of environmental cues on several occasions. For one group of rats, morphine (40 mg/kg) was injected each time the cues were presented (morphine--continuous reinforcement). For a second group of rats, morphine was injected only following one of every four cue presentations (morphine--partial reinforcement). Two additional groups were injected with only saline, one on the continuous reinforcement schedule and one on the partial reinforcement schedule. Results demonstrated less tolerance to morphine in the partially reinforced morphine-injected rats than in continuously reinforced morphine-injected rats. Unlike other demonstrations of a tolerance-retarding effect of partial reinforcement, the present results could not have resulted from nonassociative factors related to differential novelty, stress, or practice. Clinical implications for the tolerance-retarding effect of partial reinforcement are discussed.

Context Effects on Alcohol Cognitions

This article summarizes a symposium on context and alcohol-related cognitions presented at the 2004 Annual Meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada. The studies reported here examine how the manipulation of contextual variables influences the availability of alcohol outcome expectancies and implicit memories for alcohol associations. The symposium illustrates the range of context variables and shows some of the potential impact of retrieval on cognitions that predict alcohol use. Two of the studies explore naturalistic drinking contexts: one examines the impact of stress induction, and one assesses within survey question placement effects. A variety of measures of alcohol cognitions were used. The results demonstrate that alcohol cognitions are more accessible in alcohol-related contexts. Moreover, availability of alcohol associations and expectancies depended on individual differences. These results underscore the potential value of memory processes in the retrieval and measurement of alcohol cognitions. The findings have direct implications for improving methods of predicting alcohol use and in understanding the role of alcohol cognitions in various contexts associated with alcohol use.

Conditioned hyperalgesia depends on the pain sensitivity measure

Conflicting reports about the acquisition of conditioned hyperalgesia during the development of conditioned morphine tolerance have led researchers to suggest that tolerance reflects a reduction of stimulus processing rather than a compensatory response interaction. I tested conditioned hyperalgesia on both the hot-plate and tail-flick tests in the same animals. In accordance with previous reports, the tail-flick responses in drug-free animals failed to reveal a conditioned compensatory hyperalgesia. Conditioning effects in the tail-flick test were found only when the animals were challenged with a low dose of morphine. However, the hot-plate responses in drug-free animals replicated earlier demonstrations of conditioned hyperalgesia. The results suggest that the measurement of conditioned responses in drug-free animals depends on characteristics of the assessment procedure. These findings are consistent with accounts of morphine tolerance that depend on compensatory response interactions.

Modulation of tolerance to the lethal effect of morphine by extinction

In contrast with previous demonstrations that tolerance to the analgesic and thermic effects of morphine can be extinguished by repeated placebo administrations, Sklar and Amit (1978, Behavioral Biology, 22, 509–514) purportedly demonstrated that tolerance to morphine-induced mortality is not affected by such an extinction procedure. The results of the present experiment demonstrated that rats administered a fatal dose of morphine following a tolerance-extinction procedure died more quickly than rats with the same pharmacological history but without the extinction experience. The results suggest that learning is involved in tolerance to lethal doses of morphine.