Animal Models of the Withdrawal/Negative Affect Stage of the Addiction Cycle

Conditioned Place Aversion, Disrupted Operant Responding, and Drug Discrimination

The aversive stimulus effects of withdrawal can be measured using a variant of the conditioned place conditioning procedure, termed conditioned place aversion. When studying opioid dependence, one method is to precipitate or induce withdrawal by administering a competitive opioid receptor antagonist, such as naloxone (Hand et al., 1988). Although naloxone itself can produce a conditioned place aversion in nondependent rats, the dose required to produce such a place aversion decreases significantly in dependent rats. Place aversions have also been observed with precipitated nicotine withdrawal and acute spontaneous alcohol withdrawal, in which the animal is simply no longer allowed access to alcohol. The response-disruptive effects of drug withdrawal in operant schedules have also been associated with an “amotivational” state of withdrawal, in which an animal is less motivated or willing to perform the task (Figure 3.10).

Drug discrimination has also been used to characterize both specific and nonspecific aspects of withdrawal. For alcohol withdrawal, for example, animals have been trained to discriminate between saline and the anxiogenic (anxiety-inducing) drug pentylenetetrazol (Gauvin and Holloway, 1991). Generalization to a convulsant-like cue during alcohol withdrawal suggested that the withdrawal syndrome has an anxiogenic-like component. Opiate-dependent animals have been trained to discriminate an opioid receptor antagonist from saline. This generalization to an opioid antagonist provided a general nonspecific measure of the intensity of opiate withdrawal and its time course.

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