Animal Models of the Preoccupation/Anticipation Stage of the Addiction Cycle

Stress-Induced Reinstatement and Conditioned Withdrawal

In human studies, stressful situations are the most likely triggers of relapse. Animal models of stress-induced reinstatement also show that stressors elicit strong recovery of extinguished drug-seeking behavior in the absence of any further drug availability (Erb et al., 1996). Acute intermittent footshock reinstates cocaine-seeking behavior after prolonged extinction, and this effect is as strong as a priming injection of cocaine. Such effects are observed even after a 4–6 week drug-free period and appear to be specific to drugs because food-seeking behavior is not reinstated. Stressors other than shock can effectively reinstate drug seeking, including food deprivation, restraint stress, tail pinch stress, swim stress, conditioned fear, social defeat stress, and administration of the α2-adrenergic receptor antagonist yohimbine (which activates the sympathetic nervous system).

The motivational aspects of withdrawal can also be conditioned, and conditioned withdrawal has been repeatedly observed in both opiate-dependent animals and humans. Cues paired with withdrawal can elicit a withdrawal-like response in numerous animal paradigms, ranging from the suppression of operant responding to conditioned place aversions (Shippenberg and Koob, 2002).

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