Preoccupation/Anticipation Stage

Nicotine-, Cue-, and Stress-Induced Reinstatement

Nicotine, cues, and contexts will cause reinstatement of nicotine seeking behavior in mice and rats that have been trained to intravenously self-administer nicotine and then subjected to extinction. In rats, the visual cues paired with intravenous nicotine self-administration appear to be as important as nicotine in sustaining a high rate of responding once self-administration has been established. Similarly to other drugs of abuse, stress and intermittent footshock caused the reinstatement of nicotine seeking behavior in rats trained to intravenously self-administer nicotine and subsequently extinguished.

The cue-induced reinstatement of nicotine seeking in mice and rats that have been trained to intravenously self-administer nicotine self-administration and then subjected to extinction is blocked by drugs that block nicotinic receptors, most notably varenicline (an α4β2 nAChR antagonist that is on the market for the treatment of nicotine addiction). The cue-induced reinstatement of nicotine seeking in mice and rats that have been trained to intravenously self-administer nicotine self-administration and then subjected to extinction is also blocked by drugs that block dopamine receptors, cannabinoid receptors, metabotropic and ionotropic glutamate receptors, opioid receptors, and serotonin receptors.

Nicotine withdrawal in animals treated with chronic nicotine results in lower corticosterone levels during restraint stress, suggesting subsensitivity of the hypothalamic–pituitary–adrenal axis to stress, similar to other drugs of abuse and to parallel studies that have reported the sensitization of extrahypothalamic CRF systems, suggesting a key role for activation of the brain stress systems during the preoccupation/anticipation stage of the addiction cycle. Stress-induced reinstatement of nicotine seeking in rodents that have been trained to intravenously self-administer nicotine and then subjected to extinction has been shown to be blocked by CRF receptor antagonists, an α2 adrenergic receptor agonist, and a κ opioid receptor antagonist.

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