Emergence of Dormant Conditioned Incentive Approach by Conditioned Withdrawal in Nicotine Addiction

Background Nicotine is one of the determinants for the development of persistent smoking, and this maladaptive behavior is characterized by many symptoms, including withdrawal and nicotine seeking. The process by which withdrawal affects nicotine seeking is poorly understood. Method The impact of a withdrawal-associated cue on nicotine (.2 mg/kg)-conditioned place preference was assessed in male C57BL/6J mice ( n = 8–17/group). To establish a cue selectively associated with withdrawal distinct from those associated with nicotine, a tone was paired with withdrawal in their home cages; mice were chronically exposed to nicotine (200 μg/mL for 15 days) from drinking water in their home cages and received the nicotinic acetylcholine receptor antagonist mecamylamine (2.5 mg/kg) to precipitate withdrawal in the presence of a tone. The effect of the withdrawal-associated tone on nicotine-conditioned place preference was then evaluated in the place-conditioning apparatus after a delay, when nicotine-conditioned place preference spontaneously disappeared. Results A cue associated with precipitated withdrawal reactivated the dormant effect of nicotine-associated cues on conditioned place preference. This effect occurred during continuous exposure to nicotine but not during abstinence. Conclusions A conditioned withdrawal cue could directly amplify the incentive properties of cues associated with nicotine. This observation extends the contemporary incentive account of the role of withdrawal in addiction to cue–cue interaction.