Importance Reward-related disturbances after withdrawal from nicotine are hypothesized to contribute to relapse to tobacco smoking but mechanisms underlying and linking such processes remain largely unknown. Objective To determine whether withdrawal from nicotine affects reward responsiveness (ie, the propensity to modulate behavior as a function of prior reinforcement experience) across species using translational behavioral assessments in humans and rats. Design, Setting, Participants Experimental studies used analogous reward responsiveness tasks in both humans and rats to examine whether reward responsiveness varied in (1) an ad libitum smoking condition compared with a 24-hour acute nicotine abstinence condition in 31 human smokers with (n?=?17) or without (n?=?14) a history of depression; (2) rats 24 hours after withdrawal from chronic nicotine (n?=?19) or saline (n?=?20); and (3) rats following acute nicotine exposure after withdrawal from either chronic nicotine or saline administration

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