Association between nicotine withdrawal and reward responsiveness in humans and rats

Abstract

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.

Main outcomes and measures: Performance on a reward responsiveness task under nicotine and nonnicotine conditions.

Results: In both human smokers and nicotine-treated rats, reward responsiveness was significantly reduced after 24-hour withdrawal from nicotine (P < .05). In humans, withdrawal-induced deficits in reward responsiveness were greater in those with a history of depression. In rats previously exposed to chronic nicotine, acute nicotine reexposure long after withdrawal potentiated reward responsiveness (P < .05).

Conclusions and relevance: These findings across species converge in suggesting that organisms have diminished ability to modulate behavior as a function of reward during withdrawal of nicotine. This blunting may contribute to relapse to tobacco smoking, particularly in depression-vulnerable individuals, to reinstate responsiveness to natural rewards and to experience potentiated nicotine-induced reward responsiveness. Moreover, demonstration of behavioral homology across humans and rodents provides a strong translational framework for the investigation and development of clinical treatments targeting reward responsiveness deficits during early withdrawal of nicotine.

Figure 1. SCHEMATIC REPRESENTATION OF THE HUMAN (A) AND RAT (B) RESPONSE BIAS PROBABILISTIC REWARD TASK

(A) In each trial, human subjects were asked to choose whether a short (11.5 mm) or long (13 mm) mouth (briefly flashed for 100 ms) had been presented on a mouthless schematic face by pressing a key (e.g., ‘z’ for short, ‘/’ for long). In each of the 3 blocks (100 trials/block), the mouth stimuli were pseudo-randomly presented in an equal number. For some of the correct trials, the participant received a monetary reinforcement (5 cents). Unbeknownst to the participants, the reinforcement schedule was designed to favor one mouth length (i.e., rich) over the other (i.e., lean) in a 3:1 ratio. Only 40 correct trials were rewarded in each block (30 rich, 10 lean). Participants were instructed that the goal of the task was to win as much money as possible, and that not all correct responses would receive a reward feedback. Response bias, our main variable of interest, was calculated as: log b = ½ log [(Rich_Correct * Lean_Incorrect)/(Rich_Incorrect * Lean_Correct)]. As evident from the formula, a high response bias emerges when participants tend to correctly identify the rich stimulus and misclassify the lean stimulus. Discriminability, which is the degree to which the subject can distinguish the two target stimuli and is a measure of task difficulty, was used as a control variable and was calculated as: log d = ½ log [(Rich_Correct * Lean_Correct)/(Rich_Incorrect * Lean_Incorrect)]. These formulae include the addition of 0.5 to each cell, to allow for estimation in cases with a zero cell. Accuracy (percentage hit rate) and reaction time in response to the rich and lean stimuli represented additional secondary behavioral variables. (B) Rats were food restricted and trained to discriminate between two tones varying in duration (5 kHz, 60 dB, 0.5 or 2 s) by pressing one of the two levers associated with each tone. Tone durations and lever sides were counterbalanced across subjects and tones were presented in a random order over 100 trials. Each trial was initiated with presentation of a tone, after which levers were extended and rats had a 5 s limited hold period to respond. In each trial, correct identification of tones resulted in a single 45 mg food pellet (Test Diet 5TUM; Richmond, IN, USA). Both levers retracted after a correct, incorrect, or omitted response, followed by a variable intertrial interval (5-8 s). Rats were trained daily until achieving at least 70% accuracy for five consecutive days. Rats that were successful in discriminating the tones were then trained with tone durations of 0.7 and 1.8 s for two days and tone durations of 0.9 and 1.6 s for two days. During a subsequent test session, the ambiguous tone durations (i.e., 0.9 and 1.6 s) were reinforced for 60% and 20% of correct responses (counterbalanced across subjects) over 100 trials, which is identical to the 3:1 reinforcement ratio used in the human Response Bias Probabilistic Reward Task. Response bias, the primary variable, as well as the three secondary behavioral variables (discriminability, accuracy and reaction time) were computed using identical formulae as for the human experimental data.

Figure 2. WITHDRAWAL OF NICOTINE IS ASSOCIATED WITH BLUNTED REWARD RESPONSIVENESS IN HUMANS (A) AND RATS (B)

(A) Human subjects (N=31) developed a response bias towards the more frequently rewarded (“rich”) stimulus when smoking at their usual rate. By contrast, 24-hour abstinence from chronic tobacco smoking significantly decreased response bias; (B) Control rats administered saline developed a response bias towards the more frequently rewarded (“rich”) stimulus. By contrast, withdrawal from chronic nicotine administration significantly decreased response bias; *p<0.05.

Figure 3. NICOTINE ABSTINENCE AND REWARD RESPONSIVENESS IN HUMANS WITHOUT (N = 14, A) AND WITH (N = 17, B) A HISTORY OF DEPRESSION

24-hour abstinence from chronic tobacco smoking was associated with decreased response bias in Block 3 for smokers with a history of depression relative to smokers without a history of depression (*p<0.05). Moreover, unlike smokers without a history of depression (A), those with such history failed to develop a response bias towards the more frequently rewarded stimulus (B).

Figure 4. ACUTE NICOTINE-INDUCED CHANGES IN REWARD RESPONSIVENESS IN RATS PREVIOUSLY EXPOSED TO CHRONIC NICOTINE (N = 17) OR SALINE (N = 15)

Acute nicotine re-exposure in rats previously treated with chronic nicotine significantly potentiated response bias compared to acute saline exposure and compared to acute nicotine exposure in rats previously treated with chronic saline. Moreover, acute nicotine treatment did not affect reward responsiveness in previously nicotine-naïve rats. * Different from chronic nicotine-treated rats administered 0 and 0.125 mg/kg acute nicotine (p<0.05); # Different from chronic saline-treated rats administered the same acute nicotine dose (p<0.01).