Progressive withdrawal-related reward deficits after nicotine self-administration in rats

Tobacco use disorder is a chronic relapsing condition characterized by withdrawal symptoms following smoking cessation. Smoking cessation leads to anhedonia, which is a reduced ability to experience pleasure that contributes to relapse. To investigate the time course of withdrawal-related changes in reward function, we used intracranial self-stimulation to assess brain reward thresholds in rats during abstinence between intermittent long-access nicotine self-administration sessions.

Rats were implanted with intracranial self-stimulation electrodes to assess reward function and intravenous catheters for nicotine self-administration. Elevations in brain reward thresholds reflect decreased sensitivity to rewarding electrical stimuli, a preclinical measure of anhedonia-like behavior. Male rats self-administered 0.06 mg/kg per infusion of nicotine intermittently (3 days per week, 23 h per day) for 7 weeks. Brain reward thresholds were assessed at multiple time points between self-administration sessions during weeks 1-7.

Elevations in thresholds were not observed during the first 4 weeks of nicotine self-administration. However, the brain reward thresholds were elevated in weeks 5 and 7, at least 12 h after nicotine self-administration, indicating progressive development of withdrawal-related alterations in reward function. The nicotinic receptor antagonist mecamylamine precipitated similar threshold elevations, supporting the development of nicotine dependence-related neuroadaptations.

These findings indicate that changes in reward function consistent with anhedonia emerge gradually during the course of nicotine self-administration. Therefore, early behavioral or pharmacological interventions may help prevent the development of withdrawal-related anhedonia and reduce the risk of tobacco use disorder.

This study shows that anhedonia-like reward deficits emerge gradually during intermittent long-access nicotine use in male rats, indicating a critical window in which dependence begins to develop. These findings suggest that reward deficits do not contribute to nicotine intake during the earliest phase of use but may promote continued use and relapse after prolonged exposure. The emergence of withdrawal signs may make it harder to quit using nicotine products. From a public-health perspective, identifying when withdrawal symptoms first arise can inform earlier, more effective interventions to prevent the progression of tobacco use disorder.