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 (ICSS) to assess brain reward thresholds in rats during abstinence between intermittent long-access nicotine self-administration sessions.

Rats were implanted with ICSS 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 of nicotine intermittently (three days per week, 23 h/day) for seven 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 four 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.