Interactions Between Endocannabinoid and Serotonergic Systems in Mood Disorders Caused by Nicotine Withdrawal

Introduction: Endocannabinoid and serotonin systems are implicated in mechanisms underlying depression-like symptoms. Involvement of serotonin in mood disorders occurring after smoking cessation has been observed. We studied the interactions between endocannabinoid and serotonergic systems in mood and behavioral disorders caused by nicotine cessation. The effects of the endocannabinoid transport inhibitor AM404 and the cannabinoid receptor 1 antagonist AM251 in a nicotine- dependent rodent model were investigated. Methods: Dependence was induced by subcutaneous injections of nicotine (2 mg/kg, 4 injections daily) for 15 consecutive days in mice. Animals treated with AM404 or AM251 were tested for locomotor activity and abstinence signs 24 hr after nicotine withdrawal and in forced swimming test (FST) at different times: immediately after last nicotine injection (t = 0) and 15 and 30 days after nicotine withdrawal. In nicotine-dependent mice treated with AM404 or AM251, expression of diencephalic serotonin receptor 1A (5-HT1A) was also measured. Effects of AM404, AM251, and WAY 100635 (5-HT1A receptor antagonist) in mice subjected to FST were evaluated. Results: A decrease in diencephalic 5-HT1A levels was observed in mice previously injected with nicotine. In the same animals, AM251 caused (0.5–2 mg/kg) a significant decrease of abstinence signs and AM404 (0.5–2 mg/kg) provoked a significant dose-dependent reduction in immobility time in the FST. Either AM251 or WAY 100635 antagonized anti-immobility effects of AM404. Conclusions: Data indicate the existence of a link between serotonergic and endocannabinoid systems in the mechanisms underlying mood disorders caused by nicotine abstinence and suggest that these interactions are potential targets for pharmacological aid in smoking cessation.