In vivo modulation of the behavioral effects of nicotine by the coumarins xanthotoxin, bergapten, and umbelliferone

RATIONALE: Nicotine, a dominant alkaloid found in tobacco, is responsible for physical dependence, as well as addiction to cigarette smoking; consequently, smoking cessation is a very difficult process. Hepatic cytochrome P-450 2A6 (CYP2A6) is involved in the 70–80 % of the initial metabolism of nicotine and its co-metabolites. As this metabolism is slowed by inhibitors of CYP2A6, this kind of enzymatic inhibition has been proposed as a novel target for smoking cessation. OBJECTIVES: Nicotine administered alone improved memory acquisition and consolidation as well as exerted antidepressive activity in animal models. These effects persist for 24 h. However, they are completely extinguished 48 h after administration. METHODS: To investigate if the coumarins prolong the behavioral effects of nicotine, the forced swimming test (FST)—animal models of depression, and passive avoidance (PA) test—memory and learning paradigm were used. RESULTS: This study revealed that three CYP2A6 inhibitors: two furanocoumarins, xanthotoxin (15 mg/kg) and bergapten (25 mg/kg), and the simple coumarin umbelliferone (25 mg/kg), prolonged the antidepressive and procognitive effects of nicotine. CONCLUSIONS: These natural products may offer a new approach to the treatment of nicotinism as antidepressant and memory improvement actions are one of the main factors of nicotine dependence.