Preclinical evidence for combining the 5-HT receptor agonist lorcaserin and varenicline as a treatment for nicotine dependence.

Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT receptor agonist has been approved in some countries to treat obesity. Based on preclinical and preliminary clinical evidence, lorcaserin may have potential to treat nicotine dependence. These experiments examined in rats the effects of combining varenicline (0.5 or 1 mg/kg) and lorcaserin (0.3, 0.6 and 1 mg/kg) on nicotine self-administration, reinstatement of nicotine seeking, responding for food and impulsive action. Both drugs alone reduced nicotine self-administration. Combining varenicline and 0.6 mg/kg lorcaserin reduced responding to a greater extent than either drug alone. In a relapse model, extinguished nicotine seeking was reinstated by a priming injection of nicotine and nicotine-associated cues. Reinstatement was reduced by varenicline (1 mg/kg) and by lorcaserin (0.3 mg/kg). Combining lorcaserin (0.3 mg/kg) with varenicline (0.5 or 1 mg/kg) reduced reinstatement to a greater degree than either drug alone. Both drugs had minimal effects on responding for food, alone or in combination. In the five-choice serial reaction time test, varenicline (0.5 or 1 mg/kg) increased impulsivity, measured as increased premature responding. This effect was reduced by lorcaserin (0.3 mg/kg). Plasma levels of varenicline or lorcaserin were not altered by co-administration of the other drug. Varenicline and lorcaserin have additive effects on nicotine self-administration, and on nicotine seeking. Lorcaserin prevents impulsivity induced by varenicline. This pattern of effects suggests that co-administration of varenicline and lorcaserin has potential as a treatment for nicotine dependence that may exceed the value of either drug alone.