Combination Therapies of the Neurotransmitter-Targeting Drugs Dextromethorphan, Pyrilamine and Lorcaserin in a Rat Model of Nicotine Addiction

Given the current epidemic of nicotine dependence, the study of interactions between neurotransmitter receptor-targeting molecules to discover possible new forms of smoking cessation treatment is of great importance. Previous studies have shown that the neurotransmitter receptor-targeting drugs pyrilamine (an H1 histamine antagonist), lorcaserin (a selective 5-HT2C serotonin agonist), and dextromethorphan (an NMDA glutamate antagonist) can be used to significantly reduce IV nicotine self-administration in rats. Given the potential for enhanced success with smoking cessation treatment using this novel approach, the current studies were conducted to determine how 1) dextromethorphan and pyrilamine and 2) dextromethorphan and lorcaserin interact when administered together to reduce nicotine self-administration in rat models. Young-adult female rats were fitted with jugular IV catheters and trained to self-administer a nicotine infusion dose. Rats were given varying doses of both dextromethorphan and pyrilamine or dextromethorphan and lorcaserin before each self-administration session to test an acute dose-effect function and drug interactions. No significant interactions were observed between dextromethorphan and pyrilamine. Treatment with the high dose of lorcaserin showed significant reductive interactions with the low dose of dextromethorphan compared to saline injection. Treatment with the low dose of lorcaserin also showed significant reductive interaction with the high dose of dextromethorphan. All three drugs were also observed to decrease locomotor activity and food pellet self-administration in a dose-dependent manner. These results are encouraging and suggest that a combination therapy of dextromethorphan and lorcaserin may have potential as a novel smoking cessation treatment, although further research is required.