Histamine H1 antagonist treatment with pyrilamine reduces nicotine self-administration in rats

Nicotine has been definitively shown to be critically involved in the neural bases of tobacco addiction. However, nicotine releases a wide variety of neurotransmitters. Nicotine-induced dopamine release has been shown to play a key role in facilitating nicotine self-administration. Other transmitter systems may also play important roles in the pharmacological effects of nicotine and may provide important leads for combating nicotine self-administration. Clozapine, an antipsychotic drug, which blocks a variety of different transmitter receptors including serotonin 5HT2 and histamine H1 receptors, has been found to decrease smoking. Previously we found that the serotonin 5HT2 antagonist, ketanserin, significantly reduced nicotine self-administration. In the current study, we assessed histamine H1 receptor interaction with nicotine self-administration. Young adult female Sprague–Dawley rats were fitted with IV catheters and trained to self-administer nicotine (0.03 mg/kg/infusion). Acute doses of 40 mg/kg of pyrilamine, a histamine H1 antagonist, significantly reduced nicotine self-administration. We also found that repeated injections (20 mg/kg) or chronic infusion via osmotic minipumps (50 mg/kg/day) of pyrilamine also significantly decreased nicotine self-administration. The peripherally restricted H1 antagonist ebastine was ineffective in reducing nicotine self-administration, pointing to central H1 receptor blockade as key for the effectiveness of pyrilamine. H1 antagonists may be a promising avenue to explore for new treatments to aid smoking cessation.