Evaluation of α-terpineol Attenuation of Precipitated Nicotine Withdrawal Behaviors in Mice

Abstract ID 92587 Poster Board 104 Tobacco is the leading cause of preventable death in the world, and tobacco-related illness accounts for 10% of worldwide mortality. Tobacco contains nicotine, a highly addictive alkaloid. Individuals attempting to quit smoking will likely experience affective and somatic withdrawal symptoms. FDA-approved smoking cessation drugs such as varenicline and bupropion have only a 20% abstinence rate after one year. Cannabinoids may be effective alternative treatments for medical conditions. The cannabinoid receptor 1 modulates the mesolimbic dopamine pathway that is dysregulated by nicotine use. Cannabinoid Receptor 2 may play an anti-inflammatory role against chronic stress-induced inflammation caused by nicotine hyperactivation of the hypothalamic-pituitary-adrenal axis. The terpene α-terpineol is an aromatic compound that is found in cannabis. Previous studies by our lab have found that α-terpineol may possess functional activity as a cannabinoid mixed agonist with preference for cannabinoid receptor 2, and that 56 mg/kg is a therapeutically active dose. Thus, we hypothesized that, in a mouse model of precipitated nicotine withdrawal, α-terpineol will attenuate associated withdrawal behaviors. Male and female C57BL/6J mice (n = 20 female, n = 19 male) received either nicotine (2 mg/kg, base) or saline vehicle subcutaneously four times daily for 13 days. On day 14, 30 min after the first nicotine or saline injection mice received either α-terpineol (56 mg/kg) or vehicle intraperitoneal injections. One hour after nicotine injections, and 30 min after α-terpineol injections, all mice received the non-selective nicotinic acetylcholine receptor antagonist mecamylamine (3 mg/kg, intraperitoneal). Mice were immediately placed in locomotion chambers to measure locomotor behavior as well as to record video of withdrawal behaviors for later somatic sign hand scoring, and then underwent the light-dark box test for potential anxiolytic-like effects. Our data suggests no overall treatment effect on locomotion speed but demonstrates a significant effect of nicotine on time spent immobile (two-way ANOVA p = 0.012). All animals spent more time in the dark zone of the light/dark box (two-way ANOVA p < 0.001), with no overt effect of nicotine withdrawal or α-terpineol on anxiety-like behavior. Nicotine had a significant overall effect on grooming frequency (two-way ANOVA p = 0.029). The Nicotine + Vehicle group displayed increased grooming duration compared to the Saline + Vehicle control group (p = 0.044).The Nicotine + α-terpineol group displayed a strong sex-related trend for a reduced total withdrawal score compared to the Nicotine + Vehicle group. The increased immobility of nicotine treated mice may indicate a depressive-like state due to nicotine withdrawal, although further studies are needed to support this. The terpene α-terpineol may produce sex-related attenuation of nicotine withdrawal somatic behaviors. This study in C57BL/6J mice suggests α-terpineol, and other cannabinoid receptor agonists, may be useful therapeutics to alleviate precipitated nicotine withdrawal somatic and affective behaviors.