Nicotine Self-Administration with Tobacco Flavor Additives in Male Rats

Document Type


Publication Date



Introduction: Nicotine can robustly increase responding for conditioned reinforcers (CRs), stimuli that acquire reinforcing properties based on association with primary reinforcers. Menthol and licorice are tobacco flavoring agents also found in sweet foods (eg, candy and ice cream), making them putative CRs before they are consumed in tobacco. We sought to determine if intravenous self-administration (IVSA) of nicotine was enhanced by the inclusion of oral tobacco flavor CRs. Methods: Menthol (160 or 320 μM) or licorice root extract (0.1% or 1%) were established as CRs (paired with 20% sucrose) or "neutral" stimuli (paired with water) in separate groups. During subsequent IVSA tests, nicotine was delivered in conjunction with oral presentations of the CR. Results: In experiment 1, a menthol CR significantly shifted the peak nicotine dose from 15 μg/kg/infusion (Neutral group) to 3.25 μg/kg/infusion (CR group). In experiment 2, a menthol CR significantly increased operant licks for nicotine (3 μg/kg/infusion) relative to control groups. In experiment 3, both licorice and menthol CRs significantly increased operant licks for nicotine (7.5 μg/kg/infusion) relative to an "inactive" sipper. The licorice CR increased nicotine IVSA in proportion to the strength of the flavor, but both menthol concentrations increased nicotine IVSA to a similar extent. Conclusion: Tobacco flavor additives with conditioned reinforcing properties promote acquisition of nicotine self-administration at low unit doses and may have robust impact on tobacco consumption when nicotine yield is low. Implications: Tobacco flavor additives are found in rewarding foods (eg, ice cream) and gain palatability based on associations with primary rewards (eg, sugar) making them "conditioned reinforcers." Nicotine increases the motivation for flavor conditioned reinforcers and the present studies show that tobacco flavor additives can interact with nicotine to promote more nicotine self-administration. The interaction between flavors additives and nicotine may promote nicotine exposure and subsequently dependence.