Enhancing the translational relevance of the nicotine drug discrimination paradigm in rat model

Purpose: Drug discrimination has over the past 50 years been used as a tool for understanding mechanisms of drug addiction. As an operant conditioning-based technique, it is largely influenced by the specific rat training conditions such as training dose and pre-treatment time (PT). A nicotine training dose of 0.4 mg/kg at a PT of 15 min is widely used in nicotine discrimination studies. This dose in rats, however, produces a peak plasma concentration that comparatively exceeds the peak plasma concentration in tobacco smokers. Pharmacokinetic studies have shown that smaller doses of nicotine in rats produce peak plasma concentrations that closely resemble that in human cases. The question that remains is whether rats can be trained to discriminate these smaller doses of nicotine. Our goal was therefore to re-evaluate nicotine training conditions in rats and find that which is trainable and produces a translatable pharmacokinetic profile. Methods: Using a two-bar drug discrimination operant chamber, six rats trained to discriminate 0.4 mg/kg of nicotine tartrate at a PT of 15 min were tested at a fixed dose (0.4 mg/kg) of nicotine tartrate, but at different intervals after injection (0, 5, 15, 30, 60, 120, 240 min). This test was repeated but at a fixed dose of 0.1 mg/kg. Subsequently, a nicotine dose effect (0.01, 0.025, 0.05, 0.1, 0.2, 0.4 mg/kg) was conducted at a fixed pre-treatment time (5 min). Percentage of drug lever responses were recorded in all studies to measure substitution and analyzed using repeated measures ANOVA. Results: The time course study conducted with 0.4 mg/kg showed full substitution (100% nicotine lever response) at a PT of 5 min, with 240 min as the longest duration of action. The dose effect study at a fixed PT of 5 min showed full substitution at 0.1 mg/kg. At that, the discriminative effects of nicotine faded within 15 min. Conclusion: These findings show even at lower doses and shorter PTs, rats can perceive nicotine, and therefore can be trained using a lower nicotine dose of 0.1 mg/kg and at a shorter PT of 5 min (an onset that more closely resembles the onset in humans after smoking a cigarette compared to 15 min PT) Using these training conditions in place of the high training dose (0.4 mg/kg) and the long PT (15 min) provides a nicotine discrimination model of higher translational relevance to nicotine smoking studies in humans.