Browsing by Author "Kusi-Boadum, Nana Kofi"
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Item Enhancing the translational relevance of the nicotine drug discrimination paradigm in rat model(2023) Kusi-Boadum, Nana KofiPurpose: 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.Item Impact of nicotine's autonomic effect on nicotine's discriminative stimulus(2024-03-21) Kusi-Boadum, Nana Kofi; Forster, MichaelPurpose: As the leading cause of preventable death, tobacco smoking has inspired years of research into the mechanisms of addiction and pharmacological targets for smoking cessation. Nicotine, an active psychostimulant in tobacco, activates the brain's reward system and drives the addiction to smoking via dopaminergic neurons. Although some studies have suggested that the autonomic effects of psychostimulants may independently serve as cues for the release of dopamine in the brain, it has not been demonstrated behaviorally. A previous locomotor activity study in our lab showed that hexamethonium, a brain-impermeable nicotinic receptor antagonist blocks the locomotor stimulant effects of nicotine in mice. To further assess the impact of the autonomic effects of nicotine on behavior, we conducted a nicotine discrimination study. In this study, we subtracted nicotine’s autonomic effects from the overall subjective effect by using hexamethonium. Method: Using a two-lever drug discrimination operant chamber, six male Sprague-Dawley rats were trained to discriminate 0.1 mg/kg nicotine tartrate from saline by lever pressing. Subcutaneous injections of nicotine or saline for training occurred five minutes prior to the start of the training session. On test days, rats received hexamethonium (1, 2.5, 5, 10, 25, or 50 mg/kg) intraperitoneally 25 minutes prior to subcutaneous administration of nicotine at the training dose (0.1 mg/kg). Percentage of drug lever responses and response rate were recorded to measure antagonism and analyzed using repeated measures ANOVA. Results: Within the dose range of 10-50 mg/kg, hexamethonium partially antagonized nicotine’s discriminative stimulus effect by reducing the percentage nicotine-lever response to 42% of nicotine’s maximum discriminative stimulus effect. Conclusion: Although full antagonism was not observed, the partial antagonism of nicotine’s discriminative stimulus by a solely peripherally-acting antagonist shows that the autonomic effects of nicotine are a component of the overall subjective effect of nicotine that influences behavior and can be explored as a target for smoking cessation. More direct assays of reward, such as the self-administration assay will be required to affirm the autonomic contributions to the neurobiology of nicotine addiction.