Examination of tolerance to the cognitive enhancing effect of nicotine on contextual conditioning

Abstract

Nicotine addiction is a multifaceted disease that can be influenced by several factors. Emerging evidence indicates that the neural substrates of nicotine addiction overlap with the neural substrates of learning and memory. Nicotine modulates various types of learning and memory and the ability of nicotine to alter cognitive processes may contribute to its addictive liability. Acute nicotine enhances contextual conditioning in mice, tolerance develops to this effect with chronic administration, and withdrawal from chronic nicotine produces cognitive deficits. While tolerance and withdrawal deficits both occur following chronic administration, it is unknown if they share similar mechanisms. The series of experiments in Chapter 2 were designed to provide evidence that tolerance and withdrawal are dissociable. C57BL/6J mice were implanted with osmotic minipumps that delivered constant nicotine or saline for various durations and then were trained and tested in contextual conditioning either during chronic nicotine administration or 24 hours after pump removal. Chronic nicotine enhanced contextual conditioning in a dose- and time-dependent manner. Tolerance developed quickly to the enhancing effect of chronic nicotine. Furthermore, the duration of chronic nicotine treatment required to produce cognitive deficits upon cessation of treatment differed than that required to produce tolerance, which suggests that tolerance and withdrawal are mediated by separate mechanisms. Chapter 2 concludes by presenting a model that integrates nicotinic acetylcholine receptor desensitization and upregulation to explain the present findings. The model presented in Chapter 2 predicts that there will be enhanced sensitivity to acute nicotine during a period of nicotine withdrawal. Previous research indicates that prior exposure to nicotine enhances sensitivity to acute nicotine injections, but it is unclear if this enhanced sensitivity is due to prior nicotine exposure or enhanced sensitivity to nicotine during withdrawal. Therefore, the experiments in Chapter 3 were designed to determine if prior exposure to nicotine or nicotine withdrawal altered sensitivity to acute nicotine injections. This was accomplished by assessing the effects of acute nicotine on contextual conditioning immediately after cessation of chronic nicotine treatment and two weeks later, a time period not associated with withdrawal-related changes in cognitive function. Results of the study showed that acute nicotine enhanced contextual conditioning across a wide range of doses in both saline- and nicotine-withdrawn mice. However, a greater enhancement of contextual conditioning was observed in mice withdrawn from chronic nicotine treatment for 24 hours than all other withdrawal groups, suggesting enhanced sensitivity during withdrawal. The enhanced sensitivity to acute nicotine suggests altered nAChR function during withdrawal. In addition, the lowest dose of acute nicotine did not enhance contextual conditioning in groups that received chronic nicotine but did in other groups. The simultaneous observation of a hyper and hyposensitive nAChR system during withdrawal suggests that there may be a phasic response to chronic nicotine. Together, the results of the present study suggest that tolerance and withdrawal operate under separate mechanisms, and that there is overall enhanced sensitivity to nicotine during periods of nicotine withdrawal.