Chronic Sazetidine-A Maintains Anxiolytic Effects and Slower Weight Gain Following Chronic Nicotine Without Maintaining Increased Density of Nicotinic Receptors in Rodent Brain

摘要

Chronic nicotine administration increases the density of brain α4β2* nicotinic acetylcholine receptors (nAChRs), which may contribute to withdrawal symptoms associated with smoking cessation. Varenicline, a smoking cessation drug, also increases these receptors in rodent brain. The maintenance of this increase by varenicline as well as nicotine replacement may contribute to the high rate of relapse during the first year after smoking cessation. Recently we found that sazetidine-A, a potent partial agonist that desensitizes α4β2* nAChRs, does not increase the density of these receptors in brain at doses that decrease nicotine self-administration, increase attention in rats, and produce anxiolytic effects in mice. Here we investigated whether chronic sazetidine-A and varenicline maintain the density of nAChRs after their up-regulation by nicotine. In addition, we examined the effects of these drugs on a measure of anxiety in mice and weight gain in rats. After increasing nAChRs in the rodent brain with chronic nicotine, replacing nicotine with chronic varenicline maintained the increased nAChR binding, as well as the subunit proteins measured by western blots. In contrast, replacing nicotine treatments with chronic sazetidine-A resulted in the return of the density of nAChRs to the levels seen in saline controls. Nicotine, sazetidine-A and varenicline each demonstrated anxiolytic effects in mice, but only sazetidine-A and nicotine attenuated the gain of weight over a 6-week period in rats. These findings suggest that apart from its modest anxiolytic and weight control effects, sazetidine-A, or drugs like it, may be useful in achieving long-term abstinence from smoking.