Furthermore, few studies have examined the time course for return of protocol receptors to baseline levels following cessation of chronic treatment. Therefore, to determine if heteromeric nAChRs were upregulated following chronic administration of nicotine and varenicline and to evaluate the time course of upregulated nAChRs to return to baseline, we treated mice with either nicotine or varenicline for 14 days and then examined receptor levels with [3H]EB, which binds with very high affinity to all heteromeric nAChR subtypes in brain. As shown in Figure 1A�CD, both chronic nicotine (18 mg/kg/day, free base) and chronic varenicline (1.8 mg/kg/day) administration resulted in significant upregulation of nAChRs in the cortex, striatum, hippocampus, and thalamus.

Drug-specific effects were observed in the cortex (A), striatum (B), and hippocampus (C), where the upregulation induced by varenicline treatment was significantly longer lasting compared with chronic nicotine treatment. Additionally, a region-specific effect was observed. Overall upregulation of nAChRs following cessation of treatment remained significantly elevated for up to 72 hr in the cortex (A) and striatum (B), while the hippocampus (C) and thalamus (D) rapidly downregulated nAChRs following termination of treatment. Figure 1. Effects of chronic treatment of nicotine and varenicline on nicotinic receptor regulation. Homogenate-binding experiments with a saturating concentration of [3H]epibatidine ([3H]EB, 2 nM) were performed on cortical (A), striatal (B), hippocampal (C), …

Chronic nicotine and varenicline have anxiolytic-like effects in the marble-burying test and duration of this effect correlates to regulation of the ��4��2* nAChR subtype. We previously found both acute nicotine and acute varenicline to have anxiolytic effects in the marble-burying paradigm (Turner et al., 2010). However, the effects of chronic nicotine or varenicline administration in Drug_discovery this test are unknown. Therefore, to evaluate if changes in anxiety behaviors correlated with receptor upregulation, chronically treated animals were tested in the marble-burying paradigm prior to receptor-binding studies with [3H]EB. As shown in Figure 2A, both chronic nicotine (18 mg/kg/day) and chronic varenicline (1.8 mg/kg/day) resulted in a reduced number of marbles being buried, indicating an anxiolytic-like response. In nicotine-treated animals, this effect was only observed during drug administration and behavior returned to baseline by 24 hr. However, in varenicline-treated animals, an anxiolytic-like effect was observed up to 48 hr following cessation of treatment. Figure 2. Chronic nicotine and varenicline had anxiolytic effects in the marble-burying test, which correlated to nAChR levels in the cortex.