Developmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning

Abstract

Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 hours post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 hours post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus-dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction.

Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP

“…Using different protocols of nicotine administration and testing, some found clear impairments in learning and memory (Sorenson et al , 1991; Vaglenova et al , 2004; Yanai et al , 1992; Portugal et al , 2012), whereas others reported no nicotine effects (Cutler et al , 1996; Huang et al , 2007), only subtle impairments (Levin et al , 1993), or only dose- or sex-specific impairments (Ankarberg et al , 2001; Eppolito and Smith, 2006). Combined, this body of work demonstrates that the effects of nicotine exposure during development are sensitive to a combination of factors including sex, dose and timing of exposure.…”

“…Cigarette smoke has been shown to contain more than 4,000 chemicals, but among these nicotine is thought to be the primary neuroteratogen (Pauly and Slotkin, 2008). Indeed, several studies using rodent models of perinatal nicotine treatment have demonstrated that exposure to the drug during early development causes long-lasting deficits in learning and memory (Ankarberg et al , 2001; Eppolito and Smith, 2006; Sorenson et al , 1991; Vaglenova et al , 2004; Yanai et al , 1992; Portugal et al , 2012). However, the outstanding question in the field remains which cellular and molecular changes induced by nicotine underlie this cognitive impairment.…”

Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice

“…32,33 Hippocampi from BDNF Val/Val and BDNF Met/Met mice treated with either saline, chronic nicotine (18 mg kg −1 day −1 ) or undergoing 24-hour withdrawal was homogenized and lysed in 1% triton X-100 (Sigma), 1% nonidet P-40 (Roche, Indianapolis, IN) in Tris-buffered saline pH 7.4 with protease inhibitor cocktail (Sigma). Protein concentration was quantified by Bradford (Bio-Rad, Hercules, CA).…”

ABT-089, but not ABT-107, ameliorates nicotine withdrawal-induced cognitive deficits in C57BL6/J mice

“…Studies with rodents have shown that withdrawal from chronic nicotine impairs hippocampus-dependent learning (Davis et al ., 2005; Andre et al ., 2008; Portugal and Gould, 2009; Kenney et al ., 2011; Portugal et al ., 2012a, 2012b). Withdrawal from chronic nicotine selectively disrupts contextual, but not cued, fear conditioning (Davis et al ., 2005), a paradigm that approximates important aspects of declarative memory in humans (Kenney and Gould, 2008), whereas acute nicotine enhances this hippocampus-specific learning and memory paradigm (Gould and Wehner, 1999).…”