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.

The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction.

Rationale Spatial and novel object recognition learning is different from learning that uses aversive or appetitive stimuli to shape acquisition because no overt contingencies are needed. While this type of learning occurs on a daily basis, little is known about how nicotine administration affects it. Objectives To determine the effects of acute, chronic, and withdrawal from chronic nicotine on two related but distinct incidental learning tasks, novel and spatial object recognition. Methods In C57BL/6J mice, the effects of acute (0.045–0.18 mg/kg), chronic (6.3 mg/kg/day), and withdrawal from chronic nicotine on novel and spatial object recognition were examined. Results With a 48-h delay between training and testing, acute nicotine enhanced spatial (difference score, saline=3.34 s, nicotine=7.71 s, p=0.029) but resulted in a deficit in novel object recognition (difference score, saline=8.76 s, nicotine= 4.48 s, p=0.033). Chronic nicotine resulted in a strong trend towards a deficit in spatial object recognition (difference score, saline=4.01 s, nicotine=1.81 s, p=0.059) but had no effect on novel object recognition, and withdrawal from chronic nicotine disrupted spatial object recognition (difference score, saline=3.00 s, nicotine=0.17 s, p=0.004) but had no effect on novel object recognition. Conclusions The effects of nicotine on spatial object recognition shift from enhancement to deficit as administration changes from acute to chronic and withdrawal. These effects were specific for spatial object recognition, which may be due to differing underlying neural substrates involved in these tasks. Understanding how nicotine alters learning has implications for understanding diseases associated with altered cholinergic function.

Introduction-Despite known health risks, nicotine use remains high, especially in populations diagnosed with mental illnesses, including anxiety disorders and Post-Traumatic Stress Disorder (PTSD). Smoking in these populations may relate to the effects of nicotine on emotional memories. The current study examined the effects of nicotine administration on the extinction of conditioned fear memories.

Rationale The effects of nicotine on cognitive processes may play an important role in nicotine addiction. Nicotine withdrawal impairs hippocampus-dependent learning and genetic factors influence this effect. However, the neural changes that contribute to these impairments are unknown. Chronic nicotine upregulates hippocampal nicotinic acetycholine receptors (nAChRs), which may contribute to cognitive deficits when nicotine administration ceases. If nAChR upregulation underlies withdrawal-deficits in learning, then strains of mice exhibiting withdrawal-deficits in hippocampus-dependent learning should also show upregulation of hippocampal nAChRs. Objectives Here, we examined the effects of nicotine withdrawal on fear conditioning and [3H]epibatidine binding in the dorsal and ventral hippocampus in two inbred mouse strains and their F1 hybrids. Methods Male C57BL/6NTac, 129S6/SvEvTac, and B6129SF1/Tac mice were administered chronic nicotine (18 mg/kg/d) for 12 days through osmotic pumps and then were trained and tested in fear conditioning 24 hours after cessation of nicotine treatment. Results Nicotine withdrawal impaired hippocampus-dependent contextual conditioning in C57BL/6NTac mice but not 129S6/SvEvTac or B6129SF1/Tac mice; no changes were observed in hippocampus-independent cued fear conditioning. Upregulated [3H]epibatidine binding was found in the dorsal, but not ventral, hippocampus of C57BL/6NTac mice and in the ventral hippocampus of B6129SF1/Tac mice after chronic nicotine. Conclusions Upregulation of high-affinity binding sites in the dorsal hippocampus of C57BL/6NTac mice, the only strain that exhibited nAChR upregulation in this region and withdrawal-deficits in contextual conditioning, suggests that upregulation of high-affinity binding sites in the dorsal hippocampus mediates, in part, nicotine withdrawal-deficits in contextual conditioning and genetic background modulates these effects.