Strain-dependent and age-dependent effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning.

Abstract

Research in both humans and animals demonstrates that nicotine addiction is a complex disorder that can be influenced by several factors. For instance, individual differences in genetics can impact sensitivity to nicotine and can modulate the severity of nicotine withdrawal. Although nicotine alters cognitive processes such as learning and memory, it remains unknown whether genetic variability modulates the effects of nicotine on these cognitive functions. Thus, the present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning in 8 strains of inbred mice. Furthermore, nicotine withdrawal-related changes in somatic signs and the elevated plus maze were examined because nicotine withdrawal consists of multiple symptoms that can include increased somatic signs and increased anxiety. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed in several inbred strains. However, the effects of acute nicotine on contextual fear conditioning were not associated with the effects of nicotine withdrawal, suggesting that different genetic substrates may mediate these two effects. Nicotine withdrawal produced few changes in somatic signs and exploration in the elevated plus maze. Overall, these data demonstrate that genetics contribute to variability in the effects of acute nicotine and withdrawal from chronic nicotine treatment on contextual fear conditioning. The identification of genes that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction. The age during which nicotine use begins is a second factor that may influence the severity of nicotine addiction. Pre-adolescence and adolescence are periods of development that have an increased risk for developing addiction to nicotine. Nicotine alters contextual learning, but it remains unknown whether these effects are age-dependent. Therefore, the present study examined the effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning in pre-adolescent, adolescent, and adult mice. In addition, we investigated whether exposure to chronic nicotine during pre-adolescence or adolescence has long-lasting effects on contextual learning that occurs during adulthood. Pre-adolescent mice were more sensitive to the effects of acute nicotine than adolescents and adults, showed enhanced contextual learning when treated with high doses of chronic nicotine, and were less sensitive than adolescents and adults to nicotine withdrawal-related deficits in contextual learning. In contrast, adolescent mice were less sensitive to the effects of acute nicotine on contextual learning than pre-adolescents and adults and were more sensitive to nicotine withdrawal-related deficits in contextual learning relative to pre-adolescents and adults. Chronic nicotine exposure during pre-adolescence or adolescence also produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure had no effect on fear conditioning. Together, these data suggest that pre-adolescent and adolescent nicotine exposure has both short-term and long-term effects on contextual learning that may play an important role in the development and maintenance of nicotine addiction.