Nicotine-Related Histone Acetylation at FosB Promoter Increases Susceptibility to Cocaine Addiction in Adolescents
Andrea Scott
Introduction. Nicotine use is associated with long-term deleterious cognitive effects; however, many of the molecular mechanisms are unknown, specifically those with consequences during adolescence. Nicotine has a priming effect on addiction by inducing FosB, a striatal protein important in addiction. FosB accumulates in the nucleus accumbens (NAc) and prefrontal cortex (PFC) with chronic substance use, specifically cocaine use.1 Nicotine increases the level of acetylated histones H3 and H4,2 which further enhances cocaine’s ability to induce FosB.3 Methods. Adolescent and adult male ICR mice received nicotine or saline subcutaneous (s.c.) injections twice daily for seven days.4 Mice were sacrificed for immunoblot studies; samples were separated by electrophoresis; and fluorescent intensity was visualized.4 Additional male ICR mice were treated with nicotine or saline s.c. injections twice daily for seven days during early adolescence (postnatal day (PND) 28), late adolescence (PND 50), or adulthood (PND 70). Mice matured for 42 days and cocaine preference was assessed using conditioned place preference (CPP) test.4 Results. Both early adolescent (PND 28) and adult (PND 70) mice treated with 7 days of nicotine had increased DFosB (FosB protein splice variant) levels in the NAc compared to saline treated groups (p<0.05).4 Early adolescent treated mice had a greater increase in DFosB compared to adult treated mice (p<0.05).4 Male ICR mice pre-treated with nicotine during early adolescence (PND 28) had an increased preference for cocaine compared to mice pre-treated with saline (p<0.0001).4 Mice pre-treated during late adolescence or adulthood did not have an increased preference for cocaine compared to the saline treated groups (late adolescence: p>0.05; adulthood: p>0.05).4 Conclusion. The increased accumulation of DFosB is implicated in the long-term effects of adolescent nicotine use and is associated with enhanced sensitivity to cocaine. While the buildup of DFosB is not permanent, it is thought to play a role in drug addictions by altering the expression of specific genes.4 Further, earlier use of nicotine is associated with increased DFosB accumulation, implicating more severe consequences with adolescent nicotine use compared to adult use. The specificity of early adolescent (PND 28) nicotine pre-treatment on cocaine preference suggests that early adolescent exposure to nicotine is critical in affecting the outcomes of cocaine use and dependence. Because adolescence is a period of increased vulnerability and substance abuse,5 further research is needed to develop appropriate diagnostic techniques, treatment regimens, and prevention measures to decrease the adverse effects of nicotine use during adolescence.
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