Pleiotropic impact of constitutive Fosb inactivation on nicotine-induced behavioral alterations and stress-related traits in mice

Abstract

Smoking is a serious problem worldwide. Tobacco smoking causes the second major death in the world. Nicotine is the substance in the tobacco products that contributes to addiction. Studies have focused on the nicotine acetylcholine receptor on the cell surface; however, the genetic and intracellular mechanisms of nicotine dependence are poorly understood, thereby limiting the therapeutic strategies.;It has been suggested that addictive substances generally act on brain regions that normally mediate behavioral responses essential for survival. Although it is known that motivational and affective behaviors are under genetic control, how specific genes concurrently modulate these behaviors and addictive behaviors is still unknown. The transcription factor FosB/DeltaFosB is induced in the mesolimbic dopamine pathway by cocaine, and contributes to the behavioral effects of cocaine. Nicotine acts on the mesolimbic dopamine pathway. Because this pathway is thought to mediate various motivational/affective behaviors, we hypothesized that (1) FosB/DeltaFosB is part of the intracellular cascades that mediate nicotine cue-induced preference and sustained nicotine intake, and (2) FosB/DeltaFosB is part of the intracellular cascades that mediate dependence-related behavioral traits in mice.;To test the first hypothesis, we used Fosb knockout (KO) mice and wild-type (WT) littermates to examine the role of this transcription factor in distinct behavioral effects of nicotine. KO mice were impaired in nicotine-induced conditioned place preference, a 2-bottle oral nicotine intake and nicotine-induced motor suppression; these impairments were present following repeated or prolonged, but not acute, nicotine administration. Control experiments suggested that these phenotypes were not due to abnormalities in taste response or metabolism of nicotine. In WT mice, repeated nicotine injections increased FosB/DeltaFosB in the nucleus accumbens and the caudate-putamen, but not in ventral tegmental area or substantia nigra. However, no detectable level of FosB/DeltaFosB was found in KO mice. Our findings strongly suggest that the presence FosB/DeltaFosB in the nucleus accumbens and the caudate-putamen is functionally required for maintaining the behavioral effects of repeated or prolonged nicotine administration.;We next tested the second hypothesis that Fosb contributes to dependence-related pre-existing behavioral traits. To test the function of FosB/DeltaFosB in behavioral traits, we compared Fosb KO mice and WT littermates in a variety of behavior paradigms that have been commonly used to test dependence-related behavioral traits in rodents. These paradigms include novelty preference, locomotor activity in an inescapable open field, elevated plus maze, light-dark discrimination, and tail suspension. Moreover, we analyzed the basal blood levels of corticosterone maker of stress reactivity. Fosb KO mice exhibited more robust behavioral abnormalities when stress levels were high. KO mice showed a higher degree of locomotor activity compared with WT mice in an inescapable open field when an additional stress factor was given; and KO mice exhibited a lower level of immobility in tail suspension. Additionally, the basal level of corticosterone was lower in Fosb KO mice than WT mice. However, Fosb KO and WT mice did not differ in anxiety-related behaviors or novelty preference.;Our data suggest that the constitutive absence of Fosb has a pleiotropic influence on the behavioral effects of repeated or prolonged nicotine administration and on stress-related traits in mice.