DEVELOPMENTAL NICOTINE EXPOSURE AND COGNITIVE VULNERABILITY: IS THE IMMUNE SYSTEM INVOLVED?
Authors: Parikh *Vinay , Harrington Evelynn , Steinberg Zoe R , Gaisinsky Jane , Meissler Joseph , Eisenstein Toby K 
Published: February 2025

Abstract

Background
Vulnerability to nicotine addiction and the risk of psychosis is known to significantly increase in individuals who begin smoking during adolescence1,2; however the underlying mechanism for this phenomenon remains poorly understood. Dysfunction in the prefrontal cortex (PFC)-dependent cognitive processes is hypothesized to contribute to impairments in behavioral control in drug addicts3. Moreover, hypofrontality is linked to the cognitive symptoms of schizophrenia4.

Aims and Objectives
Previously, we found that developmental nicotine exposure biases the reinforcement sensitivity towards nicotine as opposed to natural rewards, and this change may involve alterations in cognitive control5. Here, we examined the consequences of adolescent nicotine experience on cognitive flexibility to probe PFC function during adulthood. Because nicotine exerts immunosuppressive effects, we also conducted immuno-proteomic profiling in the PFC.

Method
Adolescent C57BL/6J mice (PND33-35) of either sex (N=30; 15M and 15F) were implanted with mini-osmotic pumps for subcutaneous delivery of either saline or nicotine (low dose: 3mg/kg/day; high dose: 12mg/kg/day) for 2 weeks. After a 2-week washout period, behavioral testing in adult mice commenced. Animals were trained and tested in an operant cognitive flexibility task that required the animals to switch from using a spatial response-driven strategy to a visual cue-based strategy to achieve rewards. After the behavioral testing, brains were removed to analyze immune mediators using the Proteome Profiler Cytokine Arrays.

Results
Mice exposed to nicotine during adolescence required more trials to reach strategy set-shifting criterion (F(2,29)=5.49, p=0.01). Moreover, these animals committed more perseverative errors as compared to saline-treated mice (both doses: p&lt;0.05) indicating that the former adhered to using the previously engaged strategy despite a new rule was implemented. Examination of maintenance errors revealed no significant differences (F(2,29=0.32, p=0.73). Although the performance remained similar between the two nicotine doses, we observed a sex x dose interaction for trials to criterion (F(2,29)=6.72, p=0.005). Surprisingly, lower nicotine dose impaired performance in female mice while higher nicotine dose was more detrimental to male mice (both p&lt;0.05). It is possible that this dissociation might be linked to sex-specific differences in nicotine pharmacokinetics in adolescent mice. Analysis of immune mediators based on the results of the array revealed significant reduction of complement component C5a, s-ICAM, IL-27,and IFN-γ in the PFC of adolescent nicotine-exposed mice (all p&lt;0.03).

Discussion and Conclusion
Our data suggests that nicotine exposure during adolescence, regardless of dose, disrupts cognitive flexibility in mice during adulthood. These cognitive deficits are mainly associated with a disruption in the animals’ ability to disengage from a previously acquired behavioral strategy. Because PFC networks are implicated in flexible adaptive control, it is plausible that long-term detrimental effects of adolescent nicotine on executive processes is linked to disruption in immune signaling that interferes with the developmental maturation and refinement of these circuits. These developmental perturbations may increase the risk of nicotine dependence and its comorbidity with schizophrenia later in life.

References
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2)Parikh,, Kutlu, M.G. and Gould, T.J. (2016) nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction. Schizophrenia Research, 171: 1-15.
3)Goldstein, R.Z. and Volkow, N.D. (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nature Reviews Neuroscience, 12: 652-669.
4)Yoon, J. H., Minzenberg, M. J., Ursu, S., Ryan Walter, B. S., Walters, R., Wendelken, C., et al. (2008). Association of dorsolateral prefrontal cortex dysfunction with disrupted coordinated brain activity in schizophrenia: Relationship with impaired cognition, behavioral disorganization, and global function. American Journal of Psychiatry 165: 1006–1014.
5)Cole, R.D., Wolsh, C., Zimmerman, M., Gould, T.J. and Parikh, V. (2019) Adolescent nicotine exposure facilitates motivated nicotine but not saccharin self-administration following adult drug re-exposure in mice. Behavioral Brain Research, 359: 836-844.