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Adolescent nicotine exposure induces long-term, sex-specific disturbances in mood and anxiety-related behavioral, neuronal and molecular phenotypes in the mesocorticolimbic system

Neuropsychopharmacology (2024)Cite this article

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Abstract

The majority of lifetime smokers begin using nicotine during adolescence, a critical period of brain development wherein neural circuits critical for mood, affect and cognition are vulnerable to drug-related insults. Specifically, brain regions such as the medial prefrontal cortex (mPFC), the ventral tegmental area (VTA), nucleus accumbens (NAc) and hippocampus, are implicated in both nicotine dependence and pathological phenotypes linked to mood and anxiety disorders. Clinical studies report that females experience higher rates of mood/anxiety disorders and are more resistant to smoking cessation therapies, suggesting potential sex-specific responses to nicotine exposure and later-life neuropsychiatric risk. However, the potential neural and molecular mechanisms underlying such sex differences are not clear. In the present study, we compared the impacts of adolescent nicotine exposure in male vs. female rat cohorts. We performed a combination of behavioral, electrophysiological and targeted protein expression analyses along with matrix assisted laser deionization imaging (MALDI) immediately post-adolescent exposure and later in early adulthood. We report that adolescent nicotine exposure induced long-lasting anxiety/depressive-like behaviors, disrupted neuronal activity patterns in the mPFC-VTA network and molecular alterations in various neural regions linked to affect, anxiety and cognition. Remarkably, these phenotypes were only observed in males and/or were expressed in the opposite direction in females. These findings identify a series of novel, sex-selective biomarkers for adolescent nicotine-induced neuropsychiatric risk, persisting into adulthood.

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Fig. 1: Long-lasting sex-specific effects of adolescent nicotine exposure on anxiety-related behaviors.
Fig. 2: Adolescent NIC exposure induces sex-specific depressive-like phenotypes and cognitive deficits in adulthood.
Fig. 3: Adolescent nicotine exposure induces sex-specific alterations to mPFC and VTA spontaneous neuronal spiking activity and spontaneous mPFC oscillations in adulthood.
Fig. 4: Long-term sex-selective effects of adolescent nicotine exposure on anxiety and depressive-related molecular markers in the mPFC and NAc.
Fig. 5: MALDI imaging of acute and long-term impacts of adolescent nicotine exposure on GABA/glutamate levels in the male mPFC, NAc and Hipp.

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Data availability

The data that support the findings of this study are available from the corresponding author, [S.R.L.], upon reasonable request.

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Funding

This work was supported by the Canadian Institutes of Health Research (CIHR; PJT-189943) and Natural Sciences and Engineering Research Council (NSERC) Graduate Student fellowships to THJN., MS, DG and EP.

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Authors and Affiliations

  1. Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada

    Tsun Hay Jason Ng, Mohammed H. Sarikahya, Roger Hudson, Hanna J. Szkudlarek, Enzo Pérez-Valenzuela, Taygun C. Uzuneser, Emma Proud, Dana Gummerson, Miray Youssef, Madeline Machado, Kuralay Zhaksylyk, Marieka V. DeVuono, Walter J. Rushlow & Steven R. Laviolette

  2. Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, N6A 3K7, Canada

    Tsun Hay Jason Ng, Mohammed H. Sarikahya, Roger Hudson, Hanna J. Szkudlarek, Enzo Pérez-Valenzuela, Taygun C. Uzuneser, Emma Proud, Dana Gummerson, Miray Youssef, Madeline Machado, Kuralay Zhaksylyk, Marieka V. DeVuono, Walter J. Rushlow & Steven R. Laviolette

  3. Department of Chemistry, University of Western Ontario, London, ON, N6A 3K7, Canada

    Chaochao Chen & Ken K.-C. Yeung

  4. Department of Biochemistry, University of Western Ontario, London, ON, N6A 3K7, Canada

    Chaochao Chen & Ken K.-C. Yeung

  5. Department of Psychiatry, Western University, London, ON, N6A 3K7, Canada

    Walter J. Rushlow & Steven R. Laviolette

  6. Lawson Health Research Institute, London, ON, N6C 2R5, Canada

    Steven R. Laviolette

  7. Division of Maternal, Fetal and Newborn Health, Children’s Health Research Institute (CHRI), London, ON, Canada

    Steven R. Laviolette

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  1. Tsun Hay Jason Ng
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Contributions

THJN and SRL designed the research; THJN, MHS, RH, HJS, EPV, TCU, MVD, MM, KZ, MY, performed research; THJN, MHS, HJS, EPV, TCU, EP, DG, CC, KKCY and WJR contributed to data analysis; THJN and SRL wrote the paper.

Corresponding author

Correspondence to Steven R. Laviolette.

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Ng, T.H.J., Sarikahya, M.H., Hudson, R. et al. Adolescent nicotine exposure induces long-term, sex-specific disturbances in mood and anxiety-related behavioral, neuronal and molecular phenotypes in the mesocorticolimbic system. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01853-y

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