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Nicotine preference and affective behavior of Cd81 knockout mice

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Abstract

Rationale

Cd81 -/- (knockout) mice have previously been reported to have reduced cocaine preference and increased striatal dopamine content and dopamine turnover, but normal learning and memory in the Morris water maze. The effects of Cd81 on other behaviors and drugs of abuse have not been investigated.

Objectives and methods

We measured the effects of Cd81 -/- in a modified two-bottle choice test for nicotine, as well as in somatic signs of nicotine withdrawal, four tests of affective behavior, and tyrosine hydroxylase gene expression assays.

Results

We found that Cd81 loss-of-function significantly increased voluntary nicotine consumption and somatic signs of nicotine withdrawal. Nicotine consumption of Cd81 -/- female mice increased for 3 weeks and then remained relatively stable for the next 5 weeks, suggesting that their nicotine consumption continued to be limited by aversion to higher nicotine doses. Cd81 -/- also produced a dramatic and significant increase in struggling in the forced swim test and a significant increase in the time spent in the light chamber of the light/dark box. The elevated plus maze and the tail suspension test did not show a main effect of genotype. Therefore, we conclude that Cd81 did not have an overall effect on anxiety- or depression-like behavior. Tyrosine hydroxylase mRNA levels were unchanged.

Conclusions

Cd81 knockouts have a strongly increased nicotine preference, plus a proactive response to specific stressful situations. Together with reports of increased striatal dopamine content and anecdotal reports of increased aggressiveness, these provide intriguing parallels to some aspects of post-traumatic stress disorder.

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Acknowledgements

The authors would like to thank Dr. Shoshana Levy for helpful comments, and particularly for the gift of Cd81 -/- (knockout) mice. We also thank Robert Hallenberg for helpful comments, Stephen Traskos and Jaidep Singh for assistance with the nicotine withdrawal experiments, and Katharina Scholz for assistance with the light/dark box assay. The computational image analysis software used in this project was written by ADH, based on algorithms suggested by KJF and software packages selected by RLM.

Funding

Research in this report was supported by the Virginia Youth Tobacco Programs (VYTP) and the Virginia Foundation for Healthy Youth (VFHY).

Author information

Author notes

  1. R. Logan Murphy and Laura L. Locklear are the first two authors and contributed equally to this work.

Authors and Affiliations

  1. School of Systems Biology, and the Interdisciplinary Program in Neurosciences, George Mason University, Mail Stop 1J1, Institute of Advanced Biomedical Research Building, 10920 George Mason Circle, Manassas, VA, 20110, USA

    R. Logan Murphy, Laura L. Locklear, M. Haris Niaz, Rebecca L. Walton, Alexandra D. Hudson & Karl J. Fryxell

  2. Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA

    R. Logan Murphy

  3. Thomas Jefferson High School for Science and Technology, Alexandria, VA, USA

    Laura L. Locklear

  4. Lawrence Livermore National Laboratory, Livermore, CA, USA

    Rebecca L. Walton

  5. Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA, USA

    Alexandra D. Hudson

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  1. R. Logan Murphy
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Correspondence to Karl J. Fryxell.

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All animal procedures were approved by the George Mason University Institutional Animal Care and Use Committee, and were in accordance with the guidelines published in the “Guide for the Care and Use of Laboratory Animals” adopted by the National Institutes of Health.

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Murphy, R.L., Locklear, L.L., Niaz, M.H. et al. Nicotine preference and affective behavior of Cd81 knockout mice. Psychopharmacology 238, 3477–3497 (2021). https://doi.org/10.1007/s00213-021-05966-w

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