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Effects of nicotine, nornicotine and cotinine, alone or in combination, on locomotor activity and ultrasonic vocalization emission in adult rats

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Abstract

Rationale

The behavioral effects of the nicotine metabolites nornicotine and cotinine have not been investigated extensively.

Objectives

To evaluate the effects of nicotine, cotinine, and nornicotine, given alone or in combination, on locomotor activity and emission of ultrasonic vocalizations in male adult rats.

Methods

Rats were first given home cage nicotine injections to make them tolerant to the drug’s locomotor depressant effects. On subsequent days, locomotor activity (LMA) and ultrasonic vocalizations were recorded in an open field, for 60 min after challenge injection, using repeated measures designs. In single-drug experiments, subjects were tested with nicotine 0.05–0.4 mg/kg, cotinine 0.03–3 mg/kg, or nornicotine 0.1–10 mg/kg. In drug-combination experiments, saline or nicotine 0.2 mg/kg challenge was preceded by cotinine (0, 0.3, 3 mg/kg) or nornicotine (0, 0.1, 0.3, 1, 3 mg/kg) injection.

Results

High doses of nornicotine increased LMA and blunted the locomotor stimulant effect of nicotine. Less consistently, nicotine and high doses of nornicotine decreased the 50-kHz call rate, with no clear evidence of a nornicotine × nicotine interaction. Cotinine, given alone or before nicotine injection, altered neither LMA nor the call rate. No drug altered the relative prevalence of flat vs. trill 50-kHz call subtypes, except that the highest dose of nornicotine promoted flat calls over trills. No drug evoked 22-kHz calls.

Conclusion

Nornicotine can exert an acute anti-nicotine effect in vivo, as previously reported in vitro. The finding that nicotine did not detectably alter the 50-kHz call profile appears consistent with this drug’s mild subjective effects in human subjects.

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Acknowledgments

We wish to thank Lucas Marques and Adithi Sundarakrishnan for providing comments on the manuscript.

Funding

This study was supported by a Natural Science and Engineering Research Council of Canada (NSERC) discovery grant (155055, to P.B.S.C). Y.W. was supported by a McGill University Faculty of Medicine BSc/MSc fast-track award. P.B.S.C. is a member of the Center for Studies in Behavioral Neurobiology at Concordia University, Montreal.

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  1. Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building Rm. 1320, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada

    Yufei Wang, Benson Wan, Jodie Huang & Paul B. S. Clarke

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  1. Yufei Wang
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  2. Benson Wan
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Correspondence to Paul B. S. Clarke.

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All experiments comply with the current laws of Canada. All research procedures were reviewed and approved by the McGill Animal Care Committee in accordance with the guidelines of the Canadian Council on Animal Care.

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Wang, Y., Wan, B., Huang, J. et al. Effects of nicotine, nornicotine and cotinine, alone or in combination, on locomotor activity and ultrasonic vocalization emission in adult rats. Psychopharmacology 237, 2809–2822 (2020). https://doi.org/10.1007/s00213-020-05574-0

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