Effects of nicotine, nornicotine and cotinine, alone or in combination, on locomotor activity and ultrasonic vocalizatio
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ORIGINAL INVESTIGATION
Effects of nicotine, nornicotine and cotinine, alone or in combination, on locomotor activity and ultrasonic vocalization emission in adult rats Yufei Wang 1 & Benson Wan 1 & Jodie Huang 1 & Paul B. S. Clarke 1 Received: 7 February 2020 / Accepted: 31 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Nicotine . Nornicotine . Cotinine . Ultrasonic vocalization . Locomotion . Rat behavior
Introduction Nornicotine is a tobacco constituent and minor metabolite of nicotine, whereas cotinine is a major nicotine metabolite and a commonly used biomarker of smoking status (Hukkanen et al. 2005). Thus, in smokers, less than 1% of nicotine is metabolized to nornicotine, with a similar amount derived from inhaled tobacco smoke, whereas around 70% of nicotine is metabolized to cotinine (Benowitz and Jacob, III 1994; Benowitz et al. 1994). Nornicotine and cotinine possess longer elimination half-lives than nicotine (Hukkanen et al. 2005;
* Paul B. S. Clarke [email protected] 1
Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building Rm. 1320, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
Kyerematen et al. 1990b), and rodent studies additionally suggest that both metabolites accumulate in the brain during prolonged exposure to nicoti
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