Abstract
The behavioral effects of the nicotine metabolites nornicotine and cotinine have not been investigated extensively. 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. 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 60min after challenge injection, using repeated measures designs. In single-drug experiments, subjects were tested with nicotine 0.05-0.4mg/kg, cotinine 0.03-3mg/kg, or nornicotine 0.1-10mg/kg. In drug-combination experiments, saline or nicotine 0.2mg/kg challenge was preceded by cotinine (0, 0.3, 3mg/kg) or nornicotine (0, 0.1, 0.3, 1, 3mg/kg) injection. 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. 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.
Highlights
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)
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)
Kyerematen et al 1990b), and rodent studies suggest that both metabolites accumulate in the brain during prolonged exposure to nicotine (Ghosheh et al 2001)
Summary
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). 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 activate neuronal nicotinic cholinergic receptors (nAChRs), often only at higher doses than nicotine (Crooks and Dwoskin 1997; Dwoskin et al 1999b). Nornicotine activates certain recombinant nAChR subtypes more potently than nicotine
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