The Effect of Cotinine on Nicotine- and Cocaine-Induced Dopamine Release in the Nucleus Accumbens

Sziráki, István; Sershen, Henry; Benuck, M.; Lipovac, M. N.; Hashim, Audrey; Cooper, Thomas B.; Allen, David W.; Lajtha, Ábel

doi:10.1007/s11064-999-0001-1

Cited by 18 publications

(11 citation statements)

References 29 publications

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“…Ki values for displacing [ 3 H]cytisine binding (presumably high-affinity α4β2 * subtype; the * denotes other nAChR subunits) were over 200 µM for cotinine and 0.6 nM for nicotine (Anderson and Arneric, 1994). Consistently, cotinine up to 1 µM produced minimal effect on [ 3 H]cytisine binding, whereas nicotine induced over 70% inhibition of [ 3 H]cytisine binding in rat cerebral cortex preparations (Sziraki et al, 1999). Cotinine and nicotine were reported to display equal efficacy in displacing [ 125 I]α-bungarotoxin binding (presumably lowaffinity α7 nAChRs), but cotinine was ∼100 fold less potent than nicotine, with IC 50 values at 1 mM and 10 µM, respectively (Riah et al, 1999).…”

Section: Pharmacodynamics Of Cotininementioning

confidence: 86%

Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions

Tan

Vrana

Ding

2021

Front. Behav. Neurosci.

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Tobacco use disorder continues to be a leading public health issue and cause of premature death in the United States. Nicotine is considered as the major tobacco alkaloid causing addiction through its actions on nicotinic acetylcholine receptors (nAChRs). Current pharmacotherapies targeting nicotine’s effects produce only modest effectiveness in promoting cessation, highlighting the critical need for a better understanding of mechanisms of nicotine addiction to inform future treatments. There is growing interest in identifying potential contributions of non-nicotine components to tobacco reinforcement. Cotinine is a minor alkaloid, but the major metabolite of nicotine that can act as a weak agonist of nAChRs. Accumulating evidence indicates that cotinine produces diverse effects and may contribute to effects of nicotine. In this review, we summarize findings implicating cotinine as a neuroactive metabolite of nicotine and discuss available evidence regarding potential mechanisms underlying its effects. Preclinical findings reveal that cotinine crosses the blood brain barrier and interacts with both nAChRs and non-nAChRs in the nervous system, and produces neuropharmacological and behavioral effects. Clinical studies suggest that cotinine is psychoactive in humans. However, reviewing evidence regarding mechanisms underlying effects of cotinine provides a mixed picture with a lack of consensus. Therefore, more research is warranted in order to provide better insight into the actions of cotinine and its contribution to tobacco addiction.

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Section: Pharmacodynamics Of Cotininementioning

confidence: 86%

Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions

Tan

Vrana

Ding

2021

Front. Behav. Neurosci.

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“…Further, cotinine binds to nicotinic receptors, although at a substantially lower potency and lower affinity than nicotine (Anderson and Arneric, 1994; O’Leary et al, 2008; Sloan et al, 1984; Vainio and Tuominen, 2001). Interestingly, cotinine also inhibits nicotine-induced dopamine release in the NAc in adult rats (Sziraki et al, 1999). Thus, cotinine appears to act as a partial agonist at nicotinic receptors in the mesolimbic system.…”

Section: Discussionmentioning

confidence: 99%

Tobacco's minor alkaloids: Effects on place conditioning and nucleus accumbens dopamine release in adult and adolescent rats

Marusich

Darna

Wilson

et al. 2017

European Journal of Pharmacology

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Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8mg/kg), cotinine (0.5-5.0mg/kg), anatabine (0.5-5.0mg/kg), and myosmine (5.0-20.0mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated.

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“…These studies suggest that cotinine is much less potent than nicotine in binding to nAChRs. Furthermore, cotinine at physiological concentrations (0.1-1µM) did not inhibit 3 Hcytisine binding (Sziraki et al 1999). Cotinine at 10µM had no agonistic or antagonistic activity on α4β2* or α7 nAChRs (Terry et al 2015).…”

Section: Downloaded Frommentioning

confidence: 91%

Self-Administration of Cotinine in Wistar Rats: Comparisons to Nicotine

Ding

Gao

Sentir

et al. 2020

J Pharmacol Exp Ther

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Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents However, it remains undetermined whether cotinine can be selfadministered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg/infusion) under fixed-(FR) and progressive-ratio (PR) schedules.Blood nicotine and cotinine levels were determined following the last FR session. Effects of mecamylamine, a non-selective nAChRs antagonist, and varenicline, a partial agonist for α4β2* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to selfadminister cotinine when reinforcement requirement increased. Blood cotinine levels ranged from 77-792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules, and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine, but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine, and exhibited no sex difference. nAChRs appeared to be differentially involved in selfadministration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse.

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The Effect of Cotinine on Nicotine- and Cocaine-Induced Dopamine Release in the Nucleus Accumbens

Cited by 18 publications

References 29 publications

Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions

Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions

Tobacco's minor alkaloids: Effects on place conditioning and nucleus accumbens dopamine release in adult and adolescent rats

Self-Administration of Cotinine in Wistar Rats: Comparisons to Nicotine

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