Abstract
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.
Highlights
Cigarette smoking remains to be a leading public health issue
Nicotine is widely accepted as the major addictive component in cigarette, and it mainly activates nicotinic acetylcholine receptors to produce its reinforcing and rewarding effects (Prochaska and Benowitz, 2016)
In isolated rat adrenal gland, cotinine inhibited catecholamine release evoked by high calcium and acetylcholine, but not by high K+, whereas nicotine produced biphasic effect on catecholamine release induced by acetylcholine and high K+
Summary
Cigarette smoking remains to be a leading public health issue. Despite a steady decline over the past decades, smoking rate remained at 17.2 percent in people aged 12 or older in 2018 in the United States (Substance Abuse and Mental Health Services Administration [SAMHSA], 2019). There is a remaining need for better understanding of mechanisms underlying nicotine addiction and tobacco smoking. There are growing efforts investigating the potential involvement of minor tobacco alkaloids and nicotine metabolites in nicotine’s effects and tobacco use (Crooks and Dwoskin, 1997; Hoffman and Evans, 2013). Cotinine is a minor tobacco alkaloid and the major metabolite of nicotine. It is most commonly used as a biomarker for nicotine exposure (Benowitz and Jacob, 1994; Zhu et al, 2013). There is recognition that cotinine may contribute to some effects of nicotine (Crooks and Dwoskin, 1997; Majdi et al, 2019), raising the possibility that cotinine may play a role in tobacco use, abuse, and dependence. The focus is on cotinine interactions with the nervous system, and on neuropharmacological and behavioral effects of cotinine (Figure 1)
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