The DOI matches its Crossref record; 68 of the 73 references it cites were found in a registry or an index.
(S)-(−)-Cotinine, the Major Brain Metabolite of Nicotine, Stimulates Nicotinic Receptors to Evoke [3H]Dopamine Release from Rat Striatal Slices in a Calcium-Dependent Manner
Abstract
Cotinine, a major peripheral metabolite of nicotine, has recently been shown to be the most abundant metabolite in rat brain after peripheral nicotine administration. However, little attention has been focused on the contribution of cotinine to the pharmacological effects of nicotine exposure in either animals or humans. The present study determined the concentration-response relationship for (S)-(-)-cotinine-evoked 3H overflow from superfused rat striatal slices preloaded with [3H]dopamine ([3H]DA) and whether this response was mediated by nicotinic receptor stimulation. (S)-(-)-Cotinine (1 microM to 3 mM) evoked 3H overflow from [3H]DA-preloaded rat striatal slices in a concentration-dependent manner with an EC50 value of 30 microM, indicating a lower potency than either (S)-(-)-nicotine or the active nicotine metabolite, (S)-(-)-nornicotine. As reported for (S)-(-)-nicotine and (S)-(-)-nornicotine, desensitization to the effect of (S)-(-)-cotinine was observed. The classic nicotinic receptor antagonists mecamylamine and dihydro-beta-erythroidine inhibited the response to (S)-(-)-cotinine (1-100 microM). Additionally, 3H overflow evoked by (S)-(-)-cotinine (10-1000 microM) was inhibited by superfusion with a low calcium buffer. Interestingly, over the same concentration range, (S)-(-)-cotinine did not inhibit [3H]DA uptake into striatal synaptosomes. These results demonstrate that (S)-(-)-cotinine, a constituent of tobacco products and the major metabolite of nicotine, stimulates nicotinic receptors to evoke the release of DA in a calcium-dependent manner from superfused rat striatal slices. Thus, (S)-(-)-cotinine likely contributes to the neuropharmacological effects of nicotine and tobacco use.
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In the citing paper
“both nicotine59 and cotinine60 have been shown to facilitate dopamine release”
From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [60]
In the citing paper
“Dopamine release has been associated with the feeling of craving58, and both nicotine59 and cotinine60 have been shown to facilitate dopamine release, thus the prolonged partial occupancy of the receptor by nicotine or cotinine, may contribute to the feelings of craving that are reported 2 h after the last cigarette and throughout the first week of abstinence.”
From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [60]
In the citing paper
“The rather high circulating plasma cotinine levels after nicotine ingestion, coupled with findings that cotinine stimulates nAChRs, has prompted the suggestion that cotinine per se may have biological effects (Dwoskin et al., 1999;O'Leary et al., 2008).”
From Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization (2010) · cites this paper as Dwoskin et al., 1999
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Nicotine and the adolescent brain: insights from an animal model
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Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder
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Demethylation of the aryl hydrocarbon receptor repressor as a biomarker for nascent smokers
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Metadata
- Authors
- Dwoskin, L. P., Teng, L., Buxton, S. T., & Crooks, P. A.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Dwoskin, Linda P.
- ORCID
- Crooks, Peter A.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1999-03
- Volume
- 288
- Issue
- 3
- Pages
- 905-911
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1911378236
- Cited by
- 120
- References
- 73
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 12 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 10 · 2014: 10 · 2013: 2 · 2012: 6
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institutes of Health (5r01da008656-03)
- National Institute on Drug Abuse (DA-08656)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cotinine, nicotine metabolites, nicotinic acetylcholine receptors, dopamine release, striatum, calcium dependence, receptor desensitization, mecamylamine, dihydro-beta-erythroidine, dopamine uptake, tobacco use
- MeSH terms
- Animals, Calcium, Corpus Striatum, Cotinine, Dopamine, Male, Nicotine, Receptors, Nicotinic, Synaptosomes, Tritium, Rats, Sprague-Dawley, Nicotinic Agonists, Nicotinic Antagonists, Rats, In Vitro Techniques
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