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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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
Citations
Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302
The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine
Corrigall, W. A., Franklin, K. B. J., Coen, K. M., & Clarke, P. B. S. (1992) · Psychopharmacology · doi:10.1007/bf02245149 · Cited by 829
Corrigall, W. A., Coen, K. M., & Adamson, K. L. (1994) · Brain Research · doi:10.1016/0006-8993(94)90401-4 · Cited by 740
Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats
Imperato, A., Mulas, A., & Di Chiara, G. (1986) · European Journal of Pharmacology · doi:10.1016/0014-2999(86)90629-1 · Cited by 693
Presynaptic regulation of neurotransmitter release in the brain: Facts and hypothesis
Chesselet, M.-F. (1984) · Neuroscience · doi:10.1016/0306-4522(84)90058-7 · Cited by 577
Cotinine disposition and effects
Benowitz, N. L., Kuyt, F., Jacob, P., Jones, R. T., & Osman, A.-L. (1983) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1983.222 · Cited by 484
Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers.
Russell, M. A., Jarvis, M., Iyer, R., & Feyerabend, C. (1980) · BMJ · doi:10.1136/bmj.280.6219.972 · Cited by 465
A Major Role for CYP2A6 in Nicotine C-Oxidation by Human Liver Microsomes
Messina, E. S., Tyndale, R. F., & Sellers, E. M. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)36947-2 · Cited by 455
Nicotine metabolism defect reduces smoking
Pianezza, M. L., Sellers, E. M., & Tyndale, R. F. (1998) · Nature · doi:10.1038/31623 · Cited by 437
Role of human cytochrome P4502A6 in C-oxidation of nicotine.
Nakajima, M., Yamamoto, T., Nunoya, K., Yokoi, T., Nagashima, K., Inoue, K., Funae, Y., Shimada, N., Kamataki, T., & Kuroiwa, Y. (1996) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)08453-3 · Cited by 419
Peng, X., Gerzanich, V, Anand, R., Whiting, P. J., & Lindstrom, J. (1994) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09730-5 · Cited by 391
Higher levels of nicotine in arterial than in venous blood after cigarette smoking
Henningfield, J. E. (1993) · Drug and Alcohol Dependence · doi:10.1016/0376-8716(93)90030-t · Cited by 370
Nicotine metabolic profile in man: comparison of cigarette smoking and transdermal nicotine.
Benowitz, N. L., Jacob, P., Fong, I., & Gupta, S. (1994) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)38479-x · Cited by 366
Grady, S., Marks, M. J., Wonnacott, S., & Collins, A. C. (1992) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1992.tb08322.x · Cited by 350
Brain reward systems and abuse
Holman, B. (1988) · Neurochemistry International · doi:10.1016/0197-0186(88)90042-3 · Cited by 278
Giorguieff, M. F., Kemel, M. L., Wandscheer, D. E., & Glowinski, J. (1979) · Life Sciences · doi:10.1016/0024-3205(79)90469-7 · Cited by 248
Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers
Benowitz, N. L., & Jacob III, P. (1993) · Clinical Pharmacology and Therapeutics · doi:10.1038/clpt.1993.27 · Cited by 232
Westfall, T. C. (1974) · Neuropharmacology · doi:10.1016/0028-3908(74)90015-x · Cited by 214
Cashman, J. R., Park, S. B., Yang, Z., Wrighton, S. A., Jacob, P., & Benowitz, N. L. (1992) · Chemical Research in Toxicology · doi:10.1021/tx00029a008 · Cited by 211
RAPIER, C. M., Lunt, G. G., & Wonnacott, S. (1988) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1988.tb10582.x · Cited by 206
Mulle, C., Vidal, C., Benoit, P., & Changeux, J. (1991) · Journal of Neuroscience · doi:10.1523/jneurosci.11-08-02588.1991 · Cited by 200
RAPIER, C. M., Lunt, G. G., & Wonnacott, S. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb02341.x · Cited by 196
Tóth, E., Sershen, H. W., Hashim, A. T., Vizi, E. S., & Lajtha, Á. (1992) · Neurochemical Research · doi:10.1007/bf00966669 · Cited by 194
Petersen, D. R., Norris, K. J., & Thompson, J. A. (1984) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)07789-x · Cited by 160
Stimulation of [3H]Dopamine Release by Nicotine in Rat Nucleus Accumbens
Rowell, P. P., Carr, L. A., & Garner, A. C. (1987) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1987.tb01013.x · Cited by 154
Pharmacokinetics, metabolism, and pharmacodynamics of nicotine
Benowitz, N. L., Porchet, H. C., & Jacob, P. (1990) · Oxford University Press eBooks · doi:10.1093/oso/9780192616142.003.0004 · Cited by 150
Desensitization of Nicotine‐Stimulated [3H]Dopamine Release from Mouse Striatal Synaptosomes
Grady, S. R., Marks, M. J., & Collins, A. C. (1994) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1994.62041390.x · Cited by 126
Sacaan, A. I., Dunlop, J. L., & Lloyd, G. K. (1995) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)10508-9 · Cited by 123
Varanda, W. A., Aracava, Y., Sherby, S. M., VanMeter, W. G., Eldefrawi, M. E., & Albuquerque, E. X. (1985) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)13493-7 · Cited by 120
Crooks, P. A., & Dwoskin, L. P. (1997) · Biochemical Pharmacology · doi:10.1016/s0006-2952(97)00117-2 · Cited by 118
Self-citationMartin, W. R., Loon, G. R. V., Iwamoto, E. T., & Davis, L. (1987) · Advances in behavioral biology · doi:10.1007/978-1-4613-1911-5 · Cited by 117
Kyerematen, G. A., Morgan, M. L., Chattopadhyay, B., deBethizy, J. D., & Vesell, E. S. (1990) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1990.208 · Cited by 107
Goldberg, S. R., Risner, M. E., Stolerman, I. P., Reavill, C. A., & Garcha, H. S. (1989) · Psychopharmacology · doi:10.1007/bf00439441 · Cited by 105
Reavill, C. A., Jenner, P. G., Kumar, R. C., & Stolerman, I. P. (1988) · Neuropharmacology · doi:10.1016/0028-3908(88)90039-1 · Cited by 100
Sites and mechanisms for nicotine's action in the brain
Abood, L. G., Reynolds, D. T., Booth, H., & Bidlack, J. M. (1981) · Neuroscience & Biobehavioral Reviews · doi:10.1016/0149-7634(81)90018-x · Cited by 96
Robust modulation of [3H]dopamine release from rat striatal slices by D-2 dopamine receptors.
Dwoskin, L. P., & Zahniser, N. R. (1986) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)23604-7 · Cited by 94
Self-citationNicotine-induced eeg and behavioral arousal
Yamamoto, K.-I., & Domino, E. F. (1965) · International Journal of Neuropharmacology · doi:10.1016/0028-3908(65)90016-x · Cited by 92
Nicotine-induced release of catecholamines from rat hippocampus and striatum
Arqueros, L., Naquira, D., & Zunino, E. (1978) · Biochemical Pharmacology · doi:10.1016/0006-2952(78)90040-0 · Cited by 92
Crooks, P. A., Li, M., & Dwoskin, L. P. (1997) · PubMed · Cited by 92
Self-citationInitial Characterization of the Nicotinic Acetylcholine Receptors in Rat Hippocampal Neurons
Alkondon, M., & Albuquerque, E. X. (1991) · Journal of Receptor Research · doi:10.3109/10799899109064693 · Cited by 83
DISTRIBUTION OF NICOTINE IN THE CENTRAL NERVOUS SYSTEM
Schmiterlöw, C. G., Hansson, E., Andersson, G., Appelgren, L., & Hoffmann, P. C. (1967) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1967.tb13708.x · Cited by 81
El-Bizri, H., & Clarke, P. B. S. (1994) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1994.tb14749.x · Cited by 79
Vidal, C., & Changeux, J. (1989) · Neuroscience · doi:10.1016/0306-4522(89)90056-0 · Cited by 76
Safety of Cotinine in Humans: Physiologic, Subjective, and Cognitive Effects
Hatsukami, D. K., Grillo, M. A., Pentel, P. R., Oncken, C. A., & Bliss, R. (1997) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(97)80001-9 · Cited by 75
Pathways of dopamine metabolism in the rabbit caudate nucleus in vitro
Zumstein, A., Karduck, W., & Starke, K. (1981) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf00505651 · Cited by 74
Izenwasser, S., Jacocks, H. M., Rosenberger, J. G., & Cox, B. M. (1991) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1991.tb08192.x · Cited by 72
Rowell, P. P., & Hillebrand, J. A. (1994) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1994.63020561.x · Cited by 70
Rowell, P. P. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)11471-8 · Cited by 64
Poor metabolisers of nicotine and CYP2D6 polymorphism
Cholerton, S., Arpanahi, A., McCracken, N. W., Boustead, C., Taber, H., Johnstone, E. C., Leathart, J. B. S., Daly, A. K., & Idle, J. R. (1994) · The Lancet · doi:10.1016/s0140-6736(94)90921-0 · Cited by 64
Pharmacodynamic effects of cotinine in abstinent cigarette smokers
Keenan, R. M., Hatsukami, D., Pentel, P. R., Thompson, T. N., & Grillo, M. A. (1994) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1994.72 · Cited by 59
Cubeddu, L. X., Hoffmann, I., & Ferrari, G. B. (1979) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)31637-x · Cited by 55
Dopamine Efflux from Striatum After Chronic Nicotine: Evidence for Autoreceptor Desensitization
Hársing, L. G., Sershen, H. W., & Lajtha, Á. (1992) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1992.tb08874.x · Cited by 53
Risner, M. E., Goldberg, S. R., Prada, J. A., & Cone, E. J. (1985) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)23321-3 · Cited by 52
Nicotine and related alkaloids : absorption, distribution, metabolism, and excretion
Gorrod, J. W., & Wahren, J. (1993) · Chapman & Hall eBooks · Cited by 51
Teng, L., Crooks, P. A., Buxton, S. T., & Dwoskin, L. P. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37097-1 · Cited by 51
Self-citationDwoskin, L. P., Buxton, S. T., Jewell, A. L., & Crooks, P. A. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03502.x · Cited by 49
Self-citationEffects of Increased Liver Metabolism of Nicotine on Its Uptake, Elimination and Toxicity in Mice
Stålhandske, T. (1970) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1970.tb04786.x · Cited by 46
Kogan, M. J., Verebey, K., Jaffee, J., & Mulé, S. J. (1981) · Journal of Forensic Sciences · doi:10.1520/jfs11324j · Cited by 45
The Accumulation and Metabolism of C14‐labelled Nicotine in the Brain of Mice and Gats
Appelgren, L., Hansson, E., & Schmiterlöw, G. G. (1962) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1962.tb02502.x · Cited by 42
Takada, K., Swedberg, M. D. B., Goldberg, S. R., & Katz, J. L. (1989) · Psychopharmacology · doi:10.1007/bf00442809 · Cited by 37
Masserano, J. M., Venable, D., & Wyatt, R. J. (1994) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)22347-3 · Cited by 35
Comparison of the binding of optically pure (?)- and (+)-[3H]nicotine to rat brain membranes
Abood, L. G., Grassi, S., & Noggle, H. D. (1985) · Neurochemical Research · doi:10.1007/bf00964572 · Cited by 31
Deutsch, J., Hegedũs, L., Greig, N. H., Rapoport, S. I., & Soncrant, T. T. (1992) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/0378-4347(92)80366-x · Cited by 29
Takano, Y., Sakurai, Y., Kohjimoto, Y., Honda, K., & Kamiya, H. (1983) · Brain Research · doi:10.1016/0006-8993(83)90204-4 · Cited by 29
Crooks, P. A., Li, M., & Dwoskin, L. P. (1995) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)06762-5 · Cited by 29
Self-citationLoiacono, R. E., Stephenson, J., Stevenson, J., & Mitchelson, F. J. (1993) · Neuropharmacology · doi:10.1016/0028-3908(93)90139-t · Cited by 26
Schulz, D. W., Kuchel, G. A., & Zigmond, R. E. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb07463.x · Cited by 26
Mechanisms of Nicotine Regulation of Dopamine Release in Neostriatum
Westfall, T. C., Perry, H., & Vickery, L. E. (1987) · Advances in behavioral biology · doi:10.1007/978-1-4613-1911-5_14 · Cited by 16
Research works printed but not linked: 3
- Balfour, 1993, The role of brain dopamine systems in the psychopharmacological responses to nicotine., Asia Pacific J Pharmacol, 8, 153
- Flammang, 1992, Nicotine metabolism by cDNA expressed human cytochrome P-450s., Biochem Arch, 8, 1
- McCracken, 1992, Cotinine formation by cDNA-expressed human cytochromes P450., Med Sci Res, 20, 877
Cited by
Sorted by citations
Nicotine and the adolescent brain: insights from an animal model
Slotkin, T. (2002) · Neurotoxicology and Teratology · doi:10.1016/s0892-0362(02)00199-x · Cited by 284
Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder
Froehlich, T. E., Lanphear, B. P., Auinger, P., Hornung, R., Epstein, J. N., Braun, J., & Kahn, R. S. (2009) · Pediatrics · doi:10.1542/peds.2009-0738 · Cited by 234
Trauth, J. A., Seidler, F. J., & Slotkin, T. A. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02208-3 · Cited by 189
Cosgrove, K. P., Batis, J., Bois, F., Maciejewski, P. K., Esterlis, I., Kloczynski, T., Stiklus, S., Krishnan-Sarin, S., O’Malley, S., Perry, E., et al. (2009) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2009.41 · Cited by 165
Demethylation of the aryl hydrocarbon receptor repressor as a biomarker for nascent smokers
Philibert, R. A., Beach, S. R. H., & Brody, G. H. (2012) · Epigenetics · doi:10.4161/epi.22520 · Cited by 157
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
