Cotinine, a Neuroactive Metabolite of Nicotine: Potential for Treating Disorders of Impaired Cognition

Overview

Journal CNS Drug Rev

Specialties Neurology
Pharmacology

Date 2006 Jan 4

PMID 16389292

Citations 39

Authors

Alvin V Terry Jr

Caterina M Hernandez

Elizabeth J Hohnadel

Kristy P Bouchard

Jerry J Buccafusco

Affiliations

Soon will be listed here.

Abstract

The pharmacological effects of the tobacco-derived alkaloid nicotine have been widely studied in humans and animals for decades. However, relatively little attention has been given to the potential actions of its major metabolite, cotinine. After nicotine consumption the duration of cotinine's presence in blood and brain greatly exceeds that of nicotine. Therefore, cotinine could mediate the more protracted pharmacological effects of nicotine. The studies described in this report were thus designed to further investigate certain neuropharmacological actions of cotinine. Behavioral tests (e.g., delayed matching-to-sample) were conducted in aged rhesus monkeys to assess the effects of cotinine on working memory and attention. In rats a prepulse inhibition (PPI) procedure was used to assess the effects of the compound on auditory gating - a method for predicting the potential antipsychotic properties of drugs. Cotinine exhibited significant effectiveness in these tasks. The drug was also cytoprotective in differentiated PC-12 cells with a potency equivalent to that of nicotine. The effects of chronic cotinine treatment on the expression of nicotinic and muscarinic acetylcholine receptors in rat brain were measured by [125I]epibatidine, [125I]alpha-bungarotoxin ([125I]BTX), [3H]pirenzepine ([3H]PRZ), and [3H]AFDX-384 ([3H]AFX) autoradiography. Unlike nicotine, cotinine failed to upregulate the expression of brain nicotinic receptors. Based on its relative safety in man, cotinine should prove useful in the treatment of diseases of impaired cognition and behavior without exhibiting the toxicity usually attributed to nicotine.

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References

Briggs C, McKenna D, Monteggia L, Touma E, Roch J, Arneric S . Gain of function mutation of the alpha7 nicotinic receptor: distinct pharmacology of the human alpha7V274T variant. Eur J Pharmacol. 1999; 366(2-3):301-8. DOI: 10.1016/s0014-2999(98)00909-1. View

van der Zee E, Luiten P . Muscarinic acetylcholine receptors in the hippocampus, neocortex and amygdala: a review of immunocytochemical localization in relation to learning and memory. Prog Neurobiol. 1999; 58(5):409-71. DOI: 10.1016/s0301-0082(98)00092-6. View

Audesirk T, Cabell L . Nanomolar concentrations of nicotine and cotinine alter the development of cultured hippocampal neurons via non-acetylcholine receptor-mediated mechanisms. Neurotoxicology. 1999; 20(4):639-46. View

Drisdel R, Green W . Neuronal alpha-bungarotoxin receptors are alpha7 subunit homomers. J Neurosci. 2000; 20(1):133-9. PMC: 6774106. View

Vainio P, Tornquist K, Tuominen R . Cotinine and nicotine inhibit each other's calcium responses in bovine chromaffin cells. Toxicol Appl Pharmacol. 2000; 163(2):183-7. DOI: 10.1006/taap.1999.8863. View

Paterson D, Nordberg A . Neuronal nicotinic receptors in the human brain. Prog Neurobiol. 2000; 61(1):75-111. DOI: 10.1016/s0301-0082(99)00045-3. View

Corringer P, Le Novere N, Changeux J . Nicotinic receptors at the amino acid level. Annu Rev Pharmacol Toxicol. 2000; 40:431-58. DOI: 10.1146/annurev.pharmtox.40.1.431. View

Lima P, Wonnacott S . The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism. Neuropharmacology. 2000; 39(13):2799-807. DOI: 10.1016/s0028-3908(00)00127-1. View

Dani J . Overview of nicotinic receptors and their roles in the central nervous system. Biol Psychiatry. 2001; 49(3):166-74. DOI: 10.1016/s0006-3223(00)01011-8. View

10.

Shimohama S, Kihara T . Nicotinic receptor-mediated protection against beta-amyloid neurotoxicity. Biol Psychiatry. 2001; 49(3):233-9. DOI: 10.1016/s0006-3223(00)01100-8. View

11.

Rezvani A, Levin E . Cognitive effects of nicotine. Biol Psychiatry. 2001; 49(3):258-67. DOI: 10.1016/s0006-3223(00)01094-5. View

12.

Vainio P, Tuominen R . Cotinine binding to nicotinic acetylcholine receptors in bovine chromaffin cell and rat brain membranes. Nicotine Tob Res. 2001; 3(2):177-82. DOI: 10.1080/14622200110043095. View

13.

GRAHAM F . Presidential Address, 1974. The more or less startling effects of weak prestimulation. Psychophysiology. 1975; 12(3):238-48. DOI: 10.1111/j.1469-8986.1975.tb01284.x. View

14.

Geyer M, Braff D, Swerdlow N . Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl). 2001; 156(2-3):117-54. DOI: 10.1007/s002130100811. View

15.

Stanhope K, Mirza N, Bickerdike M, Bright J, Harrington N, Hesselink M . The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat. J Pharmacol Exp Ther. 2001; 299(2):782-92. View

16.

Jonnala R, Buccafusco J . Relationship between the increased cell surface alpha7 nicotinic receptor expression and neuroprotection induced by several nicotinic receptor agonists. J Neurosci Res. 2001; 66(4):565-72. DOI: 10.1002/jnr.10022. View

17.

Perry D, Xiao Y, Nguyen H, Musachio J, Davila-Garcia M, Kellar K . Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography. J Neurochem. 2002; 82(3):468-81. DOI: 10.1046/j.1471-4159.2002.00951.x. View

18.

Jonnala R, Graham 3rd J, Terry Jr A, Beach J, Young J, Buccafusco J . Relative levels of cytoprotection produced by analogs of choline and the role of alpha7-nicotinic acetylcholine receptors. Synapse. 2003; 47(4):262-9. DOI: 10.1002/syn.10176. View

19.

Buccafusco J, Terry Jr A . The potential role of cotinine in the cognitive and neuroprotective actions of nicotine. Life Sci. 2003; 72(26):2931-42. DOI: 10.1016/s0024-3205(03)00226-1. View

20.

Chao M . Neurotrophin receptors: a window into neuronal differentiation. Neuron. 1992; 9(4):583-93. DOI: 10.1016/0896-6273(92)90023-7. View