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J Pharmacol Exp Ther
2015 Feb 01;3522:405-18. doi: 10.1124/jpet.114.219881.
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R-(+) and S-(-) isomers of cotinine augment cholinergic responses in vitro and in vivo.
Terry AV
,
Callahan PM
,
Bertrand D
.
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The nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2-pyrrolidinone), like its precursor, has been found to exhibit procognitive and neuroprotective effects in some model systems; however, the mechanism of these effects is unknown. In this study, both the R-(+) and S-(-) isomers of cotinine were initially evaluated in an extensive profiling screen and found to be relatively inactive across a wide range of potential pharmacologic targets. Electrophysiological studies on human α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes confirmed the absence of agonistic activity of cotinine at α4β2 or α7 nAChRs. However, a significant increase in the current evoked by a low concentration of acetylcholine was observed at α7 nAChRs exposed to 1.0 μM R-(+)- or S-(-)-cotinine. Based on these results, we used a spontaneous novel object recognition (NOR) procedure for rodents to test the hypothesis that R-(+)- or S-(-)-cotinine might improve recognition memory when administered alone or in combination with the Alzheimer's disease (AD) therapeutic agent donepezil. Although both isomers enhanced NOR performance when they were coadministered with donepezil, neither isomer was active alone. Moreover, the procognitive effects of the drug combinations were blocked by methyllycaconitine and dihydro-β-erythroidine, indicating that both α7 and α4β2 nAChRs contribute to the response. These results indicate that cotinine may sensitize α7 nAChRs to low levels of acetylcholine (a previously uncharacterized mechanism), and that cotinine could be used as an adjunctive agent to improve the effective dose range of cholinergic compounds (e.g., donepezil) in the treatment of AD and other memory disorders.
Abood,
Sites and mechanisms for nicotine's action in the brain.
1981, Pubmed
Abood,
Sites and mechanisms for nicotine's action in the brain.
1981,
Pubmed
Alkondon,
Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes.
1993,
Pubmed
Alkondon,
Nicotinic acetylcholine receptor alpha7 and alpha4beta2 subtypes differentially control GABAergic input to CA1 neurons in rat hippocampus.
2001,
Pubmed
Anderson,
Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain.
1994,
Pubmed
Arroyo,
Nicotinic modulation of cortical circuits.
2014,
Pubmed
Arroyo,
Prolonged disynaptic inhibition in the cortex mediated by slow, non-α7 nicotinic excitation of a specific subset of cortical interneurons.
2012,
Pubmed
Bennett,
Xenopus laevis RIC-3 enhances the functional expression of the C. elegans homomeric nicotinic receptor, ACR-16, in Xenopus oocytes.
2012,
Pubmed
,
Xenbase
Benowitz,
Cotinine as a biomarker of environmental tobacco smoke exposure.
1996,
Pubmed
Berger,
Nicotinic receptor-induced apoptotic cell death of hippocampal progenitor cells.
1998,
Pubmed
Bitner,
Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways.
2007,
Pubmed
,
Xenbase
Bitner,
In vivo pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107: preclinical considerations in Alzheimer's disease.
2010,
Pubmed
Bloem,
Cholinergic modulation of the medial prefrontal cortex: the role of nicotinic receptors in attention and regulation of neuronal activity.
2014,
Pubmed
Briggs,
Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists.
1998,
Pubmed
,
Xenbase
Briggs,
Gain of function mutation of the alpha7 nicotinic receptor: distinct pharmacology of the human alpha7V274T variant.
1999,
Pubmed
,
Xenbase
Broadbent,
Spatial memory, recognition memory, and the hippocampus.
2004,
Pubmed
Buccafusco,
A reversible model of the cognitive impairment associated with schizophrenia in monkeys: potential therapeutic effects of two nicotinic acetylcholine receptor agonists.
2009,
Pubmed
Buccafusco,
The potential role of cotinine in the cognitive and neuroprotective actions of nicotine.
2003,
Pubmed
Burghaus,
Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients.
2000,
Pubmed
Callahan,
Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates.
2013,
Pubmed
Callahan,
Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats.
2014,
Pubmed
Chang,
Nicotinic acetylcholine receptors containing alpha7 subunits are required for reliable synaptic transmission in situ.
1999,
Pubmed
Christophe,
Two types of nicotinic receptors mediate an excitation of neocortical layer I interneurons.
2002,
Pubmed
Dwoskin,
(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.
1999,
Pubmed
Echeverria,
Cotinine reduces amyloid-β aggregation and improves memory in Alzheimer's disease mice.
2011,
Pubmed
Echeverria,
Cotinine: a potential new therapeutic agent against Alzheimer's disease.
2012,
Pubmed
Ennaceur,
A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data.
1988,
Pubmed
Flicker,
A visual recognition memory test for the assessment of cognitive function in aging and dementia.
1987,
Pubmed
Freedman,
Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia.
1995,
Pubmed
Gao,
Evaluation of nicotine and cotinine analogs as potential neuroprotective agents for Alzheimer's disease.
2014,
Pubmed
Gotti,
Heterogeneity and complexity of native brain nicotinic receptors.
2007,
Pubmed
Gray,
Hippocampal synaptic transmission enhanced by low concentrations of nicotine.
1996,
Pubmed
Grizzell,
Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice.
2014,
Pubmed
Grizzell,
New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine.
2015,
Pubmed
Guan,
Decreased protein levels of nicotinic receptor subunits in the hippocampus and temporal cortex of patients with Alzheimer's disease.
2000,
Pubmed
Hatsukami,
Safety of cotinine in humans: physiologic, subjective, and cognitive effects.
1997,
Pubmed
Hefft,
Synaptic transmission at nicotinic acetylcholine receptors in rat hippocampal organotypic cultures and slices.
1999,
Pubmed
Hogg,
An automated system for intracellular and intranuclear injection.
2008,
Pubmed
,
Xenbase
Hukkanen,
Metabolism and disposition kinetics of nicotine.
2005,
Pubmed
Kem,
The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21).
2000,
Pubmed
Maelicke,
Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease.
2000,
Pubmed
McGehee,
Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors.
1995,
Pubmed
Messi,
Activation of alpha7 nicotinic acetylcholine receptor promotes survival of spinal cord motoneurons.
1997,
Pubmed
Myhrer,
The role of medial and lateral hippocampal perforant path lesions and object distinctiveness in rats' reaction to novelty.
1988,
Pubmed
O'Leary,
Cotinine selectively activates a subpopulation of alpha3/alpha6beta2 nicotinic receptors in monkey striatum.
2008,
Pubmed
Patel,
Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice.
2014,
Pubmed
Prickaerts,
EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors.
2012,
Pubmed
Purdy,
Changes to the object recognition system in patients with dementia of the Alzheimer's type.
2002,
Pubmed
Rampon,
Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice.
2000,
Pubmed
Reed,
Impaired recognition memory in patients with lesions limited to the hippocampal formation.
1997,
Pubmed
Riordan,
Effectiveness of adding memantine to an Alzheimer dementia treatment regimen which already includes stable donepezil therapy: a critically appraised topic.
2011,
Pubmed
Rosecrans,
Nicotine as a discriminative stimulus to behavior: its characterization and relevance to smoking behavior.
1979,
Pubmed
Schiavetto,
Neural correlates of memory for object identity and object location: effects of aging.
2002,
Pubmed
Sloan,
Nature of nicotine binding to rat brain P2 fraction.
1984,
Pubmed
Squire,
Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans.
1992,
Pubmed
Squire,
The medial temporal lobe.
2004,
Pubmed
Terry,
The nicotine metabolite, cotinine, attenuates glutamate (NMDA) antagonist-related effects on the performance of the five choice serial reaction time task (5C-SRTT) in rats.
2012,
Pubmed
Terry,
Cotinine, a neuroactive metabolite of nicotine: potential for treating disorders of impaired cognition.
2005,
Pubmed
Vainio,
Cotinine binding to nicotinic acetylcholine receptors in bovine chromaffin cell and rat brain membranes.
2001,
Pubmed
Wildeboer-Andrud,
Cotinine impacts sensory processing in DBA/2 mice through changes in the conditioning amplitude.
2014,
Pubmed
