Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine

Buccafusco, Jerry J.; Shuster, Laura; Terry, Alvin V.

doi:10.1016/j.neulet.2006.11.028

Cited by 30 publications

(20 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, at levels found in brains of smokers, cotinine may influence striatal function by chronically desensitizing nAChRs, thereby inhibiting acetylcholine-induced effects. This phenomenon has been demonstrated in a number of experimental systems including rats and bovine chromaffin cells (Vainio et al, 1998a(Vainio et al, , 2000Koh et al, 2003;Buccafusco et al, 2007). Because excitotoxicity may be involved in neuronal loss in Parkinson's disease (PD), cotinine inhibition of nAChRs through desensitization may protect against nigrostriatal degeneration by decreasing dopaminergic terminal excitability (Egea et al, 2006).…”

Section: Medial Lateralmentioning

confidence: 98%

“…These observations raise the question of whether cotinine is pharmacologically active in vivo, thereby contributing to the overall effects of tobacco exposure. Indeed, numerous studies indicate that cotinine influences autonomic functions including heart rate, blood pressure, respiration, and hormone regulation (Borzelleca et al, 1962;Dominiak et al, 1985;Andersson et al, 1993;Buccafusco et al, 2007), and it also affects behavioral and cognitive task performance (Risner et al, 1985;Buccafusco and Terry, 2003;Terry et al, 2005).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cotinine Selectively Activates a Subpopulation of α3/α6β2 Nicotinic Receptors in Monkey Striatum

O’Leary

Parameswaran

McIntosh³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

The nicotine metabolite cotinine is an abundant long-lived bioactive compound that may contribute to the overall physiological effects of tobacco use. Although its mechanism of action in the central nervous system has not been extensively investigated, cotinine is known to evoke dopamine release in the nigrostriatal pathway through an interaction at nicotinic receptors (nAChRs). Because considerable evidence now demonstrates the presence of multiple nAChRs in the striatum, the present experiments were done to determine the subtypes through which cotinine exerts its effects in monkeys, a species that expresses similar densities of striatal ␣4␤2* (nAChR containing the ␣4 and ␤2 subunits, but not ␣3 or ␣6) and ␣3/␣6␤2* (nAChR composed of the ␣3 or ␣6 subunits and ␤2) nAChRs. Competition binding studies showed that cotinine interacts with both ␣4␤2* and ␣3/␣6␤2* nAChR subtypes in the caudate, with cotinine IC 50 values for inhibition of 5-[ ]dopamine release from two ␣3/␣6␤2* nAChR populations, one of which was sensitive to cotinine and the other was not. This cotinine-insensitive subtype was only present in the medial caudate and was preferentially lost with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal damage. In contrast, cotinine and nicotine elicited equivalent levels of ␣4␤2* nAChR-mediated dopamine release. These data demonstrate that cotinine functionally discriminates between two ␣3/␣6␤2* nAChRs in monkey striatum, with the cotinine-insensitive ␣3/␣6␤2* nAChR preferentially vulnerable to nigrostriatal damage.Cotinine is one of the major metabolites of nicotine in a number of mammalian species, including humans (Fig. 1). Cotinine has a much longer pharmacokinetic half-life (15-19 h) than nicotine (2-3 h), which results in plasma cotinine levels 5 to 10-fold greater than those of the parent compound (Hukkanen et al., 2005). These observations raise the question of whether cotinine is pharmacologically active in vivo, thereby contributing to the overall effects of tobacco exposure. Indeed, numerous studies indicate that cotinine influences autonomic functions including heart rate, blood pressure, respiration, and hormone regulation (Borzelleca et al., 1962;Dominiak et al., 1985;Andersson et al., 1993;Buccafusco et al., 2007), and it also affects behavioral and cognitive task performance (Risner et al., 1985;Buccafusco and Terry, 2003;Terry et al., 2005).The cotinine-induced changes described above seem to be independent of, and frequently opposite to, those of nicotine. However, like nicotine, they seem to be mediated by interaction with nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated ion channels composed of various combinations of ␣ and ␤ subunits. Cotinine displaces binding of various radiolabeled nAChR ligands to rat whole brain, hippocampal, and cortical membrane preparations, with a potency ϳ100-fold less than that of nicotine (Sloan et al., 1984;Anderson and Arneric, 1994;Vainio and Tuominen, 2001). This interaction is of functional relevance because coti...

show abstract

Section: Medial Lateralmentioning

confidence: 98%

mentioning

confidence: 99%

Cotinine Selectively Activates a Subpopulation of α3/α6β2 Nicotinic Receptors in Monkey Striatum

O’Leary

Parameswaran

McIntosh³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…Preliminary data suggest that cotinine exhibits the properties of a weak α7 subtype nicotinic agonist and that cotinine administration leads to improvement in performance accuracy on a delayed matching task in monkeys and can reverse drug induced deficits in pre-pulse inhibition of acoustic startle in rats. The drug has also been shown to be as potent as nicotine in the ability to act as a cytoprotective agent in cells that express a neuronal cholinergic phenotype (Buccafusco and Terry 2003;Buccafusco et al 2007). …”

Section: Neuroprotective Effects Of Nicotine and Cotininementioning

confidence: 99%

The Effects of Tobacco Smoke and Nicotine on Cognition and the Brain

2007

View full text Add to dashboard Cite

Tobacco smoke consists of thousands of compounds including nicotine. Many constituents have known toxicity to the brain, cardiovascular, and pulmonary systems. Nicotine, on the other hand, by virtue of its short-term actions on the cholinergic system, has positive effects on certain cognitive domains including working memory and executive function and may be, under certain conditions, neuroprotective. In this paper, we review recent literature, laboratory and epidemiologic, that describes the components of mainstream and sidestream tobacco smoke, including heavy metals and their toxicity, the effect of medicinal nicotine on the brain, and studies of the relationship between smoking and (1) preclinical brain changes including silent brain infarcts; white matter hyperintensities, and atrophy; (2) single measures of cognition; (3) cognitive decline over repeated measures; and (4) dementia. In most studies, exposure to smoke is associated with increased risk for negative preclinical and cognitive outcomes in younger people as well as in older adults. Potential mechanisms for smoke's harmful effects include oxidative stress, inflammation, and atherosclerotic processes. Recent evidence implicates medicinal nicotine as potentially harmful to both neurodevelopment in children and to catalyzing processes underlying neuropathology in Alzheimer's Disease. The reviewed evidence suggests caution with the use of medicinal nicotine in pregnant mothers and older adults at risk for certain neurological disease. Directions for future research in this area include the assessment of comorbidities (alcohol consumption, depression) that could confound the association between smoking and neurocognitive outcomes, the use of more specific measures of smoking behavior and cognition, the use of biomarkers to index exposure to smoke, and the assessment of cognition-related genotypes to better understand the role of interactions between smoking/nicotine and variation in genotype in determining susceptibility to the neurotoxic effects of smoking and the putative beneficial effects of medicinal nicotine.

show abstract

“…Alternatively, to explain the beneficial effects of cotinine on cognitive abilities, it has been postulated that cotinine desensitizes nAChRs located on inhibitory GABAergic neurons of the hippocampus, provoking the activation of the excitatory glutamate receptors in this region of the brain, and thereby stimulating cognitive abilities [73,74]. This hypothesis is interesting; however, direct evidence that cotinine desensitizes the hippocampal α7 receptor is still needed.…”

Section: Cotinine As a Modulator Of The Nicotinic Acetylcholine Recepmentioning

confidence: 99%

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Echeverrı́a

Zeitlin

2012

CNS Neuroscience & Therapeutics

View full text Add to dashboard Cite

SUMMARYTobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD. Alzheimer's disease: The Cholinergic System as a Therapeutic TargetAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia [1,2]. The disease is characterized by extracellular accumulation of senile plaques, mainly composed of aggregated forms of the amyloid-beta peptide (Aβ), as well as intracellular accumulation of neurofibrillary tangles of the microtubule-associated protein tau [1]. These neuropathological changes are associated with structural brain abnormalities, inflammation, and cognitive impairment such as impairment of working memory in AD patients. The progressive loss of memory in AD patients correlates with increased levels of Aβ and the deterioration of the cholinergic system in the brain. The degenerative process involves a sequence of pathological events, including early degeneration of the cerebral basal forebrain and subsequent deterioration of the cortical cholinergic system [3,4]. This deterioration commonly includes a reduction in the levels of acetylcholine (ACh) and α3, α4, and α7 nicotinic ACh receptors (nAChRs) as well as a decrease in the activity of choline acetyltranferase in the brain [5].Of these nAChRs, the α7 receptors are considered to be ideal therapeutic targets for several neurological conditions, including AD, schizophrenia, and Parkinson's disease (PD) as well as tobacco addiction [6,7]. The α7nAChR is a homomeric pentamer that has a high permeability to calcium (P Ca :P Na ≈ 10), and undergoes rapid and reversible desensitization and pronounced inward rectification [8]. The α7 subunit is highly expressed in the cortex, hippocampus, and hypothalamus [8], and has also been suggested to have functionally important expression in ...

show abstract

Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine

Cited by 30 publications

References 16 publications

Cotinine Selectively Activates a Subpopulation of α3/α6β2 Nicotinic Receptors in Monkey Striatum

Cotinine Selectively Activates a Subpopulation of α3/α6β2 Nicotinic Receptors in Monkey Striatum

The Effects of Tobacco Smoke and Nicotine on Cognition and the Brain

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Contact Info

Product

Resources

About