Calcium Regulation of Agonist Binding to α7‐Type Nicotinic Acetylcholine Receptors in Adult and Fetal Rat Hippocampus

Ospina, Jose A.; Broide, Ron S.; Acevedo, Diana; Robertson, Richard T.; Leslie, Frances M.

doi:10.1046/j.1471-4159.1998.70031061.x

Cited by 25 publications

(19 citation statements)

References 30 publications

(40 reference statements)

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“…In rodents, early and transient expression of a7 nAChRs has also been observed in other brain regions, including the developing hippocampal formation (Ospina et al, 1998;Adams et al, 2002) and spinal cord (Tribollet et al, 2004). A similar early developmental pattern of expression has also been observed in chick brain and spinal cord (Couturier et al, 1990).…”

Section: A7 Nachrsmentioning

confidence: 72%

Nicotine and brain development

Dwyer

Broide

Leslie

2008

Birth Defects Research Pt C

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226

180

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Preclinical studies, using primarily rodent models, have shown acetylcholine to have a critical role in brain maturation via activation of nicotinic acetylcholine receptors (nAChRs), a structurally diverse family of ligand-gated ion channels. nAChRs are widely expressed in fetal central nervous system, with transient upregulation in numerous brain regions during critical developmental periods. Activation of nAChRs can have varied developmental influences that are dependent on the pharmacologic properties and localization of the receptor. These include regulation of transmitter release, gene expression, neurite outgrowth, cell survival, and synapse formation and maturation. Aberrant exposure of fetal and neonatal brain to nicotine, through maternal smoking or nicotine replacement therapy (NRT), has been shown to have detrimental effects on cholinergic modulation of brain development. These include alterations in sexual differentiation of the brain, and in cell survival and synaptogenesis. Long-term alterations in the functional status and pharmacologic properties of nAChRs may also occur, which result in modifications of specific neural circuitry such as the brainstem cardiorespiratory network and sensory thalamocortical gating. Such alterations in brain structure and function may contribute to clinically characterized deficits that result from maternal smoking, such as sudden infant death syndrome and auditory-cognitive dysfunction. Although not the only constituent of tobacco smoke, there is now abundant evidence that nicotine is a neural teratogen. Thus, alternatives to NRT should be sought as tobacco cessation treatments in pregnant women.

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Section: A7 Nachrsmentioning

confidence: 72%

Nicotine and brain development

Dwyer

Broide

Leslie

2008

Birth Defects Research Pt C

Self Cite

226

180

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“…Mice were killed by CO 2 asphyxiation, and brains were extracted and frozen in isopentane at Ϫ20°C. Coronal sections (20 m thick) through selected brain regions were prepared on a cryostat at Ϫ20°C and labeled with [ 125 I]epibatidine for measurement of ␣4␤2 nAChR binding sites (18) or [ 125 I]␣-bungarotoxin for measurement of ␣7 nAChRs (19). For [ 125 I]epibatidine binding, slides were preincubated at room temperature for 10 min in buffer (50 mM Tris⅐HCl͞120 mM NaCl͞5 mM KCl͞2.5 mM CaCl 2 ͞1 mM MgCl 2 , pH 7.4) and incubated with 0.08 nM radioligand at room temperature for 90 min in the absence and presence of nicotine (300 M) to define nonspecific binding.…”

Section: Methodsmentioning

confidence: 99%

“…19. A calibration curve of optical density against radioligand concentration (fmol͞mg of tissue) was constructed by using values of known radioactivity.…”

Section: Methodsmentioning

confidence: 99%

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Oddo

Caccamo

Green

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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188

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The association between nicotinic acetylcholine receptor (nAChR) dysfunction and cognitive decline in Alzheimer's disease (AD) has been widely exploited for its therapeutic potential. The effects of chronic nicotine exposure on A␤ accumulation have been studied in both humans and animal models, but its therapeutic efficacy for AD neuropathology is still unresolved. To date, no in vivo studies have addressed the consequences of activating nAChRs on tau pathology. To determine the effects of chronic nicotine administration on A␤ and tau pathology, we chronically administrated nicotine to a transgenic model of AD (3xTg-AD) in their drinking water. Here, we show that chronic nicotine intake causes an up-regulation of nicotinic receptors, which correlated with a marked increase in the aggregation and phosphorylation state of tau. These data show that nicotine exacerbates tau pathology in vivo. The increase in tau phosphorylation appears to be due to the activation of p38-mitogen-activated protein kinase, which is known to phosphorylate tau in vivo and in vitro. We also show that the 3xTg-AD mice have an age-dependent reduction of ␣7nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of ␣7nAChRs is first apparent at 6 months of age and is restricted to brain regions that show intraneuronal A␤42 accumulation. Finally, this study highlights the importance of testing compounds designed to ameliorate AD pathology in a model with both neuropathological lesions because of the differential effects it can have on either A␤ or tau.T he loss of cholinergic neurons is a critical event in the pathogenesis of Alzheimer's disease (AD) (1, 2). Acetylcholine (ACh) is a key neuromodulator in the synaptic mechanisms involved with learning and memory (3) and acts through two major receptor subtypes: nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). Whereas mAChRs are metabotropic, nAChRs are ligand-gated ion channels formed by a combination of five subunits (␣, ␤, ␥, ␦, and ), each encoded by a member of a gene superfamily (4). The ␣7 and ␣4␤2 are two of the major nicotinic receptors subtypes present in the brain (4, 5). For the past several years, a mainstay of AD therapy has been aimed at inhibiting acetylcholinesterase, the enzyme responsible for degrading ACh in the synaptic cleft, and thereby increasing ACh levels in the brain (6). These compounds slow the phenotypical memory impairments; however, their effectiveness is diminished over time.The AD brain is characterized by two pathological hallmarks: amyloid plaques, which are mainly composed of the A␤ peptide, and neurofibrillary tangles (NFTs), which consist of hyperphosphorylated tau protein. Several studies have shown that nAChRs are selectively reduced in the AD brain, particularly in regions harboring plaques and neurofibrillary tangles, suggesting a potential relationship between nicotinic receptors and AD neuropathology (5, 7-9). Notably, chronic nicotine treatment has also been shown to redu...

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“…To compare the affinities of nicotine and CSE for various nAChR types, brains were sectioned on a cryostat, mounted to slides, and processed for binding under conditions that selectively label different nAChR types (Perry et al, 2002;Ospina et al, 1998). Treated slides were placed in light-tight cassettes with 14 C standards of known radioactivity and exposed to Kodak BioMax MR film.…”

Section: Neurochemical Studiesmentioning

confidence: 99%

Comparison of the Reinforcing Properties of Nicotine and Cigarette Smoke Extract in Rats

Costello

Reynaga

Mojica

et al. 2014

Neuropsychopharmacol

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Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used selfadministration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rats, made by bubbling cigarette smoke through a saline solution. CSE is more potent than nicotine alone in both the acquisition and maintenance of self-administration, but did not exhibit higher progressive ratio responding. Mecamylamine and varenicline had similar potencies to block nicotine and CSE selfadministration, indicating the involvement of nicotinic receptors in CSE reinforcement. Following extinction of responding, reinstatement was triggered by exposing animals to a pharmacological stressor, yohimbine (2.5 mg/kg, i.p.), alone and in combination with cues. Animals that self-administered CSE were significantly more sensitive to stress-induced reinstatement than those that self-administered nicotine. Ligand binding autoradiography studies showed nicotine and CSE to have similar affinities for different nicotinic receptor types. CSE significantly reduced MAO-A and MAO-B activities in vitro, whereas nicotine did not. Although CSE inhibition of MAO-A activity in vitro was found to be partially irreversible, irreversible inhibition was not observed in vivo. These experiments show that CSE is an effective reinforcer acting via nicotinic receptors. Furthermore, it better models MAO inhibition and is more sensitive to stress-induced reinstatement than nicotine alone, which is a potent trigger for relapse in smokers.

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Calcium Regulation of Agonist Binding to α7‐Type Nicotinic Acetylcholine Receptors in Adult and Fetal Rat Hippocampus

Cited by 25 publications

References 30 publications

Nicotine and brain development

Nicotine and brain development

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Comparison of the Reinforcing Properties of Nicotine and Cigarette Smoke Extract in Rats

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