Neuronal nicotinic acetylcholine receptors: a new target site of ethanol

Narahashi, Toshio; Aistrup, Gary L.; Marszalec, William; Nagata, Keiichi

doi:10.1016/s0197-0186(99)00055-8

Cited by 109 publications

(61 citation statements)

References 83 publications

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“…These observations are consistent with most other studies available to date in neuronal cells showing that ethanol acts mainly via nAChRs (37,38).…”

Section: Role Of Nachrs In Ethanol-induced Fibronectin Expressionsupporting

confidence: 93%

Mechanisms of Tissue Remodeling in Sepsis-Induced Acute Lung Injury

Roman¹

2004

PsycEXTRA Dataset

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“…These observations are consistent with most other studies available to date in neuronal cells showing that ethanol acts mainly via nAChRs (37,38).…”

Section: Role Of Nachrs In Ethanol-induced Fibronectin Expressionsupporting

confidence: 93%

Mechanisms of Tissue Remodeling in Sepsis-Induced Acute Lung Injury

Roman¹

2004

PsycEXTRA Dataset

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“…Furthermore, heavy drinkers tend to be heavy smokers, and alcohol influences nicotine dependence (16). Both nicotine and ethanol can either directly or indirectly activate the brain reward system through neuronal nicotinic acetylcholine receptors (nAChRs) (16)(17)(18). The nAChRs are well characterized ligandgated ion channels that, in addition to mediating the rewarding properties of nicotine, also regulate several central functions, such as memory and attention, sleep and wakefulness, anxiety and pain (19).…”

mentioning

confidence: 99%

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Steensland

Simms

Holgate

et al. 2007

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

344

370

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Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the ␣4␤2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the ␣4␤2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.A lcohol dependence constitutes one of the most serious public health problems worldwide. There are only three medications available for the treatment of alcohol dependence; disulfiram, acamprosate, and naltrexone. The opioid antagonist, naltrexone, has demonstrated the most consistent effect in reducing alcohol consumption in the context of behavioral therapy (1). Naltrexone has been shown to decrease ethanol consumption in numerous animal (2-6) and clinical studies (7-10) and has been shown to be more effective in heavy or excessive drinkers (11). However, not all patients respond to naltrexone, which is partly explained by genetic variations in the opioid receptor gene (12). Furthermore, opioid receptor antagonists decrease both ethanol and sucrose intake in rodents (13,14). Alcohol dependence is a complex disorder that will require the use of different therapeutic approaches to treat the disease effectively.Environmental and genetic factors contribute to an individual's risk of becoming dependent on drugs of abuse such as ethanol and nicotine. Approximately 85% of alcoholics smoke, and it has been suggested that common genes control the development of both alcohol and nicotine dependence (15). Furthermore, heavy drinkers tend to be heavy smokers, and alcohol influences nicotine dependence (16). Both nicotine and ethanol can either directly or indirectly activate the brain reward system through neuronal nicotinic acetylcholine re...

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“…It has been found to have a role in a wide range of pathological conditions and diseases including epilepsy (2), schizophrenia (3), Alzheimer's (4), Parkinson's (5), neuromuscular diseases (6), inflammation (7), nicotine addiction (8), and addiction to other drugs such as alcohol (9) and cocaine (10), as well as a role in anesthetic action (11). The nicotinic acetylcholine receptor is a member of a superfamily of pentameric receptors that include the serotonin (excitory), GABA, and glycine (inhibitory) receptors that are all involved in the transmission and modification of electrical signals in excitory cells.…”

mentioning

confidence: 99%

A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

Law

Henchman

McCammon

2005

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

134

142

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The nicotinic acetylcholine receptor is a well characterized ligandgated ion channel, yet a proper description of the mechanisms involved in gating, opening, closing, ligand binding, and desensitization does not exist. Until recently, atomic-resolution structural information on the protein was limited, but with the production of the x-ray crystal structure of the Lymnea stagnalis acetylcholine binding protein and the EM image of the transmembrane domain of the torpedo electric ray nicotinic channel, we were provided with a window to examine the mechanism by which this channel operates. A 15-ns all-atom simulation of a homology model of the homomeric human ␣7 form of the receptor was conducted in a solvated palmitoyl-2-oleoyl-sn-glycerol-phosphatidylcholine bilayer and examined in detail. The receptor was unliganded. The structure undergoes a twist-to-close motion that correlates movements of the C loop in the ligand binding domain, via the ␤10-strand that connects the two, with the 10°rotation and inward movement of two nonadjacent subunits. The Cys loop appears to act as a stator around which the ␣-helical transmembrane domain can pivot and rotate relative to the rigid ␤-sheet binding domain. The M2-M3 loop may have a role in controlling the extent or kinetics of these relative movements. All of this motion, along with essential dynamics analysis, is suggestive of the direction of larger motions involved in gating of the channel.T he nicotinic acetylcholine receptor is one of the best-studied ligand-gated ion channels (LGICs) (1). It has been found to have a role in a wide range of pathological conditions and diseases including epilepsy (2), schizophrenia (3), Alzheimer's (4), Parkinson's (5), neuromuscular diseases (6), inflammation (7), nicotine addiction (8), and addiction to other drugs such as alcohol (9) and cocaine (10), as well as a role in anesthetic action (11). The nicotinic acetylcholine receptor is a member of a superfamily of pentameric receptors that include the serotonin (excitory), GABA, and glycine (inhibitory) receptors that are all involved in the transmission and modification of electrical signals in excitory cells. The family is known as the Cys-loop LGIC family, because of a conserved pair of linked cysteines in the N-terminal domain of the receptor (12). Within the superfamily, an array of different nicotinic receptor subunits exists (13,14), making different subunit assemblies possible, for different roles, in different cell types. In all of these receptors, the ligand binds at the interface between the ␣ and other subunits of the ligand binding domain (LBD). This event begins a chain reaction of conformational changes within the receptor that transmits the message of ligand binding to the transmembrane domain (TMD), which then opens to allow the passage of ions through the channel. Although the genetics, kinetics, electrophysiology, and many topological aspects are well characterized for the nicotinic receptor (15, 16), the exact nature of the structural rearrangments involved in activ...

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Neuronal nicotinic acetylcholine receptors: a new target site of ethanol

Cited by 109 publications

References 83 publications

Mechanisms of Tissue Remodeling in Sepsis-Induced Acute Lung Injury

Mechanisms of Tissue Remodeling in Sepsis-Induced Acute Lung Injury

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

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