Nicotine addiction: the possible role of functional upregulation

Buisson, Bruno; Bertrand, Daniel

doi:10.1016/s0165-6147(00)01979-9

Cited by 228 publications

(176 citation statements)

References 37 publications

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“…1 ) and modulate neuronal excitability and synaptic communication [1-4]. The health consequences of smoking and the mechanisms involved in nicotine dependence continue to be subjects of great interest [5-9]. In addition, recent attention has been directed to the potential role of nAChRs in diseases and therapeutic targets [10-23].…”

Section: α7 Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

Toyohara¹,

Hashimoto²

2010

Open Med Chem J

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Accumulating evidence suggests that α7 nicotinic receptors (α7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). A number of psychopharmacological and genetic studies shown that α7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that (α nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that α7 nAChRs might play a key role in the amyloid-β (Aβ)-mediated pathology of AD, and that α7 nAChR agonists would be potential therapeutic drugs for Aβ deposition in the brains of patients with AD. Interestingly, the altered expression of α7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective α7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of α7 nAChRs in the pathophysiology of these diseases and into the potential use of novel α7 nAChR agonists as therapeutic drugs.

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Section: α7 Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

Toyohara¹,

Hashimoto²

2010

Open Med Chem J

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“…Occupancy of these deep desensitized states by nicotine could serve as the trigger for up-regulation in receptor number (Dani and Heinemann, 1996;Fenster et al, 1999b), shown to occur in vivo for ␣4␤2 nAChRs during chronic nicotine exposure (Marks et al, 1983;Schwartz and Kellar, 1985;Flores et al, 1992;Balfour, 1994); this again could potentially involve biochemical steps, because chronic nicotine promotes enhanced ␣4 subunit phosphorylation (Hsu et al, 1997). While controversy exists over whether prolonged agonist exposure results in up-or down-regulation of receptor function (Buisson and Bertrand, 2002), recovery from this "state," whether it requires purely time (slow transition rates) or de novo receptor synthesis (Boyd, 1987;Hsu et al, 1996), likely influences synaptic transmission for prolonged periods. Girod and Role (2001) recently observed that presynaptic nAChR function could be lost for Ͼ24 h following 24 -72 h treatment with low levels of nicotine (Fig.…”

Section: Regulation Of Desensitizationmentioning

confidence: 99%

“…After removal of agonist the receptor can recover back to its initial resting state; however, although desensitization is potentially fully reversible, complete recovery need not occur-particularly following chronic agonist treatment (Katz and Thesleff, 1957). Incomplete recovery may reflect long-lasting accumulation of receptors in one or more desensitized states or indeed may be due to the permanent loss of functional channels (Simasko et al, 1986;Boyd, 1987;Lukas, 1991; although see Buisson and Bertrand, 2002). Desensitization is qualitatively the same across all members of the nicotinic receptor family, and as such its essential behavior can be captured in a general model (see below) onto which any quantitative differences among individual nAChRs can be mapped.…”

mentioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

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“…Smoking is a chronic, relapsing disorder beginning with initiation and progressing to regular smoking. Repeated nicotine administration results in neuronal adaptations, such as upregulation of nAChRs, [50][51][52] producing dependence and tolerance such that drug abstinence is accompanied by withdrawal symptoms. 53 To avoid these effects, dependent smokers are known to regulate their nicotine intake in order to maintain levels in the blood and brain.…”

Section: Candidate Gene Association Studiesmentioning

confidence: 99%

Overview of the pharmacogenomics of cigarette smoking

Tyndale

2007

Pharmacogenomics J

102

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Cigarette smoking increases the risk of numerous health problems, including cancer, cardiovascular and pulmonary disorders, making smoking the leading cause of preventable death in the world. Nicotine is primarily responsible for the highly addictive properties of cigarettes. Although the majority of smokers express a desire to quit, few are successful in doing so. Twin and family studies have indicated substantial genetic contributions to smoking behaviors. One major research focus has been to elucidate the specific genes involved; this has been accomplished primarily through genome-wide linkage analyses and candidate gene association studies. Much attention has focused on genes involved in the neurotransmitter pathways for the brain reward system and genes altering nicotine metabolism. This paper reviews the current state of knowledge for genetic factors implicated in smoking behaviors, and examines how genetic variations may affect therapeutic outcomes for drugs used to assist smoking cessation.

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Nicotine addiction: the possible role of functional upregulation

Cited by 228 publications

References 37 publications

α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

Desensitization of neuronal nicotinic receptors

Overview of the pharmacogenomics of cigarette smoking

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