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Current Neuropharmacology 2018Cigarette smoking is the main cause of preventable death in developed countries. While the direct positive behavioral reinforcing effect of nicotine has historically... (Review)
Review
BACKGROUND
Cigarette smoking is the main cause of preventable death in developed countries. While the direct positive behavioral reinforcing effect of nicotine has historically been considered the primary mechanism driving the development of TUD, accumulating contemporary research suggests that the cognitive-enhancing effects of nicotine may also significantly contribute to the initiation and maintenance of TUD, especially in individuals with pre-existing cognitive deficits.
METHODS
We provide a selective overview of recent advances in understanding nicotine's effects on cognitive function, a discussion of the role of cognitive function in vulnerability to TUD, followed by an overview of the neurobiological mechanisms underlying the cognitive effects of nicotine.
RESULTS
Preclinical models and human studies have demonstrated that nicotine has cognitiveenhancing effects. Attention, working memory, fine motor skills and episodic memory functions are particularly sensitive to nicotine's effects. Recent studies have demonstrated that the α4, β2, and α7 subunits of the nicotinic acetylcholine receptor (nAChR) participate in the cognitive-enhancing effects of nicotine. Imaging studies have been instrumental in identifying brain regions where nicotine is active, and research on the dynamics of large-scale networks after activation by, or withdrawal from, nicotine hold promise for improved understanding of the complex actions of nicotine on human cognition.
CONCLUSION
Because poor cognitive performance at baseline predicts relapse among smokers who are attempting to quit smoking, studies examining the potential efficacy of cognitive-enhancement as strategy for the treatment of TUD may lead to the development of more efficacious interventions.
Topics: Animals; Cognition; Humans; Nicotine; Nicotinic Agonists; Tobacco Use Disorder
PubMed: 29110618
DOI: 10.2174/1570159X15666171103152136 -
Handbook of Experimental Pharmacology 2009Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and... (Review)
Review
Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDPglucuronosyltransferase (UGT), and flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications, and smoking itself. Substantial racial/ethnic differences are observed in nicotine metabolism, which are likely influenced by both genetic and environmental factors. The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails. The current optimal plasma cotinine cut-point to distinguish smokers from non-smokers in the general US population is 3 ng ml(-1). This cut-point is much lower than that established 20 years ago, reflecting less secondhand smoke exposure due to clear air policies and more light or occasional smoking.
Topics: Biomarkers; Cotinine; Humans; Nicotine; Nicotinic Agonists; Smoking; Smoking Cessation; Tissue Distribution; Nicotiana; Tobacco Use Disorder
PubMed: 19184645
DOI: 10.1007/978-3-540-69248-5_2 -
The Western Journal of Emergency... Aug 2019Given the rise in teenage use of electronic nicotine delivery systems ("vaping") in congruence with the increasing numbers of drug-related emergencies, it is critical to... (Review)
Review
Given the rise in teenage use of electronic nicotine delivery systems ("vaping") in congruence with the increasing numbers of drug-related emergencies, it is critical to expand the knowledge of the physical and behavioral risks associated with developmental nicotine exposure. A further understanding of the molecular and neurochemical underpinnings of nicotine's gateway effects allows emergency clinicians to advise patients and families and adjust treatment accordingly, which may minimize the use of tobacco, nicotine, and future substances. Currently, the growing use of tobacco products and electronic cigarettes among teenagers represents a major public health concern. Adolescent exposure to tobacco or nicotine can lead to subsequent abuse of nicotine and other substances, which is known as the gateway hypothesis. Adolescence is a developmentally sensitive time period when risk-taking behaviors, such as sensation seeking and drug experimentation, often begin. These hallmark behaviors of adolescence are largely due to maturational changes in the brain. The developing brain is particularly vulnerable to the harmful effects of drugs of abuse, including tobacco and nicotine products, which activate nicotinic acetylcholine receptors (nAChRs). Disruption of nAChR development with early nicotine use may influence the function and pharmacology of the receptor subunits and alter the release of reward-related neurotransmitters, including acetylcholine, dopamine, GABA, serotonin, and glutamate. In this review, we emphasize that the effects of nicotine are highly dependent on timing of exposure, with a dynamic interaction of nAChRs with dopaminergic, endocannabinoid, and opioidergic systems to enhance general drug reward and reinforcement. We analyzed available literature regarding adolescent substance use and nicotine's impact on the developing brain and behavior using the electronic databases of PubMed and Google Scholar for articles published in English between January 1968 and November 2018. We present a large collection of clinical and preclinical evidence that adolescent nicotine exposure influences long-term molecular, biochemical, and functional changes in the brain that encourage subsequent drug abuse.
Topics: Adolescent; Electronic Nicotine Delivery Systems; Global Health; Humans; Nicotine; Nicotinic Agonists; Substance-Related Disorders
PubMed: 31539325
DOI: 10.5811/westjem.2019.7.41661 -
Annual Review of Pharmacology and... 2009Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter... (Review)
Review
Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized by CYP 2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.
Topics: Animals; Behavior, Addictive; Benzazepines; Bupropion; Ganglionic Stimulants; Humans; Nicotine; Nicotinic Agonists; Nonprescription Drugs; Quinoxalines; Smoking; Tobacco Use Disorder; Varenicline
PubMed: 18834313
DOI: 10.1146/annurev.pharmtox.48.113006.094742 -
Neuropharmacology Sep 2015How does an agonist activate a receptor? In this article I consider the activation process in muscle nicotinic acetylcholine receptors (AChRs), a prototype for... (Review)
Review
How does an agonist activate a receptor? In this article I consider the activation process in muscle nicotinic acetylcholine receptors (AChRs), a prototype for understanding the energetics of binding and gating in other ligand-gated ion channels. Just as movements that generate gating currents activate voltage-gated ion channels, movements at binding sites that generate an increase in affinity for the agonist activate ligand-gated ion channels. The main topics are: i) the schemes and intermediate states of AChR activation, ii) the energy changes of each of the steps, iii) the sources of the energies, iv) the three kinds of AChR agonist binding site and v) the correlations between binding and gating energies. The binding process is summarized as sketches of different conformations of an agonist site. The results suggest that agonists lower the free energy of the active conformation of the protein in stages by establishing favorable, local interactions at each binding site, independently. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.
Topics: Animals; Binding Sites; Humans; Nicotinic Agonists; Receptors, Nicotinic
PubMed: 25446670
DOI: 10.1016/j.neuropharm.2014.10.004 -
Nicotine & Tobacco Research : Official... Feb 2019Interest in nicotinic acetylcholine receptor (nAChR) ligands as potential therapeutic agents for cognitive disorders began more than 30 years ago when it was first... (Review)
Review
UNLABELLED
Interest in nicotinic acetylcholine receptor (nAChR) ligands as potential therapeutic agents for cognitive disorders began more than 30 years ago when it was first demonstrated that the tobacco alkaloid nicotine could improve cognitive function in nicotine-deprived smokers as well as nonsmokers. Numerous animal and human studies now indicate that nicotine and a variety of nAChR ligands have the potential to improve multiple domains of cognition including attention, spatial learning, working memory, recognition memory, and executive function. The purpose of this review is to (1) discuss several pharmacologic strategies that have been developed to enhance nAChR activity (eg, agonist, partial agonist, and positive allosteric modulator) and improve cognitive function, (2) provide a brief overview of some of the more common rodent behavioral tasks with established translational validity that have been used to evaluate nAChR ligands for effects on cognitive function, and (3) briefly discuss some of the topics of debate regarding the development of optimal therapeutic strategies using nAChR ligands. Because of their densities in the mammalian brain and the amount of literature available, the review primarily focuses on ligands of the high-affinity α4β2* nAChR ("*" indicates the possible presence of additional subunits in the complex) and the low-affinity α7 nAChR. The behavioral task discussion focuses on representative methods that have been designed to model specific domains of cognition that are relevant to human neuropsychiatric disorders and often evaluated in human clinical trials.
IMPLICATIONS
The preclinical literature continues to grow in support of the development of nAChR ligands for a variety of illnesses that affect humans. However, to date, no new nAChR ligand has been approved for any condition other than nicotine dependence. As discussed in this review, the studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (ie, beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.
Topics: Animals; Cognition; Cognition Disorders; Drug Discovery; Drug Evaluation, Preclinical; Humans; Ligands; Nicotinic Agonists; Receptors, Nicotinic
PubMed: 30137518
DOI: 10.1093/ntr/nty166 -
Molecules (Basel, Switzerland) Jul 2019Neuronal α4β2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain...
Neuronal α4β2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer α4β2 nAChRs subtypes. The most important therapeutic use for α4β2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new α4β2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of hα4β2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds.
Topics: Binding, Competitive; Dose-Response Relationship, Drug; Humans; Kinetics; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Nicotine; Nicotinic Agonists; Protein Binding; Receptors, Nicotinic; Structure-Activity Relationship
PubMed: 31344816
DOI: 10.3390/molecules24152684 -
Biochemical Pharmacology Oct 2015The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and... (Review)
Review
The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ∼300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by αY190) that behaves similarly at all sites and a coupled pair (led by γW55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of α(1) and one each of β, δ, and either γ (fetal) or ϵ (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at αδ and either αγ or αϵ subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C→O opening rate constant and C↔O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly to reach a peak that corresponds to PO ∼0.96.
Topics: Binding Sites; Humans; Motor Endplate; Nicotinic Agonists; Protein Conformation; Protein Subunits; Receptors, Nicotinic
PubMed: 26206191
DOI: 10.1016/j.bcp.2015.06.024 -
The Journal of Physical Chemistry... Oct 2022We report a detailed structural study of cytisine, an alkaloid used to help with smoking cessation, looking forward to unveiling its role as a nicotinic agonist....
We report a detailed structural study of cytisine, an alkaloid used to help with smoking cessation, looking forward to unveiling its role as a nicotinic agonist. High-resolution rotational spectroscopy has allowed us to characterize two different conformers exhibiting axial and equatorial arrangements of the piperidinic NH group. Unexpectedly, the axial form has been found as the predominant configuration, in contrast to that observed for related molecules, such as piperidine. This anomalous behavior has been justified in terms of an intramolecular NH···N hydrogen bond. Moreover, this interaction justifies the overstabilization of the axial conformer over the equatorial one and is crucial for the mechanism of action of cytisine over the nicotinic receptor, further rationalizing its behavior as a nicotinic agonist.
Topics: Nicotinic Agonists; Alkaloids; Receptors, Nicotinic; Piperidines
PubMed: 36264108
DOI: 10.1021/acs.jpclett.2c02021 -
European Neuropsychopharmacology : the... Dec 2019Neuroimaging and preclinical studies showing that nicotinic receptors (nAChR) may play a role in mood control has increased interest in targeting the cholinergic system...
Neuroimaging and preclinical studies showing that nicotinic receptors (nAChR) may play a role in mood control has increased interest in targeting the cholinergic system for treatment of major depressive disorder. Indeed, modulation of nAChRs in the basolateral amygdala (BLA) are sufficient to produce an anti-immobility effect in the mouse tail suspension test. However, how α7 nAChR modulation impacts BLA neuronal activity in vivo as well as the downstream mechanisms involved in its mood-related effects are not understood. In this work, we used the unpredictable chronic mild stress (CMS) model to investigate the mechanisms underlying the antidepressant-like effect of an α7 nAChR full agonist on BLA-induced changes in dopaminergic neurotransmission. Male adult Sprague-Dawley rats were exposed to four weeks of CMS. Behavioral and electrophysiological experiments were performed within one week following stress. CMS exposure increased rats' immobility time in the forced swimming test, decreased the number of spontaneously active dopamine neurons in the ventral tegmental area and increased the firing rate of putative projection neurons in the BLA. Stress-induced behavioral and electrophysiological changes were reversed by a single systemic administration of PNU282987. In summary, our findings corroborate previous descriptions of a potential rapid antidepressant effect for the α7 nAChR full agonist. This effect appears to involve a mechanism distinct from those of classic antidepressants: normalization of BLA hyperactivity and, consequently, of DA hypofunction. These observations corroborate the role of α7 nAChR as a potential target for novel antidepressant drug development.
Topics: Animals; Basolateral Nuclear Complex; Benzamides; Bridged Bicyclo Compounds; Chronic Disease; Dopaminergic Neurons; Hyperkinesis; Male; Nicotinic Agonists; Rats; Rats, Sprague-Dawley; Stress, Psychological; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 31615702
DOI: 10.1016/j.euroneuro.2019.09.009