Role Of nAChRs Research Articles

Alterations in Neuronal Nicotinic Acetylcholine Receptors in the Pathogenesis of Various Cognitive Impairments.

Cognitive impairment is a typical symptom of both neurodegenerative and certain other diseases. In connection with these different pathologies, the etiology and neurological and metabolic changes associated with cognitive impairment must differ. Until these characteristics and differences are understood in greater detail, pharmacological treatment of the different forms of cognitive impairment remains suboptimal. Neurotransmitter receptors, including neuronal nicotinic acetylcholine receptors (nAChRs), dopamine receptors, and glutamine receptors, play key roles in the functions and metabolisms of the brain. Among these, the role of nAChRs in the development of cognitive impairment has attracted more and more attention. The present review summarizes what is presently known concerning the structure, distribution, metabolism, and function of nAChRs, as well as their involvement in major cognitive disorders such as Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, and diabetes mellitus. As will be discussed, the relevant scientific literature reveals clearly that the α4β2 and α7 nAChR subtypes and/or subunits of the receptors play major roles in maintaining cognitive function and in neuroprotection of the brain. Accordingly, focusing on these as targets of drug therapy can be expected to lead to breakthroughs in the treatment of cognitive disorders such as AD and schizophrenia.

Critical roles of nicotinic acetylcholine receptors in olfactory memory formation and retrieval in crickets.

Acetylcholine (ACh) is a major excitatory neurotransmitter in the insect central nervous system, and insect neurons express several types of ACh receptors (AChRs). AChRs are classified into two subgroups, muscarinic AChRs and nicotinic AChRs (nAChRs). nAChRs are also divided into two subgroups by sensitivity to α-bungarotoxin (α-BGT). The cricket Gryllus bimaculatus is one of the useful insects for studying the molecular mechanisms in olfactory learning and memory. However, the roles of nAChRs in olfactory learning and memory of the cricket are still unknown. In the present study, to investigate whether nAChRs are involved in cricket olfactory learning and memory, we tested the effects of two different AChR antagonists on long-term memory (LTM) formation and retrieval in a behavioral assay. The two AChR antagonists that we used are mecamylamine (MEC), an α-BGT-insensitive nAChR antagonist, and methyllycaconitine (MLA), an α-BGT-sensitive nAChR antagonist. In crickets, multiple-trial olfactory conditioning induced 1-day memory (LTM), whereas single-trial olfactory conditioning induced 1-h memory (mid-term memory, MTM) but not 1-day memory. Crickets injected with MEC 20min before the retention test at 1day after the multiple-trial conditioning exhibited no memory retrieval. This indicates that α-BGT-insensitive nAChRs participate in memory retrieval. In addition, crickets injected with MLA before the multiple-trial conditioning exhibited MTM but not LTM, indicating that α-BGT-sensitive nAChRs participate in the formation of LTM. Moreover, injection of nicotine (an nAChR agonist) before the single-trial conditioning induced LTM. Finally, the nitric oxide (NO)-cGMP signaling pathway is known to participate in the formation of LTM in crickets, and we conducted co-injection experiments with an agonist or inhibitor of the nAChR and an activator or inhibitor of the NO-cGMP signaling pathway. The results suggest that nAChR works upstream of the NO-cGMP signaling system in the LTM formation process.

A tonic nicotinic brake controls spike timing in striatal spiny projection neurons.

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feedforward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices from mice we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4β2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by 'priming' feedforward inhibition, a process that may shape SPN spike timing, striatal processing, and synaptic plasticity.

Possible Engagement of Nicotinic Acetylcholine Receptors in Pathophysiology of Brain Ischemia-Induced Cognitive Impairment

Post-stroke disabilities like cognitive impairment impose are complex conditions with great economic burdens on health care systems. For these comorbidities, no effective therapies have been identified yet. Nicotinic acetylcholine receptors (nAChRs) are multifunctional receptors participating in various behavioral and neurobiological functions. During brain ischemia, the increased glutamate accumulation leads to neuronal excitotoxicity as well as mitochondrial dysfunction. These abnormalities then cause the increased levels of oxidants, which play key roles in neuronal death and apoptosis in the infarct zone. Additionally, recall of cytokines and inflammatory factors play a prominent role in the exacerbation of ischemic injury. As well, neurotrophic factors' insufficiency results in synaptic dysfunction and cognitive impairments in ischemic brain. Of note, nAChRs through various signaling pathways can participate in therapeutic approaches such as cholinergic system's stimulation, and reduction of excitotoxicity, inflammation, apoptosis, oxidative stress, mitochondrial dysfunction, and autophagy. Moreover, the possible roles of nAChRs in neurogenesis, synaptogenesis, and stimulation of neurotrophic factors expression have been reported previously. On the other hand, the majority of the above-mentioned mechanisms were found to be common in both brain ischemia pathogenesis and cognitive function tuning. Therefore, it seems that nAChRs might be known as key regulators in the control of ischemia pathology, and their modulation could be considered as a new avenue in the multi-target treatment of post-stroke cognitive impairment.

E-cigarette-induced pulmonary inflammation and dysregulated repair are mediated by nAChR \u03b17 receptor: role of nAChR \u03b17 in SARS-CoV-2 Covid-19 ACE2 receptor regulation

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.

Human Nicotinic Acetylcholine Receptors: Part II. Non-Neuronal Cholinergic System

The role of nAChRs in functioning of central and peripheral nervous systems is widely known. Recently, expression of nAChRs in immune cells and tissues of epithelial origin has been shown. These non-neuronal nAChRs are involved in regulation of inflammation, cell proliferation, differentiation, migration, and apoptosis. Non-neuronal nAChRs are also involved in occurrence and development of several types of nicotine-induced cancers. Study of these receptors in epithelial and cancer cells made it possible to discover new ways of nAChRs regulation by endogenous ligands and to propose new mechanisms of signal transduction that are not related to the ion current through the receptor channel. This review presents current information on the function of human non-neuronal nAChRs.

Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice

Adolescence is a critical period in brain development that coincides with the initiation of alcohol use. Nicotinic acetylcholine receptors (nAChR) have been shown to modulate ethanol behaviors in adult humans and in animal models; however, the role of these receptors in adolescent ethanol behaviors has not been explored. Throughout adolescence, nAChR expression undergoes large-scale developmental changes which may alter behavioral responses to ethanol. Here we examined the effect of varenicline, a nAChR partial agonist, on ethanol consumption, ataxia, sedation, and metabolism in adolescent male and female C57BL/6J mice. The effect of varenicline on ethanol consumption was tested through the Drinking-in-the-Dark (DID) paradigm that models binge-like ethanol consumption. To ensure that results were specific for ethanol, we also tested the effect of varenicline on saccharin consumption. Additionally, varenicline was administered 30min prior to an acute injection of ethanol before being tested for ataxia on the balance beam, sedation using the loss of righting reflex, or ethanol metabolism. Varenicline dose dependently decreased ethanol consumption, but also influenced saccharin intake. Varenicline showed no significant effect on ethanol metabolism, ataxia, or sedation. Unlike its effects in adult animals, varenicline is able to reduce ethanol consumption without increasing the ataxic and sedative effects of ethanol. This work suggests that the neurobiological mechanisms of ethanol behaviors may change across the lifespan and highlights the need for more research on the role of nAChRs in ethanol behaviors throughout development.

神経行動毒性のメタ解析：哺乳動物におけるコリン作動性物質の毒性発現におけるnAChRの関与についての調査（続報）

神経行動毒性のメタ解析：哺乳動物におけるコリン作動性物質の毒性発現におけるnAChRの関与についての調査（続報）

BAG2 expression dictates a functional intracellular switch between the p38-dependent effects of nicotine on tau phosphorylation levels via the α7 nicotinic receptor

The histopathological hallmarks present in Alzheimer's disease (AD) brain are plaques of Aβ peptide, neurofibrillary tangles of hyperphosphorylated tau protein, and a reduction in nicotinic acetylcholine receptor (nAChR) levels. The role of nAChRs in AD is particularly controversial. Tau protein function is regulated by phosphorylation, and its hyperphosphorylated forms are significantly more abundant in AD brain. Little is known about the relationship between nAChR and phospho-tau degradation machinery. Activation of nAChRs has been reported to increase and decrease tau phosphorylation levels, and the mechanisms responsible for this discrepancy are not presently understood. The co-chaperone BAG2 is capable of regulating phospho-tau levels via protein degradation. In SH-SY5Y cell line and rat primary hippocampal cell culture low endogenous BAG2 levels constitute an intracellular environment conducive to nicotine-induced accumulation of phosphorylated tau protein. Further, nicotine treatment inhibited endogenous expression of BAG2, resulting in increased levels of phosphorylated tau indistinguishable from those induced by BAG2 knockdown. Conversely, overexpression of BAG2 is conducive to a nicotine-induced reduction in cellular levels of phosphorylated tau protein. In both cases the effect of nicotine was p38MAPK-dependent, while the α7 antagonist MLA was synthetic to nicotine treatment, either increasing levels of phospho-Tau in the absence of BAG2, or further decreasing the levels of phospho-Tau in the presence of BAG2. Taken together, these findings reconcile the apparently contradictory effects of nicotine on tau phosphorylation by suggesting a role for BAG2 as an important regulator of p38-dependent tau kinase activity and phospho-tau degradation in response to nicotinic receptor stimulation. Thus, we report that BAG2 expression dictates a functional intracellular switch between the p38-dependent functions of nicotine on tau phosphorylation levels via the α7 nicotinic receptor.

PET Imaging of the Human Nicotinic Cholinergic Pathway in Atherosclerosis.

During the past years, non-neuronal vascular nicotinic acetylcholine receptors (nAChRs) increasingly have gained interest in cardiovascular research, as they are known to mediate the deleterious effects of nicotine and nitrosamines, components of tobacco smoke, on the vasculature. Because smoking is a major risk factor for the development of atherosclerosis, it is obvious that understanding the pathophysiologic role of nAChRs in the atherosclerotic disease process, as well as in the development of new diagnostic and therapeutic nAChR-related options, has become more important. Accordingly, we briefly summarize the pathophysiologic role of vascular nAChRs in the atherosclerotic disease process. We also provide an overview of currently available nAChR positron emission tomography (PET) tracers and their performance in the noninvasive imaging of vascular nAChRs, as well as potential nAChR PET tracers that might be an option for vascular nAChR PET imaging in the future.

Megakaryocytes and platelets express nicotinic acetylcholine receptors but nicotine does not affect megakaryopoiesis or platelet function

In our previous investigations we have shown that platelets and their precursors express nicotinic α7 acetylcholine receptors (nAChRα7) that are involved in platelet function and in vitro differentiation of the megakaryoblastic cell line MEG-01. In this study, we were interested in the expression analysis of additional nAChR and the effects of nicotine in an ex vivo model using megakaryocytic cells differentiated from cord blood derived CD34+ cells (CBMK) and an in vivo model using blood samples from smokers. CBMK were differentiated with thrombopoietin (TPO) for up to 17 days. Quantitative real-time PCR (QRT-PCR), Western blot analysis and flow cytometry were used to investigate nAChR expression (nAChRα7, nAChRα4, nAChRβ2) and nicotine effects. In blood samples of 15 nonsmokers and 16 smokers platelet parameters (count, mean platelet volume – MPV and platelet distribution width – PDW) were determined as indicators for changes of in vivo megakaryopoiesis. Platelet function was determined by the use of whole blood aggregometry and flow cytometry. The functional role of nAChR was evaluated using specific antagonists in aggregometry. CHRNA7, CHRNA4 and CHRNB2 gene transcripts and the corresponding proteins could be identified in CBMK during all stages of differentiation. Platelets contain nAChRα7 and nAChRβ2 but not nAChRα4. Nicotine had no effect on TPO-induced differentiation of CBMK. There was no significant difference in all platelet parameters of the smokers compared to the nonsmokers. In line with this, cholinergic gene transcripts as well as the encoded proteins were equally expressed in both the study groups. Despite our observation of nAChR expression in megakaryopoiesis and platelets, we were not able to detect effects of nicotine in our ex vivo and in vivo models. Thus, the functional role of the nAChR in these cells remains open.

SY22-5 * NICOTINE AND COGNITION IN SCHIZOPHRENIA

Nicotine binds to presynaptic nicotinic acetylcholine receptors (nAChRs) in the brain and facilitates the release of acetylcholine, dopamine, serotonin, glutamate and other neurotransmitters known to be involved in cognitive processes. Nicotine systems in the brain play an important role in the neural basis of memory and attention. Smoking is highly prevalent in schizophrenia, and there is evidence for beneficial effects on neurocognition. Nicotine exposure to non-smoking schizophrenia patients and nicotine application after abstinence to smoking schizophrenia improved attention deficits. The study analyzing the interactional effects of diagnosis of schizophrenia and smoking history suggested a positive effect of smoking history on divided attention in schizophrenia patients. Clinical studies using transdermal nicotine patches have demonstrated the efficacy of nicotine in improving cognitive performance, particularly sustained attention in nonsmokers with schizophrenia. Mecamylamine, a nAChR antagonist, worsened performance of attention compared to varenicline, a nAChR partial agonist, in schizophrenia. There was a treatment by diagnosis interaction, such that mecamylamine worsened performance of sustained attention compared to placebo and varenicline in schizophrenia patients, effects not observed in controls. These findings support a role for nAChRs in attention and suggest that those with schizophrenia may be particularly sensitive to nAChR blockade.

Nicotinic Receptors as Therapeutic Targets for Drug Addictive Disorders

Drug addiction is a chronic neuropsychiatric disorder which is characterized by a compulsion to take drugs and loss of control in limiting intake. The worldwide impact of drug addiction on morbidity and mortality is very high. Evidence from preclinical and clinical studies suggests that brain nicotinic acetylcholine receptors (nAChRs), play a critical role in various addictive disorders, including nicotine addiction and alcoholism. Thus, there is an increasing impetus in developing new therapeutics for addictive disorders by targeting brain nAChRs. This review highlights the important preclinical findings involving nAChR ligands in regulating nicotine, alcohol and other addictive drug-induced neurobiological changes in animal models and humans. A number of partial agonists or antagonists targeting nAChRs have shown therapeutic benefit in nicotine addiction and alcohol use disorders are also discussed. Furthermore, the role of nAChRs in other addictive disorders is reviewed. Overall, novel pharmacological agents that target brain nAChRs for future drug development are discussed.

Nicotinic acetylcholine receptors mediate lung cancer growth

Ion channels modulate ion flux across cell membranes, activate signal transduction pathways, and influence cellular transport—vital biological functions that are inexorably linked to cellular processes that go awry during carcinogenesis. Indeed, deregulation of ion channel function has been implicated in cancer-related phenomena such as unrestrained cell proliferation and apoptotic evasion. As the prototype for ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs) have been extensively studied in the context of neuronal cells but accumulating evidence also indicate a role for nAChRs in carcinogenesis. Recently, variants in the nAChR genes CHRNA3, CHRNA5, and CHRNB4 have been implicated in nicotine dependence and lung cancer susceptibility. Here, we silenced the expression of these three genes to investigate their function in lung cancer. We show that these genes are necessary for the viability of small cell lung carcinomas (SCLC), the most aggressive type of lung cancer. Furthermore, we show that nicotine promotes SCLC cell viability whereas an α3β4-selective antagonist, α-conotoxin AuIB, inhibits it. Our findings posit a mechanism whereby signaling via α3/α5/β4-containing nAChRs promotes lung carcinogenesis.

Nicotinic Receptors in Addiction Pathways

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that consist of pentameric combinations of α and β subunits. These receptors are widely distributed throughout the brain and are highly expressed in addiction circuitry. The role of nAChRs in regulating neuronal activity and motivated behavior is complex and varies both in and among brain regions. The rich diversity of central nAChRs has hampered the characterization of their structure and function with use of classic pharmacological techniques. However, recent molecular approaches using null mutant mice with specific regional lentiviral re-expression, in combination with neuroanatomical and electrophysiological techniques, have allowed the elucidation of the influence of different nAChR types on neuronal circuit activity and behavior. This review will address the influence of nAChRs on limbic dopamine circuitry and the medial habenula-interpeduncular nucleus complex, which are critical mediators of reinforced behavior. Characterization of the mechanisms underlying regulation of addiction pathways by endogenous cholinergic transmission and by nicotine may lead to the identification of new therapeutic targets for treating tobacco dependence and other addictions.

Effects of G-CSF On Acute Lymphoblastic Leukemia.

AbstractAbstract 2564G-CSF is commonly used to treat chemotherapy-induced neutropenia and for the mobilization of hematopoietic stem cells for transplantation in patients with leukemia. Administration of G-CSF has profound effects on the bone marrow microenvironment including the cleavage of molecules required for the maintenance of lymphopoiesis, including CXCL12 and VLA-4. We have recently reported that G-CSF results in the dramatic suppression of B-lymphopoiesis. This, together with previous reports by ourselves, and others, showing that disruption of CXCL12 or VLA-4 slow the progression of B-lineage ALL lead us to consider that G-CSF may similarly antagonize the progression of ALL.To explore this possibility, we examined the impact of G-CSF administration on six human ALL xenografts using a NOD/SCID mouse model. Mice were engrafted without radiation and G-CSF commenced when 1% of the bone marrow consisted of ALL cells. G-CSF was administered twice daily for 10 days, at which time all animals were culled and leukemia assessed in the blood, bone marrow and spleens. Surprisingly G-CSF was found to increase disease progression in two of xenografts investigated (1345 and 0398, referred to as G-CSF responsive xenografts hereafter), while the remainder demonstrated a small reduction in leukemia, with one showing a statistical significant decrease. No evidence for a direct mitogenic effect of G-CSF could be demonstrated in any of the xenografts using exogenous G-CSF in vitro cultures in the presence or absence of human or murine stromal support. Consistent with these findings, and previous reports, little to no G-CSF receptor was detected by flow cytometry or microarray analysis of xenografts.Microarray analysis of the xenografts revealed significant differences in gene expression between the G-CSF responsive xenografts and the remainder of the samples. A total of 83 genes were expressed at a higher level and 127 genes at a lower level in the G-CSF responsive xenografts. The more highly expressed genes included cell cycle regulators (eg cyclin A1), adhesion molecules (eg ALCAM), extracellular matrix components and surface receptors. Perhaps the most interesting was the exclusive expression of the acetylcholine receptor (cholinergic receptor, nicotinic, beta 4, nAChRb4) in the G-CSF responsive cases. Analysis of a large public dataset of childhood ALL samples revealed significantly higher expression of this gene in ALL samples with rearranged MLL (p<0.03). However, small numbers of cases in all ALL subgroups had greater than an 2 fold higher expression compared to normal B cell progenitors. The role of nAChR in the response of ALL cells to micro-environmental changes induced by G-CSF remains to be determined, however, nAChR has known roles in cell proliferation and inhibition of apoptosis. Furthermore G-CSF is known to induce acetylcholine production in other tissues.In summary, G-CSF inhibited leukemia progression in the majority of patient xenografts, however, in a subset of samples G-CSF accelerated disease progression. Clinically, G-CSF administration to ALL patients has not been associated with any major adverse outcomes. However our data suggest that a small subset of patients may experience accelerated disease. Identification of features associated with adverse responses to G-CSF will permit the identification of patients for whom G-CSF may present a risk for increased disease progression. Disclosures:No relevant conflicts of interest to declare.

The effect of MII α-conotoxin and its N-terminal derivatives on Ca2+- and Na+-signals induced by nicotine in SH-SY5Y neuroblastoma cells

Nicotinic acetylcholine receptors (nAChRs) are implicated in the regulation ofintracellular Ca2+-dependent processes in cells both in normal and pathological states, alpha-Conotoxins isolated from Conus snails venom are a valuable tool for the study of pharmacological properties and functional role of nAChRs. In the present study the alpha-conotoxin MII analogue with the additional tyrosine attached to the N terminus (Y0-MII) was prepared. Also we synthesized analogs with the N-terminal glycine residue labeled with the Bolton- Hunter reagent (BH-MII) or fluorestsein isothiocyanate (FITC-MII). Fluorescence microscopy studies of the neuroblastoma SH-SY5Y cells loaded with Ca2+ indicator Fura-2 or with Ca2+ and Na+ indicators Fluo-4 and SBFI were performed to examine effect of MII modification on its ability to inhibit nicotin-induced increases in intracellular free Ca2+ and Na+ concentrations ([Ca2+] and [Na+]i respectively). Monitoring of individual cell [Ca2+]i and [Na+]i signals revealed different kinetics of [Ca2+]i and [Na+]i rise and decay in responses to brief nicotine (Nic) applications (10-30 microM, 3-5 min), which indicates to different mechanisms of Ca2+ and Na+ homeostasis control in SH-SY5Y cells. MII inhibited in concentration-dependent manner the both [Ca2+]i and [Na+]i increase induced by Nic. Additional tyrosine in the Y0-MII or, especially, more sizeable label in FITC-MII significantly reduced the inhibitory effect of MII. Whereas the efficiency of the Ca2+ response inhibition by BH-MII was found to be close to the efficiency of its inhibition by natural alpha-conotoxin MII, radioiodinated derivatives BH-MII can be used in radioligand assay.

Prefrontal neuromodulation by nicotinic receptors for cognitive processes

The prefrontal cortex (PFC) mediates executive functions, a set of control processes that optimize performance on cognitive tasks. It enables appropriate decision-making and mediates adapted behaviors, all processes impaired in psychiatric or degenerative disorders. Key players of normal functioning of the PFC are neurotransmitter (NT) systems arising from subcortical nuclei and targeting PFC subareas and, also, neuronal nicotinic acetylcholine receptors (nAChRs). These ion channels, located on multiple cell compartments in all brain areas, mediate direct cholinergic transmission and modulate the release of NTs that cross onto PFC neurons or interneurons. We compiled current knowledge concerning the role of nAChRs in NT release, focusing on the PFC. We point out plausible mechanisms of interaction among PFC circuits implicated in executive functions and emphasized the role of β2-containing nAChRs, the high-affinity receptors for acetylcholine (ACh). These receptors are more directly implicated in behavioral flexibility either when located on PFC neurons or in the monoaminergic or cholinergic systems targeting the PFC. We shed light on potentially crucial roles played by nAChRs in complex interactions between local and afferent NTs. We show how they could act on cognition via PFC networks. nAChRs are crucial for decision-making, during integration of emotional and motivational features, both mediated by different NT pathways in the PFC. We review the knowledge recently gained on cognitive functions in mice and our current understanding of PFC NT modulation. The combination of these data is expected to provide new hypotheses concerning the role of AChRs in cognitive processes.

Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120

Approximately 30-50% of the >30 million HIV-infected subjects develop neurological complications ranging from mild symptoms to dementia. HIV does not infect neurons, and the molecular mechanisms behind HIV-associated neurocognitive decline are not understood. There are several hypotheses to explain the development of dementia in HIV(+) individuals, including neuroinflammation mediated by infected microglia and neuronal toxicity by HIV proteins. A key protein associated with the neurological complications of HIV, gp120, forms part of the viral envelope and can be found in the CSF of infected individuals. HIV-1-gp120 interacts with several receptors including CD4, CCR5, CXCR4, and nicotinic acetylcholine receptors (nAChRs). However, the role of nAChRs in HIV-associated neurocognitive disorder has not been investigated. We studied the effects of gp120(IIIB) on the expression and function of the nicotinic receptor α7 (α7-nAChR). Our results show that gp120, through activation of the CXCR4 chemokine receptor, induces a functional up-regulation of α7-nAChRs. Because α7-nAChRs have a high permeability to Ca(2+), we performed TUNEL staining to investigate the effects of receptor up-regulation on cell viability. Our data revealed an increase in cell death, which was blocked by the selective antagonist α-bungarotoxin. The in vitro data are supported by RT-PCR and Western blot analysis, confirming a remarkable up-regulation of the α7-nAChR in gp120-transgenic mice brains. Specifically, α7-nAChR up-regulation is observed in mouse striatum, a region severely affected in HIV(+) patients. In summary, CXCR4 activation induces up-regulation of α7-nAChR, causing cell death, suggesting that α7-nAChR is a previously unrecognized contributor to the neurotoxicity associated with HIV infection.

Smoking-induced Human Breast Cancer Formation through Induction of α9-nicotinic Acetylcholine Receptor

Tobacco is a substance that contains human carcinogens and may contribute to the risk for tumor formation in the lung and colon via nicotinic acetylcholine receptors (nAChRs). Nicotine receptors are a family of ligand-gated ion channels that mediate the effects of the neurotransmitter acetylcholine and are among the most well-understood receptors. The α4β2 nAChR is known to exist in the central nervous system (CNS) and functions as a transmitter, whereas the α7-nAChR is a well-established molecule that is involved in lung cancer tumorigenesis. Previously, however, there was no direct evidence to provide a link between tobacco carcinogens and cellular molecules involved in breast tumorigenesis. Recently, two large cohort epidemiological studies undertaken in the USA and Japan have indicated that breast cancer risk is associated with both active and passive smoking. Analysis of α9-nAChR expression in clinical tumor tissues indicated that theα9-nAChR is important for tumor carcinogenesis in vivo and nicotine-induced transformation of normal human breast epithelial cells in vitro. Long-term exposure to estrogen and nicotine significantly increases α9-nAChR expression and forms a positively regulated loop and that can be blocked by several chemicals and natural compounds. In this paper, the structure and functional relationship of the nAChR will be discussed. The role of nAChR in breast cancer formation and its implication for prevention of cancer formation will also be discussed.