Role Of Nicotinic Receptors Research Articles

The Role of Nicotinic Receptors on Ca2+ Signaling in Bovine Chromaffin Cells.

Chromaffin cells have been used as a physiological model to understand neurosecretion in mammals for many years. Nicotinic receptors located in the cells' membrane are stimulated by acetylcholine, and they participate in the exocytosis of chromaffin granules, releasing catecholamines in response to stress. In this work, we discuss how the participation of nicotinic receptors and the localization of active zones in the borders of the cytoskeleton can generate local calcium signals leading to secretion. We use a computational model of a cytoskeleton cage to simulate Ca2+ levels in response to voltage and acetylcholine pulses. We find that nicotinic receptors are able to enhance the differences between local and average calcium values, as well as the heterogeneous distributions around the active zones, producing a non-linear, highly localized Ca2+ entry that, although consisting of a few ions, is able to improve secretion responses in chromaffin cells. Our findings emphasize the intricate interplay among nicotinic receptors, the cytoskeleton, and active zones within chromaffin cells as an example of Ca2+-dependent neurosecretion in mammals.

Theories of the pathogenesis of schizophrenia

Introduction: Schizophrenia is one of the most serious and frightening of all mental illnesses. It affects almost 1% of the population worldwide. The main concept and treatment of schizophrenia are based on the dopaminergic hypothesis. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid signaling.The aim of the study: The purpose of this systemic review was to collect and analyse current and new information on the pathogenesis of schizophrenia.Material and method: Standard criteria were used to review the literature data. The search of articles in the PubMed database was carried out using the following keywords: schizophrenia, dopamine hypothesis, serotoninergic hypothesis, hypothesis of schizophrenia .Description of the state of knowledge: There are evidence that pathogenesis of schizophrenia include dysfunction in dopaminergic, serotoninergic, GABAergic, glutamatergic systems. The use of drugs that act on any of these systems reduces the symptoms of the disease. Nicotinic receptors may also be the target for drugs in treatment of schizophrenia. Studies about the role of nicotinic receptors in pathogenesis of schizophrenia show that it normalize many of the sensory processing deficits found in schizophrenia.Summary: Despite the fact that current concept and treatment are still based on the dopaminergic hypothesis of the disease, existing theories and each new theory, open up different ways for treating schizophrenia. Considering that schizophrenia is one of the most serious and frightening of all mental illnesses and has major public health implications, more research about pathogenesis and ways of treatment is needed.

The Role of Nicotinic Receptors in the Attenuation of Autism-Related Behaviors in a Murine BTBR T + tf/J Autistic Model.

Nicotinic receptors are distributed throughout the central and peripheral nervous system. Postmortem studies have reported that some nicotinic receptor subtypes are altered in the brains of autistic people. Recent studies have demonstrated the importance of nicotinic acetylcholine receptors (nAChRs) in the autistic behavior of BTBR T + tf/J mouse model of autism. This study was undertaken to examine the behavioral effects of targeted nAChRs using pharmacological ligands, including nicotine and mecamylamine in BTBR T + tf/J and C57BL/6J mice in a panel of behavioral tests relating to autism. These behavioral tests included the three-chamber social interaction, self-grooming, marble burying, locomotor activity, and rotarod test. We examined the effect of various oral doses of nicotine (50, 100, and 400 mcg/mL; po) over a period of 2 weeks in BTBR T + tf/J mouse model. The results indicated that the chronic administration of nicotine modulated sociability and repetitive behavior in BTBR T + tf/J mice while no effects observed in C57BL/6J mice. Furthermore, the nonselective nAChR antagonist, mecamylamine, reversed nicotine effects on sociability and increased repetitive behaviors in BTBR T + tf/J mice. Overall, the findings indicate that the pharmacological modulation of nicotinic receptors is involved in modulating core behavioral phenotypes in the BTBR T + tf/J mouse model. LAY SUMMARY: The involvement of brain nicotinic neurotransmission system plays a crucial role in regulating autism-related behavioral features. In addition, the brain of the autistic-like mouse model has a low acetylcholine level. Here, we report that nicotine, at certain doses, improved sociability and reduced repetitive behaviors in a mouse model of autism, implicating the potential therapeutic values of a pharmacological intervention targeting nicotinic receptors for autism therapy. Autism Res 2020, 13: 1311-1334. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

The Role of Nicotinic Receptors in the Attenuation of Autism‐related Behaviors in a Murine BTBR T+tf/J Autistic Model

The nicotinic receptors are distributed throughout the central and peripheral nervous system. Postmortem studies have reported that some nicotinic receptor subtypes are altered in the brains of autistic people. Recent studies have demonstrated the importance of nicotinic acetylcholine receptors (nAChRs) in the autistic behavior of BTBR T+tf/J mice. This study was undertaken to examine the behavioral effects of pharmacologically targeted nAChRs using nicotine and mecamylamine (MEC) in a BTBR T+tf/J mouse model of autism. It was conducted a panel of behavioral tests relating to autism. The behavioral tests included the three‐chamber social interaction, self‐grooming, marble‐burying, locomotor activity (LA), and rota‐rod (RR) test. It was examined the effect of various oral doses of nicotine over a period of two weeks in BTBR T+tf/J mice. The results indicated that the chronic administration of nicotine modulated sociability and repetitive behavior in BTBR T+tf/J mice while no effects in C57BL/6J mice. Furthermore, the non‐selective nAChR antagonist (MEC) reduced sociability and increased the repetitive behaviors in BTBR T+tf/J mice. Overall, the findings indicate that the pharmacological modulation of nicotinic receptors is involved in modulating core behavioral phenotypes in the BTBR T+tf/J mouse model.

Nicotinic receptors modulate skin perfusion during normothermia, and have a limited role in skin vasodilatation and sweating during hyperthermia.

What is the central question of this study? What is the role of nicotinic receptors in the regulation of normothermic cutaneous blood flow and cutaneous vasodilatation and sweating during whole-body heating induced following resting in a non-heat-stress condition? What is the main finding and its importance? Nicotinic receptors modulated cutaneous vascular tone during rest in a non-heat-stress condition and in the early stage of heating, but they had a limited role in mediating cutaneous vasodilatation when core temperature increased>0.4°C. Further, the contribution of nicotinic receptors to sweating was negligible during whole-body heating. Our findings provide new insights into the role of nicotinic receptors in end-organ function of skin vasculature and sweat glands in humans. Nicotinic receptors are present in human skin including cutaneous vessels and eccrine sweat glands as well as peripheral nerves. We tested the hypothesis that nicotinic receptors do not contribute to the control of cutaneous vascular tone in the normothermic state, but are involved in mediating cutaneous vasodilatation and sweating during a whole-body passive heat stress in humans. We first performed a nicotinic receptor blocker verification protocol in six young adults (one female) wherein increases in cutaneous vascular conductance and sweating elicited by 10mm nicotine were blocked by administration of 500µm hexamethonium to confirm effective blockade. Thereafter, 12 young males participated in a passive heating protocol. After an instrumentation period in a non-heat-stress condition, participants rested for a 10min baseline period. Thereafter, oesophageal temperature was increased by 1.0°C using water-perfusion suits. Cutaneous vascular conductance, sweat rate, active sweat gland density and sweat output per individual gland were assessed with and without 500µm hexamethonium administered via intradermal microdialysis. Hexamethonium reduced cutaneous vascular conductance by 22-34% during normothermia and the early stage of heating. However, this effect was diminished as oesophageal temperature increased >0.4°C. Active sweat gland density was reduced by hexamethonium when oesophageal temperature was elevated by 0.4-0.6°C above baseline resting. However, this was paralleled by a marginal increase in sweat gland output. Consequently, sweat rate remained unchanged. We showed that nicotinic receptors modulate cutaneous perfusion during normothermia and the early stage of heating, but not when core temperature increases >0.4°C. Additionally, they play a limited role in mediating sweating during heating.

Intra-accumbal and Peripheral administration of nicotine reduces the side-effects of Inescapable Stress

Suppressive effect of Ginkgo biloba extract (EGb 761) on topsin induced ovarian toxicity and oxidative stress in albino ratsSaber A. Sakr,Hoda A. Mahran, Asmaa M. Abdel-Maksoud

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

Reperfusion injury following acute myocardial infarction is associated with significant morbidity. Activation of neuronal or non-neuronal cholinergic pathways in the heart has been shown to reduce ischemic injury, and this effect has been attributed primarily to muscarinic acetylcholine receptors. In contrast, the role of nicotinic receptors, specifically α-7 subtype (α7nAChR), in the myocardium remains unknown, which offers an opportunity to potentially repurpose several agonists/modulators that are currently under development for neurologic indications. Treatment of ex vivo and in vivo rat models of cardiac ischemia/reperfusion (I/R) with a selective α7nAChR agonist (GTS21) showed significant increases in left ventricular developing pressure and rates of pressure development, without effects on heart rate. These positive functional effects were blocked by co-administration with methyllycaconitine (MLA), a selective antagonist of α7nAChRs. In vivo, delivery of GTS21 at the initiation of reperfusion reduced infarct size by 42% (p < 0.01) and decreased tissue reactive oxygen species (ROS) by 62% (p < 0.01). Flow cytometry of MitoTracker Red-stained mitochondria showed that mitochondrial membrane potential was normalized in mitochondria isolated from GTS21-treated compared with untreated I/R hearts. Intracellular adenosine triphosphate (ATP) concentration in cultured cardiomyocytes exposed to hypoxia/reoxygenation was reduced (p < 0.001), but significantly increased to normoxic levels with GTS21 treatment, which was abrogated by MLA pretreatment. Activation of stress-activated kinases JNK and p38MAPK was significantly reduced by GTS21 in I/R. We conclude that targeting myocardial α7nAChRs in I/R may provide therapeutic benefit by improving cardiac contractile function through a mechanism that preserves mitochondrial membrane potential, maintains intracellular ATP and reduces ROS generation, thus limiting infarct size.

Cholinergic modulation of the medial prefrontal cortex: the role of nicotinic receptors in attention and regulation of neuronal activity.

Acetylcholine (ACh) release in the medial prefrontal cortex (mPFC) is crucial for normal cognitive performance. Despite the fact that many have studied how ACh affects neuronal processing in the mPFC and thereby influences attention behavior, there is still a lot unknown about how this occurs. Here we will review the evidence that cholinergic modulation of the mPFC plays a role in attention and we will summarize the current knowledge about the role between ACh receptors (AChRs) and behavior and how ACh receptor activation changes processing in the cortical microcircuitry. Recent evidence implicates fast phasic release of ACh in cue detection and attention. This review will focus mainly on the fast ionotropic nicotinic receptors and less on the metabotropic muscarinic receptors. Finally, we will review limitations of the existing studies and address how innovative technologies might push the field forward in order to gain understanding into the relation between ACh, neuronal activity and behavior.

The moderating influence of nicotine and smoking on resting-state mood and EEG changes in remitted depressed patients during tryptophan depletion

Comorbidity between depression and tobacco use may reflect self-medication of serotonergically mediated mood dysregulation, which has been associated with aberrant cortical activation and hemispheric asymmetry in patients with major depressive disorders (MDD). This randomized, double-blind study in 28 remitted MDD patients examined the moderating effects of acute nicotine and smoker vs. nonsmoker status on mood and EEG changes accompanying transient reductions in serotonin induced by acute tryptophan depletion (ATD). In smokers, who exhibited greater posterior high alpha power and increased left frontal low alpha power (signs of deactivation) compared to nonsmokers, ATD increased self-ratings of depressed mood and elevated left frontal and right parietal high alpha power (i.e. further cortical deactivation). Smokers were not affected by nicotine administration. In nonsmokers, ATD did not influence depression ratings, but it reduced vigor ratings and increased frontal and posterior theta power; both of which were blocked by acute nicotine. These findings indicate a role for nicotinic receptors in disordered mood.

Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia, and airway mucus formation in vitro and in vivo

Airway mucus hypersecretion is a key pathophysiologic feature in a number of lung diseases. Cigarette smoke/nicotine and allergens are strong stimulators of airway mucus; however, the mechanism of mucus modulation is unclear. We sought to characterize the pathway by which cigarette smoke/nicotine regulates airway mucus and identify agents that decrease airway mucus. IL-13 and γ-aminobutyric acid type Areceptors (GABA(A)Rs) are implicated in airway mucus. We examined the role of IL-13 and GABA(A)Rs in nicotine-induced mucus formation in normal human bronchial epithelial (NHBE) and A549 cells and secondhand cigarette smoke-induced, ovalbumin-induced, or both mucus formation invivo. Nicotine promotes mucus formation in NHBE cells; however, the nicotine-induced mucus formation is independent of IL-13 but sensitive to the GABA(A)R antagonist picrotoxin. Airway epithelial cells express α7-, α9-, and α10-nicotinic acetylcholine receptors (nAChRs), and specific inhibition or knockdown of α7- but not α9/α10-nAChRs abrogates mucus formation in response to nicotine and IL-13. Moreover, addition of acetylcholine or inhibition of its degradation increases mucus in NHBE cells. Nicotinic but not muscarinic receptor antagonists block allergen- or nicotine/cigarette smoke-induced airway mucus formation in NHBE cells, murine airways, or both. Nicotine-induced airway mucus formation is independent of IL-13, and α7-nAChRs are critical in airway mucous cell metaplasia/hyperplasia and mucus production in response to various promucoid agents, including IL-13. In the absence of nicotine, acetylcholine might be the biological ligand for α7-nAChRs to trigger airway mucus formation. α7-nAChRs are downstream of IL-13 but upstream of GABA(A)Rα2 in the MUC5AC pathway. Acetylcholine and α7-nAChRs might serve as therapeutic targets to control airway mucus.

Altered activity–rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the β2 nicotinic receptor

High-affinity nicotinic receptors containing beta2 subunits (β2*) are widely expressed in the brain, modulating many neuronal processes and contributing to neuropathologies such as Alzheimer’s disease, Parkinson’s disease and epilepsy. Mutations in both the α4 and β2 subunits are associated with a rare partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we introduced one such human missense mutation into the mouse genome to generate a knock-in strain carrying a valine-to-leucine mutation β2V287L.β2V287L mice were viable and born at an expected Mendelian ratio. Surprisingly, mice did not display an overt seizure phenotype; however homozygous mice did display significant alterations in their activity-rest patterns. This was manifest as an increase in activity during the light cycle suggestive of disturbances in the normal sleep patterns of mice; a parallel phenotype to that found in human ADNFLE patients. Consistent with the role of nicotinic receptors in reward pathways, we found that β2V287L mice did not develop a normal proclivity to voluntary wheel running, a model for natural reward. Anxiety-related behaviors were also affected by the V287L mutation. Mutant mice spent more time in the open arms on the elevated plus maze (EPM) suggesting that they had reduced levels of anxiety. Together, these findings emphasize several important roles of β2* nicotinic receptors in complex biological processes including the activity-rest cycle, natural reward, and anxiety.

Addressing Tobacco Dependence in Psychiatric Practice: Promises and Pitfalls

The 2 In Review papers in this issue of The Canadian Journal of Psychiatry focus on tobacco use in mental health and addictive (MHA) populations, which is timely, given the high rates of tobacco use (primarily through cigarette smoking) in MHA settings and the difficulties with smoking cessation that are well documented for MHA patients.1-3 The sobering fact is that in 2009 the primary cause of death in MHA populations is tobacco-related medical illness, such as cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer, and their lives are substantially shorter than the general public in great part owing to tobacco use.4-7 The first article, by Dr Dominique Morisano, Dr Ingrid Bacher, Dr Janet Audrain-McGovern, and Dr Tony George,8 reviews biobehavioural, psychological, and social and (or) environmental determinants of tobacco comorbidity in MHA populations. Converging lines of evidence in the past 20 years indicate that having an MHA diagnosis appears to be a vulnerability factor for the initiation and maintenance of tobacco use and tobacco dependence (TD). Moreover, there is some limited evidence in some mental health disorders (for example, schizophrenia and major depressive disorder [MDD]) that nicotine, the major component of tobacco that leads to drug reinforcement, may actually produce beneficial effects, such as remediation of cognitive deficits in people with schizophrenia911 and improvement of depressive symptoms in MDD. 1214 There are also other explanations for the high rates of TD in these populations, including vulnerability to addiction and enhanced nicotine withdrawal. Clearly more research is needed on this topic. Accordingly, increased knowledge about the role of nicotinic receptors and pathways in MHA disorders has the potential to be translated into novel and more effective treatments, both for the MHA disorders and for comorbid tobacco addiction in these patients, who bear a disproportionate burden of the economic, social, and health care costs associated with tobacco addiction.15 The second article, by Dr Brian Hitsman, Ms Taryn D Moss, Dr Ivan D Montoya, and Dr George,16 describes an evidencebased approach to, and available clinical research data supporting the use of, pharmacological and behavioural interventions for TD treatment in MHA populations. Clearly such treatment is best done in an integrated setting where both treatment for the MHA disorder and the comorbid tobacco addiction are done by the same clinicians in the same facility.1718 In addition, these populations appear to benefit from integrated treatment that includes psychosocial and pharmacological treatments. However, most studies in treatment-seeking MHA smokers have been of a small sample size, and performed at a single site, typically in an academic tertiary health care setting. This has led to limited progress in this field insofar as developing treatments for widespread dissemination and implementation in community settings, where most MHA smokers are managed. A growing number of studies have confirmed that while cessation rates are low, tobacco reduction and cessation in MHA smokers is possible, and in fact some of the more recent studies in smokers with schizophrenia,19'20 which have used optimized treatment strategies, including nicotine replacement therapies, sustained-release bupropion, and cognitive-behavioural and motivational therapies, have produced short- and long-term (6 month) quit rates that approach those in noncomorbid smokers.21 Further, while TD is considered a chronic illness, studies that have examined extended treatments in MHA populations are rare. However, one recent study17 in smokers with a history of MDD achieved very high long-term cessation rates (about 50%) with extended treatment of up to a 1-year duration. Clearly we need to consider maintenance treatments for MHA and other smokers who initially respond to treatment, and provide ongoing treatment support for those . …

Role of nicotinic receptors on carotid body function in developing rats.

Acetylcholine is an excitatory neurotransmitter in adult carotid body playing a significant role in the ventilatory response to hypoxia. We used epibatidine (Epi, 5μg/Kg i.p) as agonist and hexamethonium (Hexa, 1mg/kg i.p) as antagonist of peripheral nicotinic receptors to determine the function of nicotinic receptors in developing rats. Breathing frequency (Fr), tidal volume (VT) and minute ventilation (VE) were measured using whole body plethysmography in normoxia (21%O2) and in response to hypoxia (20 min‐12%O2) in rat pups at 1, 4, 7, 12 and 21 postnatal days before and after a single injection of Epi or Hexa. In normoxia, Epi increased significantly Fr by 4%, 21%, 30%, 40%, and 43% for P1, P4, P7, P12 and P21 respectively, p for age&lt;0.001. In hypoxia, Epi increased Fr by 15% for P4 and 30% for P12 while Hexa decreased Fr by 13% and 31% respectively, p for age&lt;0.01. We conclude that the functional expression of cholinergic nicotinic receptor on hypoxic ventilatory response is age‐dependent, thus presumably playing a significant role in the maturation of the carotid body response to hypoxia. Founded PF‐RSR, IRSC and Sick Kids Foundation.

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

Protection of neurons from neuronal damage and cell death in neurodegenerative disease is a major challenge in neuroscience research. Donepezil, galantamine and tacrine are acetylcholinesterase inhibitors used for the treatment of Alzheimer's disease, and were believed to be symptomatic drugs whose therapeutic effects are achieved by slowing the hydrolysis of acetylcholine at synaptic termini. However, recent accumulated evidence strongly suggests that these acetylcholinesterase inhibitors also possess neuroprotective properties whose mechanism is independent of acetylcholinesterase inhibition. We have shown that acetylcholinesterase inhibitors protect neurons from glutamate-induced neurotoxicity in the primary culture of rat cortical neurons. It was also found that acetylcholinesterase inhibitor treatment induces up-regulation of nicotinic receptor expression levels, a property which may also have some bearing on their therapeutic effects. We next showed that alpha4 and alpha7-nicotinic receptors play important roles in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation. Our results also demonstrate the important roles of the phosphatidylinositol 3-kinase pathway downstream of nicotinic receptors in protecting neurons from death and up-regulating nicotinic receptors. This review summarizes recent findings on the roles of the nicotinic receptor in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation.

Effects of nicotine on sensorimotor gating impairment induced by long-term treatment with neurotoxic NMDA antagonism

In order to develop a model of persistent sensorimotor gating that did not require acute NMDA (N-methyl-D-aspartate) receptor blockade, adult female Sprague-Dawley rats were pre-treated with N-methyl-scopolamine (1 mg/kg s.c.), then administered MK-801 (dizocilpine, 5 mg/kg i.p.) along with two separate doses (5 mg/kg) of pilocarpine. The drug regimen was repeated four and eight days later. Controls received saline in lieu of any drug. Ten days after the last neurotoxic treatment, rats had a significant impairment (reduction) in pre-pulse inhibition (PPI). Each treatment group (neurotoxic treated and control) was then divided into two groups for treatment with saline or 0.5 mg/kg nicotine, administered s.c. twice daily from days 10 to 23. The rats were tested for sensorimotor gating on days 17 and 22 shortly after the morning nicotine administration. Nicotine did not affect the PPI in control animals. On day 17, PPI impairment was sustained in neurotoxically treated rats, regardless of saline or nicotine treatment. On day 22, however, the effect of neurotoxic treatment on PPI was totally absent in saline treated rats, whereas in nicotine treated rats, PPI impairment was still evident. Combination of nicotine and neurotoxic treatment also caused an up-regulation of high affinity nicotinic receptors in the cortex and the thalamus and apparent normalization of low affinity nicotinic receptors in the hippocampus. The findings indicate that muscarinic activation, in conjunction with neurotoxic NMDA receptor antagonism, produces relatively long-term impairment in auditory gating, a result relevant to modeling clinical observations of schizophrenia-associated symptoms. Contrary to expectation, nicotine administration in this model resulted in further impairment rather than amelioration of PPI. The results suggest a sustainable model of PPI impairment and possible role of nicotinic receptors in selective brain regions in this behavior.

The nicotinic receptor blocker hexamethonium alters neuronal responses to glutamate in the medial septal area of the brain of the ground squirrel in vitro

Despite extensive interest in studies of the medial septal area, the nature of the interactions of its various neurochemical systems remains largely unclear. The aim of the present work was to clarify the role of nicotinic receptors in mediating the interaction of the glutamatergic and cholinergic systems in this structure. Extracellular recording of neuron activity in living slices of ground squirrel brain was used to study the influences of L-glutamate (1 microM) during application of the nicotinic receptor blocker hexamethonium (1 mM). The responses of septal neurons to glutamate depended on the type of their initial activity and the presence of pacemaker properties. This study is the first to show that glutamate increases the frequency of volleys in rhythmic neurons in the septum. Hexamethonium induced changes in neuron activity similar to the influences of glutamate. After prior application of hexamethonium, the responses of neurons to glutamate changed: activatory responses were masked and inhibitory responses were enhanced. Cholinergic modulation of the responses of septal neurons to glutamate were shown to occur, as did modulation of the strength of the oscillatory properties of the septal network by nicotinic receptors.

Nicotinic acetylcholine receptors alpha4beta2 and alpha7 regulate myelo- and erythropoiesis within the bone marrow

Nicotine consumed upon smoking affects numerous physiological processes through nicotinic acetylcholine receptors, which mediate cholinergic regulation by the neuronal and endogenous acetylcholine. Consequently, nicotinic receptors are expressed in many non-excitable tissues including the blood. In spite of the documented effect of nicotine on hematopoiesis, little is known about the expression and role of nicotinic receptors in the course of blood cell differentiation. The aim of the present study was to investigate whether and how nicotinic receptors are involved in the development of myeloid and erythroid cells within the bone marrow. The presence of nicotinic receptors containing α4(β2) and α7 subunits in the bone marrow cells of C57Bl/6 mice was shown by the binding of [ 125I]-α-bungarotoxin or [ 3H]-Epibatidine and by flow cytometry with subunit-specific antibodies or fluorescein-labeled α-cobratoxin. Both TER119 + (erythroid) and CD16 +CD43 med (myeloid) progenitor cells bound more α4-specific antibodies than their mature forms, while the binding of α-cobratoxin and α7-specific antibodies was also high in mature cells. According to morphological analysis, either the absence of α7-containing nicotinic receptors in knockout mice or their desensitization in mice chronically treated with nicotine decreased the number of myeloid and erythroid progenitors and junior cells. In contrast, the absence of β2-containing receptors favored myelocyte generation and erythroid cell maturation. It is concluded that the development of both myeloid and erythroid cell lineages is regulated by endogenous cholinergic ligands and can be affected by nicotine through α7- and α4β2-containing nicotinic receptors, which play different roles in the course of the cell maturation.

The role of nicotinic receptors in B-lymphocyte development and activation

We studied the binding of [3H]-epibatidine and [125I-]α-bungarotoxin, as well as subunit-specific antibodies with purified B lymphocytes of C57Bl/6J mice and found that these cells contained 12,200±3200 of α4(α5)β2 and 3130±750 of α7(α5β4) nicotinic acetylcholine receptors per cell. According to flow cytometry data, the highest expression of α4(α5)β2 receptors was observed in immature newly generated B lymphocytes of the bone marrow, while the number of α7(α5β4) receptors grew up along with the B cell maturation in the spleen. By using α4, β2 or α7 knockout and chimera mice, it was shown that both receptor subtypes supported the survival of B cell precursors and increased the size of B-lymphocyte population in the bone marrow. In contrast, propagation of mature B lymphocytes in the spleen was controlled by α7-containing subtype only. Moreover, mature B lymphocytes became sensitive to nicotine only in the absence of β2-containing receptors. Knockout mice had less serum IgG, IgG-producing cells and natural IgG antibodies than their wild-type counterparts, while the absence of β2-containing receptors resulted in increased B-lymphocyte activation and antibody immune response. The data obtained indicate that nicotinic receptors are involved in regulating B-lymphocyte development and activation, possibly, by affecting expression and/or signaling of CD40, the two subtypes playing different roles.

Difference in the expression of alpha 7 nicotinic receptors in the placenta in normal versus severe preeclampsia pregnancies

Objective The prevalence of preeclampsia is low in smokers, suggesting a possible role of nicotinic receptor in the pathophysiology of the disease. Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) was recently found in non-neuronal tissue with various mediating functions. Therefore, we investigated the difference in the placental expression of the α7 nAChR in normal versus severe preeclampsia placentas. Study design Central portions of placenta were obtained from 9 severe preeclampsia women and 11 gestational-age-matched normal pregnant women delivered between the gestational ages of 33 and 40 weeks following elective or emergency cesarean section. RT-PCR, western blotting, and immunohistochemical staining were performed to evaluate the α7 nAChR expression difference. Results In all the placentas, the α7 nAChR was expressed in endothelial cells, vascular smooth muscle cells, and stromal cells, but not in trophoblasts. The vascular staining was more intense in the severe preeclampsia placenta ( p = 0.02). Although the gene expression did not differ between the two groups, protein expression was greater in 7 of 9 placenta samples from the severe preeclampsia group. Conclusion Placental expression of α7 nAChR differs between normal and severe preeclampsia placentas, suggesting that it may be involved in the pathogenesis of preeclampsia.

Lobeline augments and inhibits cocaine-induced hyperactivity in rats

Lobeline has high affinity for nicotinic receptors and alters presynaptic dopamine storage and release in brain. Moreover, lobeline decreases the reinforcing and locomotor-activating properties of methamphetamine, suggesting that lobeline may be a pharmacotherapy for psychostimulant abuse. This study determined if lobeline alters cocaine-induced hyperactivity and if lobeline alters the induction and/or expression of sensitization to cocaine. On Days 1–12, male rats were administered lobeline (0.3 or 1.0 mg/kg) or saline, placed in an automated activity monitor for 20 min, administered cocaine (10, 20 or 30 mg/kg) or saline and returned to the monitor for 60 min. On Day 13, the effect of lobeline on the induction and expression of sensitization to cocaine was determined. Lobeline did not alter the effect of cocaine after acute injection. However, 1.0 mg/kg lobeline attenuated cocaine (10 and 20 mg/kg)-induced hyperactivity after repeated administration and prevented the development of sensitization to these cocaine doses. Interestingly, 0.3 mg/kg lobeline augmented cocaine (10 mg/kg)-induced hyperactivity after repeated administration. Lobeline did not alter the effect of 30 mg/kg cocaine. The present results indicate a complex interaction of lobeline with cocaine and support other research indicating a role for nicotinic receptors in the development of sensitization to psychostimulants.