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A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the antismoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKa and high affinity for a4b2-type nicotinic receptors (a4b2Rs) are trapped in intracellular acidic vesicles containing a4b2Rs in vitro. Nicotine, with lower pKa and a4b2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in vivo in male and female mouse brain and identifying the trapping brain organelle in vitro as Golgi satellites (GSats). Two PET 18F-labeled imaging ligands were chosen: [18F]2- FA85380 (2-FA) with varenicline-like pKa and affinity and [18F]Nifene with nicotine-like pKa and affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in a4b2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to a4b2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals were eliminated in b2 subunit knock-out (KO) mice or by acute nicotine (AN) injections demonstrating binding to sites on b2-containing receptors. Chloroquine (CQ), which dissipates GSat pH gradients, reduced [18F]2-FA distributions while having little effect on [18F]Nifene distributions in vivo consistent with only [18F]2-FA trapping in GSats. These results are further supported by in vitro findings where dissipation of GSat pH gradients blocks 2-FA trapping in GSats without affecting Nifene. By combining in vitro and in vivo imaging, we mapped both the brain-wide and subcellular distributions of weak-base nicotinic receptor ligands. We conclude that ligands, such as varenicline, are trapped in neurons in a4b2R-containing GSats, which results in very slow release long after nicotine is gone after smoking. [ABSTRACT FROM AUTHOR]

Background: Osteochondroma is the most common benign bone tumor; intracranial osteochondroma is a very rare finding in the neurosurgical literature and most of them arise from the skull base.Case report: We report a case of suprasellar ostheocondroma in a 16-year-old female, with its CT and MRI appearances, which caused visual deficits, resolved after surgery.Discussion: To our knowledge, this is the fifth case of osteochondroma affecting the suprasellar region that has been reported, with all the characteristic features of this tumor: optic chiasmal syndrome, intralesional calcifications, cartilage cap, and contrast enhancement.Conclusion: Multidiscplinary teams, including a neuro-ophthalmologist, endocrinologist, neuroradiologist, neurosurgeon, and neuropathologist are needed for correct treatment of the disease and appropriate follow-up. [ABSTRACT FROM AUTHOR]

Background: The α7 subtype of the nicotinic acetylcholine receptor (nAChR) is considered important in higher cognitive functions, and cholinergic loss underpins the pathophysiology of Alzheimer's disease (AD). However, the relationships between α7 nAChR function and clinical functions or amyloid-β (Aβ) deposition remain to be explored in the living AD brain.Objective: We aimed to elucidate the relationship between α7 nAChR availability in the specific cholinergic region and cognitive decline in the Aβ-confirmed AD brain.Methods: Twenty AD patients and ten age-matched healthy subjects were examined. The α7-nAChR availability and Aβ deposition were evaluated using positron emission tomography with an α7 nAChR radiotracer 11C-(R)-MeQAA and 11C-Pittsburg compound B (11C-PiB), respectively. Semi-quantified values of tracer binding were estimated with a simplified reference tissue method for BPND of 11C-(R)-MeQAA and a tissue ratio method for SUVR of 11C-PiB. These parameters and clinical scores were compared voxel-wise using a statistical parametric mapping method.Results: The levels of 11C-(R)-MeQAA BPND in the temporal and prefrontal cholinergic projection regions were significantly lower in AD, and negative correlations were found between 11C-PiB SUVR and 11C-(R)-MeQAA BPND in the region of the nucleus basalis magnocellularis and medial prefrontal cortex. Levels of 11C-(R)-MeQAA BPND were significantly correlated with memory and frontal function scores in AD.Conclusion: The association between Aβ burden and α7-nAChR reduction in the basal forebrain cholinergic system was highlighted in relation to cognitive decline in AD. This suggests that Aβ-linked α7-nAChR reduction is clinico-pathophyisologically important for considering a good therapeutic target in AD. [ABSTRACT FROM AUTHOR]

Key points Neuronal nicotinic acetylcholine receptors (nAChRs) play a fundamental role in the attentional circuitry throughout the mammalian CNS. , In the present study, we report a novel finding that ageing negatively impacts nAChR efficacy in auditory thalamus, and this is probably the result of a loss of nAChR density ( Bmax) and changes in the subunit composition of nAChRs., Our data support the hypothesis that age-related maladaptive changes involving nAChRs within thalamocortical circuits partially underpin the difficulty that elderly adults experience with respect to attending to speech and other salient acoustic signals., Abstract The flow of auditory information through the medial geniculate body (MGB) is regulated, in part, by cholinergic projections from the pontomesencephalic tegmentum. The functional significance of these projections is not fully established, although they have been strongly implicated in the allocation of auditory attention. Using in vitro slice recordings, we have analysed postsynaptic function and pharmacology of neuronal nicotinic ACh receptors (nAChRs) in young adult and the aged rat MGB. We find that ACh produces significant excitatory postsynaptic actions on young MGB neurons, probably mediated by β2-containing heteromeric nAChRs. Radioligand binding studies show a significant age-related loss of heteromeric nAChR receptor number, which supports patch clamp data showing an age-related loss in ACh efficacy in evoking postsynaptic responses. Use of the β2-selective nAChR antagonist, dihydro-β-erythroidine, suggests that loss of cholinergic efficacy may also be the result of an age-related subunit switch from high affinity β2-containing nAChRs to low affinity β4-containing nAChRs, in addition to the loss of total nAChR number. This age-related nAChR dysfunction may partially underpin the attentional deficits that contribute to the loss of speech understanding in the elderly. [ABSTRACT FROM AUTHOR]

Choline is present at cholinergic synapses as a product of acetylcholine degradation. In addition, it is considered a selective agonist for α5 and α7 nicotinic acetylcholine receptors (nAChRs). In this study, we determined how choline affects action potentials and excitatory synaptic transmission using extracellular and intracellular recording techniques in CA1 area of hippocampal slices obtained from both mice and rats. Choline caused a reversible depression of evoked field excitatory postsynaptic potentials (fEPSPs) in a concentration-dependent manner that was not affected by α7 nAChR antagonists. Moreover, this choline-induced effect was not mimicked by either selective agonists or allosteric modulators of α7 nAChRs. Additionally, this choline-mediated effect was not prevented by either selective antagonists of GABA receptors or hemicholinium, a choline uptake inhibitor. The paired pulse facilitation paradigm, which detects whether a substance affects presynaptic release of glutamate, was not modified by choline. On the other hand, choline induced a robust increase of population spike evoked by orthodromic stimulation but did not modify that evoked by antidromic stimulation. We also found that choline impaired recurrent inhibition recorded in the pyramidal cell layer through a mechanism independent of α7 nAChR activation. These choline-mediated effects on fEPSP and population spike observed in rat slices were completely reproduced in slices obtained from α7 nAChR knockout mice, which reinforces our conclusion that choline modulates synaptic transmission and neuronal excitability by a mechanism independent of nicotinic receptor activation. [ABSTRACT FROM AUTHOR]

Hemangioblastoma is a well-circumscribed, highly vascular, lipid-rich and low-grade tumor of uncertain histogenesis. Its histopathological features have been well established. Herein, we present a case of cerebellar hemangioblastoma in a 43-year-old woman. Histologically, the tumor was predominantly composed of cellular areas showing eosinophilic or vacuolated stromal cells arranged in nests and sheets. Focally, conventional reticular areas could be seen. Additionally, in some areas, the stromal cells were arranged radially around blood vessels, exhibiting perivascular pseudorosette structures, which were similar mostly to those of ependymomas. Immunohistochemically, the stromal cells markedly showed diffused staining for Vimentin, S-100, CD56, NSE, inhibin-a, podoplanin, alpha-Thalassemia/mental retardation syndrome X and carbonic anhydrase IX, and were negative for cytokeratin, epithelial membrane antigen, oligodendrocyte transcription factor 2, neuronal nuclear antigen, synaptophysin, isocitrate dehydrogenase 1 (R132H), P53 and CD34. Interestingly, the reticular and cellular areas either showed no or individual scattering of the GFAP-positive cells, respectively, while, the perivascular pseudorosette areas strongly and diffusely expressed GFAP. Nuclear mitosis and necrosis were not observed. The MIB-1 antibody labeling index was especially low (about 3%). Based on these findings, the patient was diagnosed with cerebellar hemangioblastoma. In the present case, we documented a distinctive histological appearance of perivascular pseudorosettes in hemangioblastoma and provided the evidence for stromal cells with glial differentiation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which causes the deterioration of memory and other cognitive abilities of the elderly. Previous lines of research have shown that Aβ is an essential factor in AD pathology and the soluble oligomeric species of Aβ peptide is presumed to be the drivers of synaptic impairment in AD. However, the exact mechanisms underlying Aβ-induced synapse dysfunction are still not fully understood. Recently, increasing evidence suggests that some potential receptors which bind specifically with Aβ may play important roles in inducing the toxicity of the neurons in AD pathology. These receptors include the cellular prion protein (PrPc), the α7 nicotinic acetylcholine receptor (α7nAChR), the p75 neurotrophin receptor (p75), the beta-adrenergic receptors (β-ARs), the Eph receptors, the paired immunoglobulin-like receptor B (PirB), the PirB's human ortholog receptor (LilrB2), and the Fcγ receptor II-b (FcγRIIb). This review summarizes the characters of these prominent receptors and how the bindings of them with Aβ inhibit the LTP, decrease the number of dendritic spine, damage the neurons, and so on in AD pathogenesis. Blocking or rescuing these receptors may have significant importance for AD treatments. [ABSTRACT FROM AUTHOR]

Marine snails of the genus Conus are a large family of predatory gastropods with an unparalleled molecular diversity of pharmacologically active compounds in their venom. Cone snail venom comprises of a rich and diverse cocktail of peptide toxins which act on a wide variety of ion channels such as voltage-gated sodium- (NaV), potassium- (KV), and calcium- (CaV) channels as well as nicotinic acetylcholine receptors (nAChRs) which are classified as ligand-gated ion channels. The mode of action of several conotoxins has been the subject of investigation, while for many others this remains unknown. This review aims to give an overview of the knowledge we have today on the molecular pharmacology of conotoxins specifically interacting with nAChRs along with the structure-function relationship data. [ABSTRACT FROM AUTHOR]

Here, we present the pharmacological characterisation of Lu AF64280, a novel, selective, brain penetrant phosphodiesterase (PDE) 2A inhibitor, in in vitro/in vivo assays indicative of PDE2A inhibition, and in vivo models/assays relevant to cognitive processing or antipsychotic-like activity. The in vitro selectivity of Lu AF64280 was determined against a panel of PDE enzymes and 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the hippocampus were determined using in vivo microdialysis. Lu AF64280 potently inhibited hPDE2A (Ki = 20 nM), 50-fold above moderate inhibition of both hPDE9A (Ki = 1,000 nM) and hPDE10A (Ki = 1,800 nM), and displayed a >250-fold selectivity over all other full-length human recombinant PDE family members (Ki above 5,000 nM). Lu AF64280 (20 mg/kg) significantly increased cGMP levels in the hippocampus ( p < 0.01 versus vehicle-treated mice), attenuated sub-chronic phencyclidine-induced deficits in novel object exploration in rats (10 mg/kg, p < 0.001 versus vehicle-treated), blocked early postnatal phencyclidine-induced deficits in the intradimensional/extradimensional shift task in rats (1 and 10 mg/kg, p < 0.001 versus vehicle-treated) and attenuated spontaneous P20-N40 auditory gating deficits in DBA/2 mice (20 mg/kg, p < 0.05 versus vehicle-treated). In contrast, Lu AF64280 failed to attenuate phencyclidine-induced hyperactivity in mice, and was devoid of antipsychotic-like activity in the conditioned avoidance response paradigm in rats, at any dose tested. Lu AF64280 represents a novel tool compound for selective PDE2A inhibition that substantiates a critical role of this enzyme in cognitive processes under normal and pathological conditions. [ABSTRACT FROM AUTHOR]

Background Chronic ethanol ( Et OH) abuse in humans is known to independently increase the incidence of and mortality due to acute lung injury in at-risk individuals. However, the mechanisms by which Et OH affects lung cells remain incompletely elucidated. In earlier work, we reported that Et OH increased the expression in lung fibroblasts of fibronectin, a matrix glycoprotein implicated in lung injury and repair. This effect was blocked by α-bungarotoxin, a neurotoxin that binds certain nicotinic acetylcholine receptors (n ACh Rs) thereby implicating n ACh Rs in this process. Here, we examine the identity of these receptors. Methods Mouse lung fibroblasts were stimulated with Et OH (60 mM) or acetylcholine (100 to 500 μM) and evaluated for the expression of fibronectin and n ACh Rs. Inhibitors to n ACh Rs or the antioxidant N-acetyl cysteine (NAC) were used to assess changes in fibronectin expression. Animals exposed to Et OH for up to 6 weeks were used to evaluate the expression of n ACh Rs in vivo. Results First, in Et OH-treated fibroblasts, we observed increased expression of α4 and α9 n ACh R subunits. Second, we found that acetylcholine, a natural ligand for n ACh Rs, mimicked the effects of Et OH. Dihydro-β-erythroidin hydrobromide, a competitive inhibitor of α4 n ACh R, blocked the increase in fibronectin expression and cell proliferation. Furthermore, Et OH-induced fibronectin expression was inhibited in cells silenced for α4 n ACh R. However, Et OH-treated cells showed increased α-bungarotoxin binding suggesting that α4 n ACh R mediates the effects of Et OH via a ligand-independent pathway. Knowing there are several important cysteine residues near the ligand-binding site of α4 n ACh Rs, we tested the antioxidant NAC and found that it too blocked the induction of fibronectin expression by Et OH. Also, fibroblasts exposed to oxidant stress showed increased fibronectin expression that was blocked with α-bungarotoxin. Finally, we showed increased expression of α4 n ACh Rs in the lung tissue of mice and rats exposed to Et OH suggesting a role for these receptors in vivo. Conclusions Altogether, our observations suggest that α4 n ACh Rs serve as sensors for Et OH-induced oxidant stress in lung fibroblasts, thereby revealing a new mechanism by which Et OH may affect lung cells and tissue remodeling and pointing to n ACh Rs as potential targets for intervention. [ABSTRACT FROM AUTHOR]

Introduction: It has been suggested that the homomer-forming a7 subunit (CHRNA7) of the neuronal nicotinic acetylcholine receptor (nAChR) is involved in the pathogenesis of common idiopathic generalized epilepsies (IGEs), whereas mutations of the gene coding for the a4 nAChR subunit (CHRNA4) are associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Several genes encoding nAChR subunits, including a partially duplicated isoform of CHRNA7 (CHRFAM7A), are expressed in peripheral blood lymphocytes (PBLs), and are constituents of peripheral receptors corresponding to nAChRs in the brain. Moreover, a 2-bp deletion polymorphism (c.497-498delTG; rs67158670), resulting in a frame shift and truncation of the protein product of the gene, has been found in the CHRFAM7A gene and is associated with some neurological diseases. Aim of the study: CHRFAM7A transcript levels in CD4+ T-lymphocytes were compared between ADNFLE patients harbouring the c.851C>T mutation of the CHRNA4 gene and control healthy individuals in order to determine whether there is any correlation between CHRFAM7A expression in CD4+ T-lymphocytes and the severity of epileptic symptoms. We also tested the hypothesis that the 2-bp deletion polymorphism in the partially duplicated a7 nAChR gene may be related to ADNFLE in these patients. Material and methods: Peripheral venous blood samples were collected from 3 individuals with ADNFLE and from 10 healthy individuals. From the isolated CD4+ T-lymphocytes, RNA was prepared and the CHRFAM7A transcript level was determined by RT-qPCR. In order to compare the CHRNA7 and CHRFAM7A sequences and genotype the -2bp polymorphism, genomic DNA was prepared from PBLs. Results: It has been demonstrated that CHRFAM7A is expressed in CD4+ T-lymphocytes of healthy individuals, the relative abundance of the transcript being nearly equal (about 100 copies per cell), but it is not expressed in ADNFLE patients. Genotype analysis showed that the -2bp polymorphism was found in all patients as well as in seven healthy individuals. Conclusions: Our observations confirm the hypothesis that the CHRFAM7A gene is expressed in CD4+ T-lymphocytes of healthy individuals and that this expression is legitimate. The observed lack of CHRFAM7A expression in ADNFLE patients might be an important factor in the pathogenesis of ADNFLE. [ABSTRACT FROM AUTHOR]

Background: Osteochondroma is a common bone tumor and rarely affects the central nervous system. Although intraspinal osteochondromas are known to cause neurological deficits, intracranial osteochondromas with neurological compromise are very rare. Case Description: The authors report an exceptional case of a quadriparetic 73-year-old patient with a basioccipital bone osteochondroma growing into the foramen magnum. The embryology, differential diagnoses, and optimal management strategies are discussed. Conclusion: Although extremely rare, osteochondromas should be included in the differential diagnoses of tumors within the foramen magnum. For the tumors originating from the basioccipital bone, a simple medial suboccipital approach might suffice, while for ventral tumors, a far lateral transcondylar approach is necessary to avoid any neurovascular complications. Despite potentially catastrophic presenting symptoms, these tumors are pathologically benign and complete excision often results in long-term cure. To the best of our knowledge, this is the first report of an osteochondroma arising from the basiocciput. [ABSTRACT FROM AUTHOR]

Abstract: Exposure to cigarette smoke is a major risk factor for sudden infant death syndrome (SIDS). We tested the hypothesis that nicotine increases expression of the nicotinic acetylcholine receptor (nAChR) subunits α7 and β2 in a piglet model. Piglets exposed to 2mg/kg/day nicotine for 14 days postnatally (n =14) were compared to non-exposed controls (n =14), (equal gender proportions). Immunohistochemistry was performed to identify and quantify changes in, α7 and β2 nAChR subunits in 8 nuclei of the medulla at both the rostral and caudal levels. Compared to controls, nicotine exposed piglets had decreased α7 in the rostral dorsal motor nucleus of the vagus (rDMNV) (p =0.01), and increased β2 in the caudal DMNV (cDMNV) (p =0.05), caudal nucleus of the spinal trigeminal tract (cNSTT) (p =0.03) and caudal nucleus of the solitary tract (cNTS) (p =0.04). Analysis by gender showed that in the control group, compared to males, females had higher β2 in the caudal hypoglossal (cXII) (p <0.01) and caudal inferior olivary (p =0.04) nuclei, while in the nicotine group females had higher β2 in the cDMNV (p =0.02). Compared to control males, nicotine exposed males had lower β2 in the cXII (p <0.01). Overall, changes in α7 were specific to nicotine exposure with no gender differentiation. Changes in β2 were more widespread but showed gender-specific effects. These findings provide evidence that early postnatal exposure to nicotine significantly affects nAChR subunit expressions in the developing brainstem. [Copyright &y& Elsevier]

Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents. The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats. The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central α7 nicotinic acetylcholine receptor (nAChR) and non-α7 nAChR levels (primarily α4β2 nAChRs). The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the α7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-α7 nAChR density in the dentate gyrus. Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus. [ABSTRACT FROM AUTHOR]

It is widely known that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain. This neurogenesis has been implicated in depression and antidepressant treatments. Recent evidence also suggests that the dentate gyrus is involved in the neuropathology and pathophysiology of schizophrenia and other related psychiatric disorders. Especially, abnormal neuronal development in the dentate gyrus may be a plausible risk factor for the diseases. The synapse made by the mossy fiber, the output fiber of the dentate gyrus, plays a critical role in regulating neuronal activity in its target CA3 area. The mossy fiber synapse is characterized by remarkable activity-dependent short-term synaptic plasticity that is established during the postnatal development and is supposed to be central to the functional role of the mossy fiber. Any defects, including developmental abnormalities, in the dentate gyrus and drugs acting on the dentate gyrus can modulate the mossy fiber-CA3 synaptic transmission, which may eventually affect hippocampal functions. In this paper, I review recent evidence for involvement of the dentate gyrus and mossy fiber synapse in psychiatric disorders and discuss potential importance of drugs targeting the mossy fiber synapse either directly or indirectly in the therapeutic treatments of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Schizophrenia patients and certain inbred mouse strains (i.e., DBA/2) show deficient sensory inhibition which has been linked to reduced numbers of hippocampal α7 nicotinic receptors and to underlying polymorphisms in the promoter region for the α7 gene. Increasing maternal dietary choline, a selective α7 agonist, during gestation has been shown to produce long-term changes in adult offspring behavior (i.e., improved learning and memory in rats). The objective of this study is to improve sensory inhibition in DBA/2 mice through maternal choline supplementation. DBA/2 dams were placed on normal (1.1 g/kg) or supplemented (5 g/kg) choline diet throughout gestation and lactation. Offspring were placed on normal diet at weaning and were assessed for sensory inhibition parameters at adulthood. Evoked EEG responses to identical paired auditory stimuli were compared. At the end of the study, the brains were collected for autoradiographic assessment of hippocampal levels of α-bungarotoxin binding to visualize α7 nicotinic receptors. Offspring mice which were choline supplemented during gestation showed significantly improved sensory inhibition compared to mice gestated on the normal choline diet. The improvement was produced by a significant reduction in the response to the second stimulus, demonstrating improved inhibition to that stimulus. There was a concurrent increase in α7 receptor numbers in both the CA1 and dentate gyrus regions of the hippocampus suggesting that this increase may be responsible for the improved inhibition. These data show that gestational choline supplementation produces permanent improvement in a deficit associated with schizophrenia and may have implications for human prenatal nutrition. [ABSTRACT FROM AUTHOR]

Nicotinic acetylcholine receptors (nAChRs) are integral membrane proteins and prototypic members of the ligand-gated ion-channel superfamily, which has precursors in the prokaryotic world. They are formed by the assembly of five transmembrane subunits, selected from a pool of 17 homologous polypeptides (α1–10, β1–4, γ, δ, and ε). There are many nAChR subtypes, each consisting of a specific combination of subunits, which mediate diverse physiological functions. They are widely expressed in the central nervous system, while, in the periphery, they mediate synaptic transmission at the neuromuscular junction and ganglia. nAChRs are also found in non-neuronal/nonmuscle cells (keratinocytes, epithelia, macrophages, etc.). Extensive research has determined the specific function of several nAChR subtypes. nAChRs are now important therapeutic targets for various diseases, including myasthenia gravis, Alzheimer's and Parkinson's diseases, and schizophrenia, as well as for the cessation of smoking. However, knowledge is still incomplete, largely because of a lack of high-resolution X-ray structures for these molecules. Nevertheless, electron microscopy studies on 2D crystals of nAChR from fish electric organs and the determination of the high-resolution X-ray structure of the acetylcholine binding protein (AChBP) from snails, a homolog of the extracellular domain of the nAChR, have been major steps forward and the data obtained have important implications for the design of subtype-specific drugs. Here, we review some of the latest advances in our understanding of nAChRs and their involvement in physiology and pathology. [ABSTRACT FROM AUTHOR]

Schizophrenia is a common mental illness with a high prevalence of smoking. More than 80% of schizophrenics smoke compared to 25% of the general population. Both schizophrenia and tobacco use have strong genetic components, which may overlap. It has been suggested that smoking in schizophrenia may be a form of self-medication in an attempt to treat an underlying biological pathology. Smoking normalizes auditory evoked potential and eye tracking deficits in schizophrenia, as well as improving cognitive function. Nicotine acts through a family of nicotinic receptors with either high or low affinity for nicotine. The loci for several of these receptors have been genetically linked to both smoking and to schizophrenia. Smoking changes gene expression for more than 200 genes in human hippocampus, and differentially normalizes aberrant gene expression in schizophrenia. The 7* nicotinic receptor, linked to schizophrenia and smoking, has been implicated in sensory processing deficits and is important for cognition and protection from neurotoxicity. Nicotine, however, has multiple health risks and desensitizes the receptor. A Phase I trial of DMXB-A, an 7* agonist, shows improvement in both P50 gating and in cognition, suggesting that further development of nicotinic cholinergic drugs is a promising direction in schizophrenia research. doi:10.1300/J374v03n03_05 [ABSTRACT FROM PUBLISHER]

The present studies were done to investigate the effect of long-term nicotine treatment against nigrostriatal damage in non-human primates. Monkeys were administered nicotine in drinking water for 6 months to provide chronic but intermittent delivery as with smoking. Plasma nicotine levels ranged from 10 to 15 ng/mL, which were within the range in cigarette smokers. Animals were then lesioned with low doses of the dopaminergic neurotoxin MPTP for several months while nicotine was continued. The results showed that levels of striatal tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter, dopamine and nicotinic receptors were greater in nicotine-treated MPTP-lesioned primates than in lesioned animals not receiving nicotine. Nicotine had no effect in unlesioned animals. Monoamine oxidase activity was similar in unlesioned and lesioned animals treated with or without nicotine, suggesting that nicotine did not exert its effects through changes in MPTP or dopamine metabolism. MPTP-induced cell loss in the substantia nigra was unaffected by nicotine treatment, indicating that nicotine acts at the striatal level to restore/maintain dopaminergic function. These data further support the possibility that nicotine contributes to the lower incidence of Parkinson's disease in smokers. [ABSTRACT FROM AUTHOR]

Patients with schizophrenia exhibit deficits in a range of cognitive functions, particularly working and episodic memory, which are thought to be core features of the disorder. Memory dysfunction in schizophrenia is familial and thus a promising endophenotype for genetic studies. Both human and animal studies suggest a role for the neural nicotinic acid receptor family in cognition and specifically the α7-receptor subunit in schizophrenia and its endophenotypes. Consequently, we tested mice lacking the α7 subunit of the neural nicotinic receptor (B6.129S7-Chrna7tm1Bay/J) in the delayed matching-to-place (DMP) task of the Morris water maze, a measure of working/episodic memory akin to human episodic memory. We report that a minor impairment in α7 knockout mice was observed in the DMP task, with knockout mice taking longer to find the hidden platform than their wildtype controls. This suggests a role for the α7 subunit in working/episodic memory and a potential role for the α7 neural nicotinic receptor gene ( CHRNA7) in schizophrenia and its endophenotypes. [ABSTRACT FROM AUTHOR]

Investigating correlates of tobacco smoking provides the only currently available opportunity of examining effects of long-term exposure of nicotinic receptors on a specific nicotinic agonist in human. Alzheimer-type pathology (Aβ and abnormally phosphorylated tau assessed on the basis of AT8 immunoreactivity) together with vascular markers has been compared in age-matched groups of normal elderly smokers and non-smokers in the entorhinal cortex, an area of noted age-related pathology. The density of total Aβ and diffuse Aβ immunoreactivity, together with formic acid-extractable Aβ42 but not Aβ40, was reduced in smokers ( n = 10–18) compared with non-smokers ( n = 10–20) ( P < 0.05). There was also a reduced percentage of cortical and leptomeningeal vessels with associated Aβ immunoreactivity in smokers ( n = 13) compared with non-smokers ( n = 14) ( P < 0.005 and 0.05, respectively). There was a significant inverse correlation between formic acid-extractable Aβ42 and pack years ( n = 34, r = −0.389, P = 0.025), with a similar trend for total Aβ immunoreactivity which did not reach statistical significance ( n = 30, r = −0.323, P = 0.082). In contrast, there were no significant group differences for vascular markers (collagen IV, α-actin or glucose transporter 1), AT8 immunoreactivity or phosphate-buffered saline-soluble Aβ peptides, and no significant associations with gender for any of the measured parameters. These findings are consistent with previously reported reductions in histologically assessed amyloid plaques in aged human brain associated with tobacco use and dramatic lessening of Aβ deposits in APPsw mice after nicotine treatment. Development of nicotinic drugs to protect against β-amyloidosis as one of the principal pathological hallmarks of brain ageing and Alzheimer's disease is indicated. [ABSTRACT FROM AUTHOR]

Ethanol renders the lung susceptible to acute lung injury in the setting of insults such as sepsis. The mechanisms mediating this effect are unknown, but activation of tissue remodeling is considered key to this process. We found that chronic ethanol ingestion in rats increased the expression of fibronectin. a matrix glycoprotein implicated in acute lung injury. In cultured NIH/3T3 cells and in primary rat and mouse lung fibroblasts, ethanol induced fibronectin mRNA and protein expression in a dose- and time-dependent fashion. The effect of ethanol was prevented by inhibitors of protein kinase C and mitogen-activated protein kinases and was associated with the phosphorylation and increased DNA binding of the transcription factor cAMP response element binding protein, followed by increased transcription of the fibronectin gene. Fibroblasts were found to express α7 nicotinic acetylcholine receptor (nAChR), and ethanol induction of fibronectin was abolished by α-bungarotoxin and methyllcaconitine, inhibitors of α7 nAChRs. However, ethanol was able to induce fibronectin mRNA and protein in primary lung fibroblasts isolated from α7 nAChR knockout mice. The ethanol-induced fibronectin response was dependent on ethanol metabolism since 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, abolished the effect and acetaldehyde induced it. These observations suggest that ethanol or ethanol metabolites stimulate lung fibroblasts to produce fibronectin by inducing specific signals transmitted via nAChRs independent of the α7-subunit, and this might represent a mechanism by which ethanol renders the lung susceptible to acute lung injury. [ABSTRACT FROM AUTHOR]

We investigated the neuroprotective function of α7 nicotinic acetylcholine receptor (α7nAChR) after transient hypoxia (12 h) and reoxygenation (0–72 h), comparing rat pheochromocytoma (PC12) cells overexpressing FLAG-tagged α7nAChR (α7pCMV cells) and control PC12 cells (non-transfected or transfected with vector only) in medium with and without nicotine. Plasma membrane degradation in the early phase after hypoxia was inhibited in PC12 cells with nicotine, and more profoundly in α7pCMV cells with nicotine. Inhibition of DNA fragmentation in the late phase after hypoxia was most remarkable in α7pCMV cells with nicotine, but, surprisingly, it was more remarkable in α7pCMV cells without nicotine than in PC12 cells with nicotine. G1-arrest of the cell cycle, observed in control PC12 cells at 12 h after hypoxia, preceding DNA fragmentation, was not evident in α7pCMV cells, with or without nicotine. Furthermore, in α7pCMV cells with and without nicotine, the basal expression levels of total Akt were approximately 1.5-fold higher, and the up-regulation of Akt phosphorylated at Ser473 after hypoxia was strikingly enhanced, compared with control PC12 cells. These findings suggest that α7nAChR functions constitutively in PC12 cells, that its overexpression raises tolerance against G1-arrest and DNA fragmentation after hypoxia, and that it can be considered a candidate target for treatment against hypoxia-induced acute membrane degradation and delayed DNA fragmentation in neurons. [ABSTRACT FROM AUTHOR]

Molecular identification of the genes and resulting protein sequences for a large number of nicotinic acetylcholine receptor (nAChR) subunits has stimulated numerous studies highlighting their role in several human behaviors including neurological disorders and nicotine addiction. This receptor gene family is likely to be involved in release of multiple neurotransmitters in both brain and periphery that mediate sensitivity and tolerance to nicotine. Recent findings also suggest that alterations in these receptors may lead to neurological diseases, some associated with increased incidence of smoking. This review addresses current knowledge of nicotinic receptor structure, regulation of expression, and function, in both normal and psychiatric subjects. [ABSTRACT FROM AUTHOR]

We present here a systematic mapping of nAChR subunit mRNAs in Macaca mulatta brain. A fragment, from the transmembrane segments MIII to MIV of Macaca neuronal nAChR subunits was cloned, and shown to exhibit high identity (around 95%) to the corresponding human subunits. Then, specific oligodeoxynucleotides were synthesized for in situ hybridization experiments. Both α4 and β2 mRNA signals were widely distributed in the brain, being stronger in the thalamus and in the dopaminergic cells of the mesencephalon. Most brain nuclei displayed both α4 and β2 signals with the exception of some basal ganglia regions and the reticular thalamic nucleus which were devoid of α4 signal. α6 and β3 mRNA signals were selectively concentrated in the substantia nigra and the medial habenula. The strongest signals for α3 or β4 mRNAs were found in the epithalamus (medial habenula and pineal gland), whereas there were no specific α3 or β4 signals in mesencephalic dopaminergic nuclei. α5 and α7 mRNA signals were found in several brain areas, including cerebral cortex, thalamus and substantia nigra, although at a lower level than α4 and β2. The distribution of α3, α4, α5, α6, α7, β2, β3 and β4 subunit mRNAs in the monkey is substantially similar to that observed in rodent brain. Surprisingly, α2 mRNA signal was largely distributed in the Macaca brain, at levels comparable with those of α4 and β2. This observation represents the main difference between rodent and Macaca subunit mRNA distribution and suggests that, besides α4β2*, α2β2* nAChRs constitute a main nAChR isoform in primate brain. [ABSTRACT FROM AUTHOR]

Abstract: We have recently reported evidence that a very high affinity interaction between the β-amyloid peptide Aβ1-42 and the α7 nicotinic acetylcholine receptor (α7nAChR) may be a precipitating event in the formation of amyloid plaques in Alzheimer's disease. In the present study, the kinetics for the binding of Aβ1-42 to α7nAChR and α4β2nAChR were determined using the subtype-selective nicotinic receptor ligands [3H]methyllycaconitine and [3H]cytisine. Synaptic membranes prepared from rat and guinea pig cerebral cortex and hippocampus were used as the source of receptors. Aβ1-42 bound to the α7nAChR with exceptionally high affinity, as indicated by Ki values of 4.1 and 5.0 pM for rat and guinea pig receptors, respectively. When compared with the α7nAChR, the affinity of Aβ1-42 for the α4β2nAChR was ∼5,000-fold lower, as indicated by corresponding Ki values of 30 and 23nM. The results of this study support the concept that an exceptionally high affinity interaction between Aβ1-42 and α7nAChR could serve as a precipitating factor in the formation of amyloid plaques and thereby contribute to the selective degeneration of cholinergic neurons that originate in the basal forebrain and project to the cortex and hippocampus. [ABSTRACT FROM AUTHOR]

Recent advances in human genetics and in the neurobiology of neurotransmitter receptors and channels have led to the discovery of specific genes associated with hereditary epileptic phenotypes. All the genes identified to date code for ligand- and voltage-gated ion channels. Some clinically rare idiopathic epilepsies are associated with mutations in genes coding for different neuronal nicotinic acetylcholine receptor (AChR) subunits. Distinct α subunits are found in the brain and in the peripheral nervous system, and structural, non-α subunits like β2 and β4 confer different properties to neuronal receptors. Thus, the final properties of the oligomeric AChR depend on the different combinations of α and β subunits. Most mutations found so far occur in the α4 chain, the most abundant subunit in the central nervous system. Specifically, the identification of mutations in the α4 subunit of neuronal AChR in human benign familial neonatal convulsions (BFNC) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) raise the possibility that the observed gene defects are linked (causatively) with these two diseases or, alternatively, that AChR α4 mutants increase the probability of epileptic discharges. We discuss testable hypotheses for unraveling the pathophysiology of these two disorders associated with AChR mutations. [ABSTRACT FROM AUTHOR]

Different mammalian and insect somatic host cell systems were tested in their ability to express, fold, and assemble α7-type neuronal acetylcholine receptor (AChR) both at the transcriptional and translational level. For this purpose we employed clonal cell lines derived from the neural crest, such as PC12 cells from a rat adrenal pheochromocytoma, and GH3 cells isolated from a rat pituitary tumor, as well as non-neuronal cells such as NIH-3T3 fibroblasts from embryonic NIH Swiss mouse and Sf9 cells from ovary tissue of the Spodoptera frugiperda butterfly. Total RNA, isolated from either transfected or non-transfected PC12, GH3 or 3T3 cells, or recombinant AcNPV-infected and mock-infected Sf9 cells was analyzed by Northern blot. PC12 cells, which endogenously express α7 AChR, and all its heterologous α7-transfectant clones, exhibited variable but generally high amounts of a single transcript. GH3 and NIH-3T3 transfectant clones and recombinant AcNPV-infected Sf9 cells expressed variable levels of α7-mRNA, with a single transcript that co-migrated with the 28S rat rRNA. Only the neural crest-derived cell lines appeared to functionally express the α7 AChR, as measured by their [125I]α-bungarotoxin binding ability. The results suggest that heterologous expression of α7 is regulated not at the transcriptional, but at the postranslational level and that not all host cell systems appear to express the cellular factors needed for the correct postranslational modifications leading to mature and functional α7 AChR. Furthermore, the results suggest that tightly controlled expression mechanisms have evolved in parallel with this ancient cholinergic sequence. [ABSTRACT FROM AUTHOR]

Nicotinic cholinoceptive dysfunction associated with cognitive impairment is a leading neurochemical feature of Alzheimer's disease. There-fore, nicotinic acetylcholine receptors have attracted considerable interest as potential therapeutic targets. The deficit of nicotine binding sites in Alzheimer's disease may be related to alterations of nicotinic receptor synthesis on the levels of (i) transcription, (ii) translation and post-translational modifications, (iii) receptor transport and turnover, including membrane insertion.  Current approaches aim at the elucidation of molecular changes at all three levels.  Although a com-prehensive picture has not yet been achieved, currently available data can be summarized as follows: (i) there are no changes at the level of transcription of subunit mRNAs studied so far, (ii) evidence is accumulating for a distinct decrease on the protein level in the expression especially of the á4-subunit, and (iii) preliminary findings point to a possible correlation of cytoskeletal changes (hyperphosphorylation of ô-protein) with decreased nicotinic acetylcholine receptor expression. [ABSTRACT FROM AUTHOR]

Receptor binding studies have uniform-ly found a significant reduction in the density of neuronal nicotinic cholinergic receptors in postmortem tissue obtained from Alzheimer's Disease (AD) pa-tients.  Nicotine is widely recognized as an pharma-cological agent that facilitates cognitive performance in human smokers as well as preclinical models utilizing rodents or non-human primates. Furthermore, epidemiological studies have consistently shown that the incidence of neurodegenerative diseases such as AD and Parkinson's Disease is lower in cigarette smokers than age-matched controls.  These findings have prompted speculation that brain nicotinic receptors could be important therapeutic targets for Alzheimer's Disease.  However, many questions remain with regard to the specificity and significance of the findings that have been reported with brain nicotinic receptors and AD.  Few studies have controlled for the potential influence of cigarette smoking, which increases the density of nicotinic receptors in human smokers. Questions also remain concerning alterations in individual nicotinic receptors subtypes as well as the regional variability of the deficits previously reported in AD.  Therefore, although the findings related to nicotinic receptors and AD to this date are intriguing, they appear to have raised more questions than they have answered. [ABSTRACT FROM AUTHOR]

Abstract: Neuronal nicotinic receptors have been implicated in schizophrenia on the basis of the high incidence of tobacco smoking in patients, abnormalities in cytisine and α-bungarotoxin (αBGT) binding in the hippocampus, and linkage between auditory P50 deficits and the region of chromosome 15 coding the α7 subunit. In another disease associated with psychosis, dementia with Lewy bodies (DLB), in which visual hallucinations predominate, reductions in nicotine binding have been identified in various cortical and subcortical regions. We investigated both αBGT and nicotine binding autoradiographically in different thalamic nuclei in autopsy brain tissue from patients with schizophrenia and DLB. αBGT binding in the reticular nucleus was moderately reduced (25%) in schizophrenia and more extensively reduced (50%) in DLB. There were no significant alterations in nicotine binding in schizophrenia, and in DLB, a trend towards moderate reductions in most nuclei reached significance in the lateral dorsal nucleus. It is concluded that widespread abnormalities of thalamic nicotine are not implicated in schizophrenia or DLB, but that reticular αBGT binding may be involved to a lesser and greater extent in the pathophysiology or psychopathology of both disorders. [ABSTRACT FROM AUTHOR]

Objective: Nicotine temporarily normalizes smooth pursuit eye movement deficits in schizophrenia. This study used functional magnetic resonance imaging (fMRI) to examine changes in brain hemodynamic response associated with nicotine administration during a smooth pursuit eye movement task in subjects with schizophrenia. Method: Nine subjects with schizophrenia performed the eye movement task while undergoing fMRI. Subjects then were given nicotine or placebo and repeated the task while being scanned. Subjects repeated the procedure the following week, receiving the counterbalanced condition. Results: Compared with placebo, nicotine was associated with greater activity in the anterior and posterior cingulate gyri, precuneus, and area MT/MST and less activity in the hippocampus and parietal eye fields. Conclusions: Changes in area MT/MST and the cingulate gyrus are consistent with an improvement in perception and attention to moving stimuli. The most important observed difference between nicotine and placebo-less activation of the hippocampus after nicotine than after placebo administration-is consistent with nicotinic receptor mediation of inhibitory neuronal dysfunction in schizophrenia. [ABSTRACT FROM AUTHOR]

The article lists the reviews of the journal which include A. Adesina, G. Ferrara, and M. Hieda.