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At least 19 recordsLinked to original sources
PubMed1999

Rapsyn variants in ciliary ganglia and their possible effects on clustering of nicotinic receptors.

Nicotinic acetylcholine receptors (nAChRs) containing the alpha7 gene product can influence a range of cellular events in neurons, depending on receptor location. On chick ciliary neurons, the receptors are concentrated on somatic spines, but little is known about mechanisms responsible for sequestering them there. Rapsyn is a 43-kDa protein essential for clustering nicotinic receptors at the vertebrate neuromuscular junction. RT-PCR confirmed previous studies showing that the chick ciliary ganglion expresses rapsyn transcripts, including several splice variants lacking part or all of exon 2. Heterologous expression of rapsyn constructs, together with nicotinic receptor constructs, shows that chicken full-length rapsyn can induce clustering of both muscle and neuronal nicotinic receptors. Splice variants lacking one or both leucine zipper motifs of exon 2 are unable to cluster the receptors, though, like full-length rapsyn, they cluster themselves. Immunological analysis demonstrates the presence of full-length rapsyn in chick muscle extracts but fails to detect either full-length or splice-variant versions of rapsyn at significant levels in ganglion extracts. The results suggest that rapsyn does not cluster alpha7-nAChRs on ciliary neurons in any way similar to that of receptors at the neuromuscular junction where rapsyn and the receptors are present in approximately equimolar amounts.

Alternative Splicing↗
PubMed2006

Molecular determinants of pyrantel selectivity in nicotinic receptors.

Nicotinic receptors (acetylcholine receptors, AChRs) play key roles in synaptic transmission throughout the nervous system. AChRs mediate neuromuscular transmission in nematodes, and they are targets for antiparasitic drugs. The anthelmintic agents levamisole and pyrantel, which are potent agonists of nematode muscle AChRs, are partial agonists of mammalian muscle AChRs. To further explore the structural basis of the differential activation of AChR subtypes by anthelmintics, we studied the activation of alpha7 AChRs using the high-conductance form of the alpha7-5-hydroxytryptamine-3A receptor, which is a good model for pharmacological studies involving the extracellular region of alpha7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of alpha7. It is interesting that pyrantel is a more potent agonist of alpha7 than acetylcholine (ACh). To identify determinants of this differential activation, we replaced residues of the complementary face of the binding site by the homologous residues in the muscle epsilon subunit and evaluated changes in activation. The mutation Q57G does not affect the activation by either ACh or levamisole. However, it increases EC50 values and decreases the maximal response to pyrantel. Kinetic analysis shows that gating of the mutant channel activated by pyrantel is profoundly impaired. The decreased sensitivity of alpha7-Q57G to pyrantel agrees with its weak action at muscle AChRs, indicating that when glycine occupies position 57, as in the mammalian muscle AChR, pyrantel behaves as a partial agonist. Thus, position 57 located at the complementary face of the binding site plays a key role in the selective activation of AChRs by pyrantel.

Acetylcholine↗
PubMed2006

Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine.

Cotinine is the major metabolite of nicotine in humans, and the substance greatly outlasts the presence of nicotine in the body. Recently, cotinine has been shown to exert pharmacological properties of its own that include potential cognition enhancement, anti-psychotic activity, and cytoprotection. Since the metabolite is generally less potent than nicotine in vivo, we considered whether part of cotinine's efficacy could be related to a reduced ability to desensitize nicotinic receptors as compared with nicotine. Rats freely moving in their home cages were instrumented to allow ongoing measurement of mean arterial blood pressure (MAP). The ganglionic stimulant dimethylphenylpiperazinium (DMPP) maximally increased MAP by 25mmHg. Slow (20min) i.v. infusion of nicotine (0.25-1micromol) produced no change in resting MAP, but the pressor response to subsequent injection of DMPP was significantly attenuated in a dose-dependent manner by up to 51%. Pre-infusion of equivalent doses of cotinine produced the same maximal degree of inhibition of the response to DMPP. Discrete i.v. injections of nicotine also produced a dose dependent increase in MAP of up to 43mmHg after the highest tolerated dose. In contrast, injection of cotinine produced no significant change in MAP up to 13 times the highest dose of nicotine. These results illustrate the disconnection between nicotinic receptor activation and receptor desensitization, and they suggest that cotinine's pharmacological actions are either mediated through partial desensitization, or through non-ganglionic subtypes of nicotinic receptors.

Animals↗
PubMed1995

Isoarecolone-induced enhancement of delayed matching to sample performance in monkeys: role of nicotinic receptors.

Nicotine enhances memory performance in young and aged monkeys performing a version of the delayed matching to sample (DMTS) task. However, the beneficial actions of nicotine are often limited by debilitating side effects. Isoarecolone is a piperidine derivative with nicotine-like activity, but having a slightly different profile of behavioral actions in rodents. In young monkeys, isoarecolone produced a dose-dependent enhancement of the DMTS task on the same day of testing, with a trend towards enhanced performance in animals tested 24 h after administration. Isoarecolone was about 1500-fold less potent than nicotine in enhancing DMTS performance. The ability of isoarecolone to enhance DMTS performance was well correlated with its ability to interact with cortical nicotinic receptors in vitro.

Age Factors↗
PubMed2005

Tobacco cembranoids protect the function of acute hippocampal slices against NMDA by a mechanism mediated by alpha4beta2 nicotinic receptors.

Nicotine has been reported to be neuroprotective in experimental and epidemiological studies. In addition to nicotine, tobacco and cigarette smoke contain cembranoids, which are antagonists of neuronal nicotinic receptors (nAChR). Exposure of hippocampal slices to N-methyl-D-aspartate (NMDA) decreases the population spikes (PS). This parameter has been used as a measure of excitotoxicity. Surprisingly, both nicotine and tobacco cembranoids protected against NMDA and this neuroprotection was not blocked by methyllycaconitine (MLA), an antagonist of alpha7 nAChR. On the contrary, MLA had a neuroprotective effect of its own. We examined the effect of the tobacco cembranoid (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R) on the neuroprotection against NMDA. DHbetaE, a selective antagonist of alpha4beta2 nAChR, inhibited the neuroprotection by nicotine, 4R, and MLA, suggesting the involvement of alpha4beta2 nAChRs in the neuroprotection. The cell-signaling pathways underlying the neuroprotection by 4R and by nicotine are different. The activity of phosphatidylinositol-3 kinase (PI3K) was required in both cases; however, 4R required the activity of L-type calcium channels and CAM kinase, whereas nicotine required the extracellular signal regulated kinase-1,2 (ERK) and protein kinase C (PKC). In addition, 4R did not enhance total phospho-ERK-1/2 but increased the amount of total Akt/PKB phosphorylated on the activation site and of glycogen synthase kinase 3-beta phosphorylated on the inhibitory site. Total levels of phosphoenzymes are presented instead of the ratio of phospho- over total enzyme because in preliminary experiments total ERK-1/2 levels were slightly increased by 4R. In conclusion, these findings demonstrate that there are two different nicotinic neuroprotective mechanisms mediated by alpha4beta2.

Animals↗
PubMed1998

Mutual occlusion of P2X ATP receptors and nicotinic receptors on sympathetic neurons of the guinea-pig.

1. The interaction of ion channels activated by nicotinic receptor agonists with ion channels gated by extracellular ATP (i.e. P2X receptors) was studied on sympathetic neurons acutely dissociated from coeliac ganglia of the guinea-pig. Patch clamp methods were used to measure the inward current generated through these non-selective cationic channels under voltage clamp. 2. At the whole cell level, the specific nicotinic receptor agonists nicotine (5-100 microM) or cytisine (50-75 microM) and the P2X receptor agonists ATP (0.1-7 microM) or alpha,beta-methylene ATP (6 microM) were examined separately and in the presence of the other receptor activator. When a nicotinic and P2X receptor agonist were applied together, mutually occlusive effects were generally observed. This occurred even with concentrations of agonists that in themselves generated little to no inward current. 3. The occlusive effects of nicotinic agonists on ATP-gated currents were blocked by the nicotinic receptor/ion channel blocker hexamethonium (150 microM). The occlusive effects of ATP analogues on inward currents generated by nicotinic agonists were blocked by the P2X receptor antagonist suramin (100 microM). 4. Mutual occlusion of the effects of nicotinic agonists and ATP analogues were also observed when currents through single channels were studied in excised (outside-out) patches. 5. The results suggest that nicotinic receptors and P2X ATP receptors do not act independently in these sympathetic neurons.

Adenosine Triphosphate↗
PubMed2000

Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness.

It has previously been shown that the reinforcing and dependence-producing properties of nicotine depend to a great extent on activation of nicotinic receptors within the ventral tegmental area (VTA), i.e. the site of origin of the mesolimbocortical dopaminergic projection. Based on the data reviewed in the present study, it is suggested that nicotine by stimulating presynaptic alpha7 nicotinic receptors within the VTA, that are probably localized on glutamatergic afferents from the medial prefrontal cortex, produces sequentially an increase in glutamate concentrations, stimulation of NMDA receptors found on dopamine (DA)-containing neurons in the VTA, enhanced firing activity of VTA-DA neurons, augmented DA release in the nerve terminal regions, and enhanced c-fos expression in the dopaminergic projection areas through activation of D1-DA receptors. In addition, it appears that alpha7 nicotinic receptors within the VTA are directly involved in nicotine-related reward and withdrawal responses. These data may be instrumental in understanding how nicotine interacts with the mesolimbocortical dopaminergic system, which is perhaps the most important component of the neural mechanisms underlying nicotine dependence. These results may also contribute to unraveling the cellular basis of nicotine's association with neuropsychiatric disorders, thereby offering the prospect of new therapeutic advances for their treatment.

Animals↗
PubMed2006

CNS localization of neuronal nicotinic receptors.

Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of pentameric ligand-gated ion channels, which include GABA (A and C), serotonin, and glycine receptors. Currently, 12 neuronal nAChR subunits have been identified (alpha2-10 and beta2-4) and are generally grouped into alpha subunits, which contain two adjacent cysteine residues essential for ACh binding, and beta subunits, which lack these residues. The majority of neuronal nAChRs fall into two categories: those that bind agonist with high affinity (nM concentrations); and those that bind with lower affinity (microM concentrations). The low-affinity receptors are presumably homomeric alpha7 receptors that are alpha-bungarotoxin sensitive, whereas alpha4beta2 nAChRs account for >90% of the high-affinity nicotinic receptors in the brain (Whiting and Lindstrom, 1986). Their physiological contributions to neurotransmission, signaling, and behavior are not completely understood. Precise mapping of subcellular and neuroanatomical localizations of neuronal nAChR subunits will help elucidate the physiological role of neuronal nAChRs and their role in nicotine addiction.

Animals↗
PubMed1997

Human neuronal nicotinic receptors.

Nicotine is a very widely used drug of abuse, which exerts a number of neurovegetative, behavioural and psychological effects by interacting with neuronal nicotinic acetylcholine receptors (NAChRs). These receptors are distributed widely in human brain and ganglia, and form a family of ACh-gated ion channels of different subtypes, each of which has a specific pharmacology and physiology. As human NAChRs have been implicated in a number of human central nervous system disorders (including the neurodegenerative Alzheimer's disease, schizophrenia and epilepsy), they are suitable potential targets for rational drug therapy. Much of our current knowledge about the structure and function of NAChRs comes from studies carried out in other species, such as rodents and chicks, and information concerning human nicotinic receptors is still incomplete and scattered in the literature. Nevertheless, it is already evident that there are a number of differences in the anatomical distribution, physiology, pharmacology, and expression regulation of certain subtypes between the nicotinic systems of humans and other species. This review will attempt to survey the major achievements reached in the study of the structure and function of NAChRs by examining the molecular basis of their functional diversity viewed mainly from pharmacological and biochemical perspectives. It will also summarize our current knowledge concerning the structure and function of the NAChRs expressed by other species, and the newly discovered drugs used to classify their numerous subtypes. Finally, the role of NAChRs in behaviour and pathology will be considered.

Humans↗
PubMed2006

Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors.

Nicotine elicits dopamine release by stimulating nicotinic acetylcholine receptors (nAChRs) on dopaminergic neurons. However, a modulation of these neurons by endogenous acetylcholine has not been described. We recorded, in vivo, the spontaneous activity of dopaminergic neurons in the VTA of anaesthetized wt and nAChR knockout mice and their response to nicotine injections. Deleting alpha7 or beta2 subunits modified the spontaneous firing patterns, demonstrating their direct stimulation by endogenous acetylcholine. Quantitative analysis further revealed four principal modes of firing, each depending on the expression of particular nAChR subunits and presenting unique responses to nicotine. The prominent role of the beta2 subunit was further confirmed by its selective lentiviral reexpression in the VTA. These data suggest a hierarchical control of dopaminergic neuron firing patterns by nAChRs: activation of beta2*-nAChR switches cells from a resting to an excited state, whereas activation of alpha7*-nAChRs finely tunes the latter state but only once beta2*-nAChRs have been activated.

Action Potentials↗
PubMed2003

An in vitro study of the sub-cellular distribution of nicotinic receptors.

Nicotinic and serotoninergic 5HT3 receptors share important sequence identities except for their cytoplasmic loop. Both ends of this loop display conserved 3D helical structures with distinct primary sequences. We decided to check whether these two helices named F and G play a role in the sub-cellular distribution of different nicotinic receptors. We systematically exchanged each helix with the equivalent sequence of neuronal nicotinic and alpha4, beta2 and alpha7 subunits in the functional chimeric alpha7-5HT3 receptor used as a model system. The new chimeras were expressed in vitro in polarized epithelial cells from pig kidney. We quantified synthesis and export of the receptors to the cell surface by measuring alpha-bungarotoxin binding sites. Immunogold labelling was used, at the electron microscope level, to determine the amount of each chimera present at either domain, apical and/or basolateral, of these cells. We noticed that in epithelial cells the majority of alpha-bungarotoxin binding sites remained sequestered in the cytoplasm as already observed in neurons in vivo. The majority of the pentamers present at the cell surface were located at the apical domain. Our results suggest that helix F and G differently regulate assembly and export to the cell surface of alpha-bungarotoxin binding receptors.

Amino Acid Sequence↗
PubMed2000

Development of ligands for in vivo imaging of cerebral nicotinic receptors.

Nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain functions. Findings from postmortem studies and clinical investigations have implicated them in the pathophysiology and treatment of Alzheimer's and Parkinson's diseases and other CNS disorders (e.g. Tourette's syndrome, epilepsy, nicotine dependence). Therefore, it ultimately might be useful to image nAChRs noninvasively for diagnosis, for studies on how changes in nAChRs might contribute to cerebral disorders, for development of therapies targeted at nAChRs, and to monitor the effects of such treatments. To date, only (S)-(-)-nicotine, radiolabeled with 11C, has been used for external imaging of nAChRs in human subjects. Since this radiotracer presents drawbacks, new ligands, with more favorable properties, have been synthesized and tested. Three general classes of compounds, namely, nicotine and its analogs, epibatidine and related compounds, and 3-pyridyl ether compounds, including A-85380, have been evaluated. Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the alpha4beta2 subtype of nAChRs.

Animals↗
PubMed2002

Differential rate responses to nicotine in rat heart: evidence for two classes of nicotinic receptors.

Nicotinic acetylcholine receptors are pentameric, typically being composed of two or more different subunits. To investigate which receptor subtypes are active in the heart, we initiated a series of experiments using an isolated perfused rat heart (Langendorff) preparation. Nicotine administration (100 microM) caused a brief decrease (-7 +/- 2%) followed by a much larger increase (17 +/- 5%) in heart rate that slowly returned to baseline within 10 to 15 min. The nicotine-induced decrease in heart rate could be abolished by an alpha7-specific antagonist, alpha-bungarotoxin (100 nM). In contrast, the nicotine-induced increase in heart rate persisted in the presence of alpha-bungarotoxin. These results suggest that the nicotinic acetylcholine receptors (nAChRs) that mediate the initial decrease in heart rate probably contain alpha7 subunits, whereas those that mediate the increase in heart rate probably do not contain alpha7 subunits. To investigate which subunits may contribute to the nicotine-induced increase in heart rate, we repeated our experiments with cytisine, an agonist at nAChRs that contain beta4 subunits. The cytisine results were similar to those obtained with nicotine, thereby suggesting that the nAChRs on sympathetic nerve terminals in the heart probably contain beta4 subunits. Thus, the results of this study show that pharmacologically distinct nAChRs are responsible for the differential effects of nicotine on heart rate. More specifically, our results suggest that alpha7 subunits participate in the initial nicotine-induced heart rate decrease, whereas beta4 subunits help to mediate the subsequent nicotine-induced rise in heart rate.

Animals↗
PubMed1997

Modulation by presynaptic adenosine A1 receptors of nicotinic receptor antagonist-induced neuromuscular block in the mouse.

We have investigated how altering the activation of adenosine A1 receptors modifies nicotinic receptor antagonist-induced fade of tetanic contractions in the mouse isolated hemi-diaphragm. Vecuronium-induced tetanic fade was attenuated by an adenosine A1 receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine, DPCPX, 10(-7) M) and by an inhibitor of the synthesis of extracellular adenosine from ATP (alpha,beta-methylene ADP, MeADP, 5 x 10(-5) M). Conversely, vecuronium-induced tetanic fade was potentiated by an adenosine A1 receptor agonist (N6-cyclohexyladenosine, CHA, 10(-7) M) and an inhibitor of the extracellular destruction of adenosine (erythro-9-[2-hydroxy-3-nonyl]adenine, EHNA, 10(-4) M). The ability of an adenosine A1 receptor antagonist to attenuate vecuronium-induced tetanic fade indicates that a component of this fade is due to endogenous adenosine. Further, the ability of the inhibitor of adenosine synthesis to attenuate vecuronium-induced tetanic fade indicates that this endogenous adenosine is derived from ATP. Hexamethonium-induced tetanic fade was also potentiated by increasing adenosine A1 receptor activation, albeit with a higher concentration of CHA (10(-4) M). However, unlike for vecuronium, hexamethonium-induced tetanic fade was not attenuated by reducing adenosine A receptor activation. This latter observation suggests that the tetanic fade produced by hexamethonium and vecuronium does not share a common mechanism of action.

Adenine↗
PubMed1990

Nicotine reduces the binding of [3H]MK-801 to brain membranes, but not via the stimulation of high-affinity nicotinic receptors.

Nicotine (10 and 100 microM) inhibited [3H]MK-801 binding to rat cerebral cortical membranes and this effect was not blocked by dihydro-beta-erythroidine, (+)-tubocurarine or mecamylamine. Cytisine, muscarine mecamylamine and (+)-tubocurarine also inhibited [3H]MK-801 binding. Neither raising the MK-801 concentration, nor the addition of n-methyl-D-aspartate (NMDA) receptor agonists altered the effects of nicotine. Hence this response is not mediated via high-affinity nicotinic receptor stimulation, competition for MK-801 binding sites or require NMDA receptor activation.

Animals↗
PubMed1996

The nicotinic receptor agonists (-)-nicotine and isoarecolone differ in their effects on dopamine release in the nucleus accumbens.

This study compared the effect of the nicotinic receptor agonists, (-)-nicotine and isoarecolone, on the mesolimbic dopamine system of the rat using in vivo microdialysis. Previous studies showed that (-)-nicotine but not isoarecolone produced a locomotor activating effect, and that this was probably mediated by increased concentrations of dopamine in the nucleus accumbens. Nicotine (0.4 mg/kg s.c.) significantly increased extracellular concentrations of dopamine and of dihydroxyphenylacetic acid (DOPAC) by 75-80% in nucleus accumbens of rats. Isoarecolone (3.2-32 mg/kg s.c.) had no significant effect on either dopamine or DOPAC levels in this brain region and neither drug affected extracellular levels of 5-hydroxy indole acetic acid. Both nicotine and isoarecolone induced head-bobbing behaviour. Pretreatment with ketanserin reduced nicotine-induced head-bobbing suggesting a serotonergic mechanism. In conclusion, the absence of locomotor activation after administration of isoarecolone may be related to its failure to activate the mesolimbic dopamine system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2006

L-type calcium channel ligands block nicotine-induced signaling to CREB by inhibiting nicotinic receptors.

Nicotinic acetylcholine receptors (nAChRs) are inhibited by several drugs that are commonly thought to be specific for L-type calcium channels (LTCCs). In neurons, LTCCs are activated by nicotine-induced depolarization to engage downstream signaling events; however, the role of LTCC drug interactions with nAChRs in signaling has not been examined in detail. We investigated the effects of LTCC ligands on nAChR currents and downstream signaling in rat superior cervical ganglion (SCG) neurons. We found that 10microM nicotine and 40mM K(+) both reversibly depolarize SCG neurons to -20mV, sufficient to activate LTCCs and downstream signaling, including induction of nuclear phospho-CREB (pCREB); this induction was blocked by LTCC antagonists. Interestingly, the effects of LTCC antagonists on nicotine-induced signaling to CREB are not mediated by their actions on LTCCs, but rather via inhibition of nAChRs, which prevents nicotine-induced depolarization. We show that this effect is sufficient to block pCREB induction in neurons expressing an antagonist-insensitive LTCC. Taken together, our data show that, at concentrations typically used to block LTCCs, these antagonists inhibit nAChR currents and downstream signaling. These findings serve as a caution in attributing a role for LTCCs when using these drugs experimentally or therapeutically.

Animals↗
PubMed2003

Altered anxiety-related responses in mutant mice lacking the beta4 subunit of the nicotinic receptor.

Nicotine, acting at nicotinic acetylcholine receptors (nAChRs), is the primary addictive component of tobacco. Smokers often report an anxiolytic effect of cigarettes. This relief of anxiety, attributed to nicotine, is an important contributor to relapse when smokers try to quit. Hence, the study of the anxiolytic effects of nicotine is important for understanding the mechanisms underlying nicotine addiction. Mammalian nAChRs are pentameric ion channels usually composed of alpha andbeta subunits. Taking advantage of beta4-homozygous-null mice (beta4-/-), we examined the role of the nAChR beta4 subunit in anxiety-related behaviors. The beta4-/- mice behaved as though they were less anxious than wild-type littermates on the elevated-plus and staircase mazes, tests that measure anxiety-related behaviors. To obtain an independent, physiological indication of the stress produced by several tests, we measured changes in heart rate using telemetry. Consistently with the behavioral phenotype, beta4-/- mice had a smaller heart rate increase in the elevated-plus maze than did wild-type littermates. In contrast, during social isolation, a separate test for anxiety,beta4-/- mice exhibited a greater increase in heart rate than did wild-type littermates. Finally, beta4-/- mice were indistinguishable from their wild-type littermates in the open field, the light/dark box, and the mirrored chamber. The overall results demonstrate that beta4-containing (beta4*) nAChRs influence behavioral responses during anxiety-related tests, and that this effect depends on the type of anxiety-provoking experience. Through their influence on anxiety-related behavior, beta4* nAChRs might influence both tobacco consumption and smoking relapse.

Animals↗