scholarly journals Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity

2011 ◽  
Vol 4 (6) ◽  
pp. 822-847 ◽  
Author(s):  
David Pubill ◽  
Sara Garcia-Ratés ◽  
Jordi Camarasa ◽  
Elena Escubedo
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Partial Agonist ◽  
Ros Production ◽  
Monoamine Transporters ◽  
Neuronal Nicotinic Receptors ◽  
Abused Drugs ◽  
Amphetamine Derivatives

Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower Ki values, while fluorescence calcium experiments indicated that MDMA behaves as a partial agonist on a7 and as an antagonist on heteromeric nAChR. Sustained Ca increase led to calpain and caspase-3 activation. In addition, modulatory effects of MDMA on a7 and heteromeric nAChR populations have been found.

scholarly journals A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

Marine Drugs ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 106 ◽  
Author(s):  
Hong Xing ◽  
Sunil Keshwah ◽  
Anne Rouchaud ◽  
William R. Kem
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Partial Agonist ◽  
Secondary Compounds ◽  
Piperidine Ring ◽  
Medical Disorders ◽  
In Vitro Investigation ◽  
Α7 Nachrs

Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S- and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.

N-cholinergic facilitation of glutamate release from an individual retinotectal fiber in frog

2001 ◽  
Vol 18 (4) ◽  
pp. 549-558 ◽  
Author(s):  
A. KURAS ◽  
N. GUTMANIENĖ
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Action Potentials ◽  
Acetylcholine Receptors ◽  
Kynurenic Acid ◽  
Glutamate Release ◽  
Synaptic Potentials ◽  
Lower Vertebrates ◽  
Optic Fibers ◽  
Retinotectal Transmission

Nicotinic acetylcholine receptors are localized on retinotectal axons' terminals in lower vertebrates. The effects of activation of these receptors by endogenous acetylcholine were observed under stimulation of mass optic fibers. This study was designed to determine whether endogenous acetylcholine facilitates frog retinotectal transmission, provided only the synapses of an individual optic axon are activated, and to evaluate the feasible extent of nicotinic facilitation in these synapses by applied agonist. To this end, the effects of cholinergic drugs on the extracellular action and synaptic potentials recorded from the terminal arborization of a separate retinotectal fiber (in layer F of the tectum) were investigated in vivo. Glutamatergic nature of retinotectal synapses was reexamined by treatment with kynurenic acid. Both kynurenic acid (0.25–1 mM) and d-tubocurarine chloride (10–15 μM) significantly depressed the synaptic potentials. Carbamylcholine chloride (50–150 μM) evoked a large augmentation of the synaptic potentials and a slight but statistically significant decrease of the action potentials. D-tubocurarine reduced the effect of carbamylcholine. Pilocarpine hydrochloride (50 μM) had only a weak effect. The paired-pulse facilitation of the synaptic potentials changed significantly under the action of carbamylcholine and d-tubocurarine. The obtained results suggest that the glutamate release from activated synapses of individual retinotectal axons is facilitated by endogenous acetylcholine via presynaptic nicotinic receptors. Under used stimulation conditions, this modulation mechanism was employed only partially since its activation by applied carbamylcholine could enhance synaptic transmission up to 2.8 times.

scholarly journals The Prototoxin lynx1 Acts on Nicotinic Acetylcholine Receptors to Balance Neuronal Activity and Survival In Vivo

Neuron ◽  
2006 ◽  
Vol 51 (5) ◽  
pp. 587-600 ◽  
Author(s):  
Julie M. Miwa ◽  
Tanya R. Stevens ◽  
Sarah L. King ◽  
Barbara J. Caldarone ◽  
Ines Ibanez-Tallon ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine

scholarly journals Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3808
Author(s):  
Juan Pablo González-Gutiérrez ◽  
Hernán Armando Pessoa-Mahana ◽  
Patricio Ernesto Iturriaga-Vásquez ◽  
Miguel Iván Reyes-Parada ◽  
Nicolas Esteban Guerra-Díaz ◽  
...  
Keyword(s):  
Binding Site ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Docking Studies ◽  
Binding Assays ◽  
Serotonin Transporters ◽  
Paroxetine Binding ◽  
Compound 21 ◽  
Binding Percentage

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4β2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 μM for h-DAT and 0.031 ± 0.006 μM for α4β2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 μM for α4β2 nAChR and 0.075 ± 0.009 μM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4β2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/β2 subunit interfaces of α4β2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.

scholarly journals Effects of preganglionic denervation and postganglionic axotomy on acetylcholine receptors in the chick ciliary ganglion.

1987 ◽  
Vol 105 (4) ◽  
pp. 1847-1854 ◽  
Author(s):  
M H Jacob ◽  
D K Berg
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Time Course ◽  
Ciliary Ganglion ◽  
Ciliary Ganglion Neurons ◽  
Membrane Components ◽  
Ganglion Neurons ◽  
Alpha Bungarotoxin ◽  
Binding Component

The regulation of nicotinic acetylcholine receptors (AChRs) in chick ciliary ganglia was examined by using a radiolabeled anti-AChR mAb to quantitate the amount of receptor in ganglion detergent extracts after preganglionic denervation or postganglionic axotomy. Surgical transection of the preganglionic input to the ciliary ganglion in newly hatched chicks caused a threefold reduction in the total number of AChRs within 10 d compared with that present in unoperated contralateral control ganglia. Surgical transection of both the choroid and ciliary nerves emerging from the ciliary ganglion in newly hatched chicks to establish postganglionic axotomy led to a nearly 10-fold reduction in AChRs within 5 d compared with unoperated contralateral ganglia. The declines were specific since they could not be accounted for by changes in ganglionic protein or by decreases in neuronal survival or size. Light microscopy revealed no gross morphological differences between neurons in operated and control ganglia. A second membrane component of cholinergic relevance on chick ciliary ganglion neurons is the alpha-bungarotoxin (alpha-Bgt)-binding component. The alpha-Bgt-binding component also declined in number after either postganglionic axotomy or preganglionic denervation, but appeared to do so with a more rapid time course than did ganglionic AChRs. The results imply that cell-cell interactions in vivo specifically regulate both the number of AChRs and the number of alpha-Bgt-binding components in the ganglion. Regulation of these neuronal cholinergic membrane components clearly differs from that previously described for muscle AChRs.

Effect of 1,1-dimethylphenyl 1,4-piperazinium on mouse tracheal smooth muscle responsiveness

2005 ◽  
Vol 288 (6) ◽  
pp. L1139-L1145 ◽  
Author(s):  
G. Dorion ◽  
E. Israël-Assayag ◽  
M. J. Beaulieu ◽  
Y. Cormier
Keyword(s):  
Smooth Muscle ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Bronchial Hyperresponsiveness ◽  
Smooth Muscles ◽  
Inhibitory Effect ◽  
Tracheal Smooth Muscle ◽  
In Vivo Model ◽  
Airway Response

Bronchial hyperresponsiveness is one of the main features of asthma. A nicotinic receptor agonist, 1,1-dimethylphenyl 1,4-piperazinium (DMPP), has been shown to have an inhibitory effect on airway response to methacholine in an in vivo model of asthma. The aims of this study were to 1) verify whether nicotinic acetylcholine receptors (nAChR) were present on mouse tracheal smooth muscle, 2) verify whether bronchoprotection observed in mice was due to a direct effect on airway smooth muscle, and 3) compare the effects of nicotinic agonists to that of salbutamol. α3-, α4-, and α7-nAChR subunits were detected by immunofluorescence on tracheal tissues from normal BALB/c mice. The effect of DMPP on tracheal responsiveness was verified by an isometric method. Tracheas were isolated from normal mice, placed in organ baths, and contracted with a single dose of methacholine. Cumulative doses of DMPP or salbutamol were added to the baths. Results show that mouse tracheal smooth muscle is positive for α4- and α7-nAChR subunits and that the epithelium is positive for α3-, α4-, and α7-subunits. DMPP induced a greater dose-dependent relaxation of tracheal smooth muscles precontracted with methacholine than with salbutamol. These results suggest that the smooth muscle-relaxing effect of DMPP could have some interest in the treatment of obstructive pulmonary diseases.

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