Cytisine, a Partial Agonist of α4β2 Nicotinic Acetylcholine Receptors, Reduced Unpredictable Chronic Mild Stress-Induced Depression-Like Behaviors

Cytisine (CYT), a partial agonist of α4β2-nicotinic receptors, has been used for antidepressant efficacy in several tests. Nicotinic receptors have been shown to be closely associated with depression. However, little is known about the effects of CYT on the depression. In the present study, a mouse model of depression, the unpredictable chronic mild stress (UCMS), was used to evaluate the activities of CYT. UCMS caused significant depression-like behaviors, as shown by the decrease of total distances in open field test, and the prolonged duration of immobility in tail suspension test and forced swimming test. Treatment with CYT for two weeks notably relieved the depression-like behaviors in the UCMS mice. Next, proteins related to depressive disorder in the brain region of hippocampus and amygdala were analyzed to elucidate the underlying mechanisms of CYT. CYT significantly reversed the decreases of 5-HT1A, BDNF, and mTOR levels in the hippocampus and amygdala. These results imply that CYT may act as a potential anti-depressant in the animals under chronic stress.

Mechanism of Efferent Inhibition in Cochlear Hair Cell / 대한이비인후과학회지

Efferent neurons release acetylcholine to inhibit sensory hair cells of the inner ear. The alpha9alpha10 nicotinic acetylcholine receptor (nAChR) mediates efferent inhibition of hair cell function within the auditory sensory organ. Gating of the nAChR triggers inward calcium current, and leads to activation of calcium dependent, small-conductance potassium (SK) potassium channels to hyperpolarize the hair cell. Through SK channels, large potassium outflow occurred, and outer hair cell was hyperpolarized. Thus, amplification of sound and sensitivity of hearing was reduced or modulated by efferent inhibition. In efferent system, main calcium providers to SK channel are nAChR and synaptic cistern, which contribution to efferent inhibition is different between avian and mammalian species. Calcium permeation is more effective in nAChRs of mammalian cochlea than avian cochlea, and mammalian calcium permeability of nAChRs is about 3 times more than avian hair cell. Thus, nAChRs is a main component of efferent inhibition in mammalian cochlear hair cell system.

Role of Nicotinic Acetylcholine Receptor on Efferent Inhibition in Cochlear Hair Cell

The alpha9alpha10 nicotinic acetylcholine receptors (nAChRs) mediates efferent inhibition of hair cell function within the auditory sensory organ. Gating of the nAChRs leads to activation of calcium-dependent potassium channels to hyperpolarize the hair cell. In efferent system, main calcium providers to SK channel are nAChR and synaptic cistern, which contribution to efferent inhibition is different between avian and mammalian species. Calcium permeation is more effective in nAChRs of mammalian cochlea than avian cochlea, and mammalian calcium permeability of nAChRs is about 3 times more than avian hair cell. Thus, mammalian nAChRs is a main component of efferent inhibition in cochlear hair cell system.

Role of Nicotinic Acetylcholine Receptor on Efferent Inhibition in Cochlear Hair Cell

The alpha9alpha10 nicotinic acetylcholine receptors (nAChRs) mediates efferent inhibition of hair cell function within the auditory sensory organ. Gating of the nAChRs leads to activation of calcium-dependent potassium channels to hyperpolarize the hair cell. In efferent system, main calcium providers to SK channel are nAChR and synaptic cistern, which contribution to efferent inhibition is different between avian and mammalian species. Calcium permeation is more effective in nAChRs of mammalian cochlea than avian cochlea, and mammalian calcium permeability of nAChRs is about 3 times more than avian hair cell. Thus, mammalian nAChRs is a main component of efferent inhibition in cochlear hair cell system.

Nicotine-evoked cytosolic Ca2+ increase and cell depolarization in capillary endothelial cells of the bovine adrenal medulla

Endothelial cells are directly involved in many functions of the cardiovascular system by regulating blood flow and blood pressure through Ca2+ dependent exocitosis of vasoactive compounds. Using the Ca2+ indicator Fluo-3 and the patch-clamp technique, we show that bovine adrenal medulla capillary endothelial cells (B AMCECs) respond to acetylcholine (ACh) with a cytosolic Ca2+ increase and depolarization of the membrane potential (20.3±0.9 mV; n=23). The increase in cytosolic Ca2+ induced by 10µM ACh was mimicked by the same concentration of nicotine but not by muscarine and was blocked by 100 µM of hexamethonium. On the other hand, the increase in cytosolic Ca2+ could be depressed by nifedipine (0.01 -100 µM) or withdrawal of extracellular Ca2+. Taken together, these results give evidence for functional nicotinic receptors (nAChRs) in capillary endothelial cells of the adrenal medulla. It suggests that nAChRs in B AMCECs may be involved in the regulation of the adrenal gland's microcirculation by depolarizing the membrane potential, leading to the opening of voltage-activated Ca2+ channels, influx of external Ca2+ and liberation of vasoactive compounds.

Characteristics of Nicotinic Receptor Expressed in Human Retinoblastoma

PURPOSE: To identify the characteristics and physiological function of the nicotinic receptor expressed in human retinoblastoma cells. METHODS: We measured possible nicotinic signaling in WERI-Rb-1 cells using the Ca2+ imaging technique and the patch clamp method. RESULTS: 1) Nicotine-induced [Ca2+]i rise arose entirely through Ca2+ influx, which was completely abolished by hexamethonium (100 micro M). 2) Nicotine also induced remarkable depolarization from -56.6 +/- 3.7 mV to -29.6 +/- 3.6 mV (n=4) under current clamp mode, but it failed to directly activate the T-type Ca2+ channel expressed in retinoblastoma cells. CONCLUSIONS: Nicotinic activation can increase the intracellular calcium level through calcium influx in the undifferentiated retinoblastoma cells, which may play important roles in cell proliferation, differentiation, and cell death.

Mechanisms of nicotine induced up-regulation of alfa 4 beta 2 AChRs

Nicotinic acetylcholine receptors (AChRs) formed from α4 and β2 subunits comprise the predominant brain AChR subtype with high affinity for nicotine. Human α4 β2 AChRs in a permanently transfected cell line were shown to be activated, desensitized, and upregulated by nicotine. Continuous exposure to nicotine increased the amount of AChRs by two mechanisms. Nicotine acted on assembly intermediates as a pharmacological chaperone to promote assembly of mature AChRs. Over the first few hours, this mechanism accounted for most upregulation. Nicotine also increased the lifetime of AChRs in the cell surface, thereby further contributing to upregulation. A cell line expressing mutant S247F α4β2 AChRs exhibited little nicotine¬induced AChR function but substantial nicotine-induced upregulation. This mutation is a cause of autosomal dominant nocturnal front lobe epilepsy (ADNFLE).

Beta-Amyloid Directly Inhibits Human alfa beta2-Nicotinic Acetylcholine Receptor Function

Amyloid-Beta (Aβ) accumulation and aggregation are thought to contribute to the pathogenesis of Alzheimer’s disease (AD). In AD, there also is a selective decrease in numbers of radioligand binding sites corresponding to the most abundant nicotinic acetylcholine receptor (nAChR) subtype, which contains human α4 and β2 subunits (α4β2-nAChR). However, relationships between these phenomena are uncertain, and effects of Aβ on human α4β2-nAChR function have not been investigated in detail. We created SH-EP1 cells stably transfected to heterologously express human α4β2- or α7-nAChR subtypes. Whole-cell current recording confirmed heterologous expression of functional α4β2-nAChR with characteristic responses to nicotinic agonists or antagonists. Nicotine-induced whole-cell currents were suppressed by Aβ1−42 in a dose-dependent manner. Functional inhibition was selective for Aβ1−42 compared to functionally-inactive, control peptide Aβ40-1, but was mimicked by Aβ1-40. Aβ1-42-mediated inhibition of α4β2-nAChR function was non-competitive, voltage¬independent, and use-independent. Pre-loading of cells with GDP-β-S failed to prevent Aβ1-42 –induced inhibition, suggesting that the down-regulation of α4β2-nAChR function by Aβ1-42 is not mediated by nAChR internalization. Sensitivity to Aβ1-42 antagonism at 1 nM was evident for α4β 2-nAChR, but not for heterologously expressed, human α7-nAChR, although both nAChR subtypes were functionally inhibited by 100 nM Aβ1-42, with the magnitude of functional block being higher for 100 nM Aβ1-42 acting at α7-nAChR. These findings suggest that α4β2-nAChR are sensitive and perhaps pathophysiologically-relevant targets for Aβ neurotoxicity in AD.

Potential Roles for Nicotinic Acetylcholine Receptors in Parkinson’s and Alzheimer’s

Nicotinic acetylcholine receptors (nAChRs) exist as a diverse family of subtypes composed of different subunit combinations. They play many important physiological roles, and have been implicated in nicotine dependence and in a variety of neuropsychiatric conditions. Here I review the cholinergic hypotheses of Alzheimer’s and Parkinson’s diseases. I provide an overview of evidence for changes in numbers of nAChR¬like binding and immunoreactive sites in both Parkinson’s and Alzheimer ’s diseases, concerning apparent neuroprotective effects of nicotinic ligands in animal or cell culture models of those neurodegenerative disorders, and regarding therapeutic promise of nicotine and its analogs. A perspective will be presented about factors that warrant consideration in understanding possible etiopathological roles of nAChR in Alzheimer’s and Parkinson’s diseases and in prospective nicotinic pharmacotherapy.

Desensitization of nicotinic receptors / 中国药理学通报

Nicotinic acetylcholine receptors, a ligand-gated ion c hannels,mediates many important physiological processes. Chronic nicotine admini stration could desensitize nicotinic receptors. Many factors which modulate dese nsitization have been described, including different subunits, agonist, signal t ransduction and cellular microenivornment. The important physiological functions of desensitized receptors still remain controversial, may be modulate synaptic transmission,synapse plasticity and mediate self-protection.

Studies on the Interactions of M1-, M2- Receptors with Nicotinic Receptors in Rabbit Sympathetic Ganglia

Effects of a M1 receptor antagonist, pirenzepine, a M2 receptor antagonist, AF-DX116, and a nicotinic receptor antagonist, mecamylamine on the pressor responses to preganglionic sympathetic nerve stimulation(PNS) and McN-A-343 and DMPP in spinal(pithed) rabbits were investigated in order to elucidate a functional role of M1, M2 and nicotinic receptors in ganglionic transmission. Pirenzepine and AF-DX116 selectively inhibited the McN-A-343-induced pressor reponse in chlorisondamine-treated rabbit and the BCh-induced bradycardia, respectively. Electrical stimulations of preganglionic sympathetic outflow at T8 level produced increases in blood pressure. Pirenzepine(3 microgram/kg) significantly inhibited the PNS-induced pressor response and the degree of inhibition was not changed by increasing the doses to 100 microgram/kg. AF-DX116(100 microgram/kg) had no effect on the PNS-induced pressor response. Mecamylamine inhibited the PNS-induced pressor response in a dose-dependent manner. The inhibitory action of mecamylamine was significantly augmented by combined-treatment with pirenzepine(30 microgram/kg) but AF-DX116(100 microgram/kg) did not affect the inhibitory action of mecamylamine. McN-A-343 and DMPP elicited pressor response in the spinal rabbit. Pirenzepine and AF-DX116 dose-dependently inhibited the McN-A-343-induced pressor response but they did not affect DMPP-induced pressor response. Mecamylamine inhibited both pressor responses induced by Mc-N-343- and DMPP. These results suggest that not only nicotinic receptors but also M1 receptors play a facilitatory role in ganglionic transmission but M2 receptors do not contribute the transmission in spinal(pithed) rabbits.

The Inhibitory Effect of Dihydro-?-erythroidine on Nicotine Induced-current in Cultured Sympathetic Neurons / 中国药房

AIM:To investigate the inhibitory effect of dihydro-?-erythroidine on nicotine induced-current in cultured superior cervical ganglion of neonatal rats.METHODS:Pneumatic pressure administration of drug and whole-cell recording techniques were performed to compare induced-current amplitude.RESULTS:Dihydro-?-erythroidine competitively antagonized nicotinic effect,and EC50 was about 0.015mmol/L.CONCLUSION:Dihydro-?-erythroidine is a competitive antagonist of nicotinic receptors in sympathetic neurons.