Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In rats lesioned by injecting the ibotenic acid (8 micrograms/site) into the unilateral nucleus basalis magnocellularis (NBM), the effect of treatment with bifemelane hydrochloride (BIF) or autotransplantation of the vagal nodosal ganglion was studied electrophysiologically by serial measurement of the event-related potential (ERP, P300) for 4 weeks. In addition, the effects on cholinergic markers were assessed by determining the specific binding of [3H]QNB (quinuclidinyl benzilate) to the muscarinic acetylcholine receptor (mAChR) as well as the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). The P300 latency was delayed and its amplitude remained low for 4 weeks in NBM-lesioned rats. In contrast, a return to normal occurred after 2-3 weeks in rats given daily intraperitoneal injections of BIF (15 mg/kg) and in autotransplanted rats. In lesioned rats, the cortical ChAT and AChE activities on the affected side did not recover, but the postsynaptic receptor response was transiently activated soon after lesioning. BIF increased specific mAChR binding (an early increase of affinity and a subsequent increase of receptor density) as well as presynaptic ChAT activity. Transplantation achieved the early activation of mAChR binding (increased receptor density) and continuously increased ChAT activity. Thus, the postsynaptic compensatory receptor mechanism of denervation supersensitivity acted as an early response to the depression of presynaptic cholinergic activity, but it could not improve the P300 response until the subsequent increase of cortical ChAT activity. Improvement of P300 combined with cortical cholinergic recovery after nodosal ganglion grafting or administration of BIF suggests that the neocortical ACh level may play an important role in regulating ERP.
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PMID:Effect of vagal autotransplantation and bifemelane hydrochloride on cholinergic markers and event-related potentials in rats with lesions of the nucleus basalis magnocellularis. 854 4

The muscarinic acetylcholine receptor antagonists, atropine and pirenzepine, produced an apparent insurmountable antagonism of muscarinic M(1) receptor-mediated intracellular Ca(2+) mobilization in Chinese hamster ovary (CHO) cells when tested against the agonists carbachol or xanomeline. Each antagonist caused a dextral shift of the agonist concentration-response curves with depression of the maximum response that was incomplete (i.e., saturated) and which varied with the pairs of agonist and antagonist. Equilibrium competition binding assays found no deviation from simple, reversible competitive behavior for either antagonist. The relative rates of dissociation of unlabeled atropine and pirenzepine were also assessed in radioligand kinetic studies and it was found that atropine dissociated from the receptor approximately 8-fold slower than pirenzepine. Numerical dynamic simulations suggested that the insurmountability of antagonism observed in the present study was probably a kinetic artifact related to the measurement of transient responses to a non-equilibrated agonist in the presence of a slowly dissociating antagonist. Importantly, the patterns of antagonism observed included a saturable depression of agonist maximal response, a mode of antagonism that is incompatible with the previously described phenomenon of hemi-equilibrium states. Monte Carlo simulations indicated that reasonable, semi-quantitative estimates of antagonist potency could be determined by a minor modification of standard methods, where equieffective agonist concentrations, rather than EC(50) values, are compared in the absence and presence of antagonist. Application of the latter approach to the functional data yielded estimates of antagonist potency that were in excellent agreement with those derived from the equilibrium binding assays, thus indicating that the present method can be useful for quantifying antagonist potency under non-equilibrium conditions.
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PMID:The assessment of antagonist potency under conditions of transient response kinetics. 1055 73

We investigated the effect of the muscarinic acetylcholine receptor (mAChR) antagonist scopolamine on eyeblink conditioning in glutamate receptor subunit 62 null mice, which have severe impairments in cerebellar long-term depression (LTD). Mice were injected intraperitoneally with scopolamine (0.5 mg/kg) or saline, and conditioned using a delay paradigm with tone and periorbital shock but with no overlap between them. The saline-injected mutant mice learned this paradigm normally, as predicted from our previous study. When scopolamine was injected, learning was impaired more severely in the mutant mice than in the wild type mice. Basic sensory and motor performances were not affected. These results suggest that eyeblink conditioning in cerebellar LTD deficient mice depends largely on neural functions susceptible to blocking of mAChRs.
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PMID:Scopolamine impairs eyeblink conditioning in cerebellar LTD-deficient mice. 1192 80

We examined the effects of chronic cerebral hypoperfusion on the endogenous oxidative stress-related indices, nitrite and nitrate (NOx) concentration, glutathione (GSH) content, superoxide dismutase and catalase activities, and thiobarbituric acid-reactive substances level in the rat striatum, to clarify the participation of oxidative stress in the chronic cerebral hypoperfusion-induced alterations. Our present results indicate that chronic cerebral hypoperfusion produces oxidative stress and disturbs intracellular redox regulation in two distinct phases: at 1 day, "acute" and at 6 weeks, "chronic" alterations after the operation. Therefore, striatal neural cell damage may be mainly attributed to the transient increase of NOx production at 1 day after, and the delayed reduction of muscarinic acetylcholine receptor binding in the striatum may be mostly attributed to the continuous depression of GSH content from the 1st to the 6th postoperative week. In particular, the continuous GSH depression may be considered to accompany the pathophysiology of chronic cerebral hypoperfusion.
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PMID:Chronic cerebral hypoperfusion induces striatal alterations due to the transient increase of NO production and the depression of glutathione content. 1195 36

Our objective was to identify the sites of interaction of cannabinoids with cardiovascular sympathetic regulation in the rat. Effects on sympathetic tone were first determined in anaesthetised animals following i.v. administration of the drugs. Central effects were evaluated in anaesthetised rats receiving microinjections of cannabinoids into brain stem nuclei. Peripheral effects were identified in pithed rats with electrically stimulated sympathetic outflow. In anaesthetised and artificially ventilated rats, i.v. injection of the cannabinoid agonists WIN55212-2 and CP55940 decreased mean arterial pressure, heart rate and the plasma noradrenaline concentration. These effects were antagonized by the CB(1) cannabinoid receptor antagonist SR141716A. The bradycardia was abolished by the muscarinic acetylcholine receptor antagonist methylatropine. The decreases in mean arterial pressure and heart rate caused by cannabinoids in ventilated rats were much less pronounced than in spontaneously breathing rats. Microinjection of WIN55212-2 into the nucleus tractus solitarii had no effect. Microinjected into the rostral ventrolateral medulla oblongata, WIN55212-2 lowered mean arterial pressure slightly without changing other parameters. In pithed rats, WIN55212-2 inhibited the increases in mean arterial pressure, heart rate and the plasma noradrenaline concentration evoked by electrical stimulation of the sympathetic outflow. Our results show that activation of CB(1) cannabinoid receptors induces sympathoinhibition and enhancement of cardiac vagal tone, leading to hypotension and bradycardia. Presynaptic inhibition of noradrenaline release from terminals of postganglionic sympathetic neurons is the major component of the sympathoinhibition, but an effect in the rostral ventrolateral medulla oblongata may also contribute. The cannabinoid-evoked cardiovascular depression depends strongly on the respiratory state of the animals.
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PMID:The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression. 1270 82

The objective of the present study was to evaluate the respiratory effects of cannabinoids and their influence on cardiovascular homeostasis.In spontaneously breathing urethane-anaesthetised rats, intravenous injection of the two synthetic cannabinoid receptor agonists WIN55212-2 and CP55940 strongly and dose-dependently lowered mean arterial pressure, heart rate and the plasma noradrenaline concentration. The cardiovascular depressive effects were associated with a large decrease in respiratory rate, hypoxia, hypercapnia and blood acidosis. All depressor effects of WIN55212-2 were abolished by the selective CB(1) cannabinoid receptor antagonist SR141716A. The bradycardia elicited by WIN55212-2 was inhibited by the muscarinic acetylcholine receptor antagonist methylatropine. The natural agonist Delta(9)-tetrahydrocannabinol also elicited cardiovascular and respiratory depression. In contrast, WIN55212-3, an enantiomer of WIN55212-2 lacking affinity for cannabinoid receptors, had no effect. The cannabinoid-evoked decreases in blood pressure and heart rate were much more pronounced in spontaneously breathing than in artificially ventilated urethane-anaesthetised rats. In contrast, the plasma noradrenaline concentration was lowered equally in both preparations. Our results show that activation of CB(1) cannabinoid receptors not only induces cardiovascular depression, but also markedly impairs ventilation. The second major finding of the present study is that the respiratory depression evoked by cannabinoids largely amplifies the cardiovascular depression.
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PMID:Analysis of the respiratory effects of cannabinoids in rats. 1368 88

myo-Inositol (mI) is a key metabolic precursor to the phospoinositide (PI) metabolic pathway as a key component of central G-protein coupled receptor signaling systems, including several subtypes of adrenergic, cholinergic, serotonergic and metabotropic glutamatergic receptors. High dose mI has also been shown to be clinically effective in the treatment of obsessive-compulsive disorder, as well as panic and depression, although its mechanism of action remains elusive. The current study aimed to investigate the possible modulatory role of mI versus fluoxetine or imipramine pretreatments on serotonin-2A receptor (5HT2A-R) and muscarinic acetylcholine receptor (mAChR) function and binding in in vitro systems. After pretreating human neuroblastoma cells with different concentrations of mI, fluoxetine, or imipramine, receptor function was measured by second messenger [3H]-IPx accumulation and [35S]-GTPgammaS binding to G alpha(q) protein. Total [3H]-mI uptake into cells was measured, as well as specific receptor binding to determine receptor binding after the pretreatments. Results suggest that mI reduces 5HT2A-R function at the receptor-G protein level. While fluoxetine also reduced 5HT2A-R function, but to a lesser degree, imipramine increased 5HT2A-R function, which may explain why mI seems to be effective exclusively in selective serotonin reuptake inhibitor-sensitive disorders. In addition mI, and at high concentrations fluoxetine and imipramine, also reduces mAChR function. Furthermore the results suggest that the attenuating effect of mI on mAChRs is partially dependent on the PI metabolic pathway. The data provide novel information on understanding the mechanism of action of mI in depression and related anxiety disorders and added to the evidence suggesting a role for the cholinergic system in the pathophysiology of depression.
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PMID:Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells. 1521 6

The phosphodiesterase (PDE) 5 inhibitor sildenafil has been shown to display psychotropic actions in humans and animals, and has been used for the treatment of antidepressant-associated erectile dysfunction. However, its effects on the neurobiology of depression are unknown. Nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) inhibition is anti-depressant in animals, and increasing cGMP with sildenafil is anxiogenic in rodents. Substantial cholinergic-nitrergic interaction exists in the brain, while sildenafil shows modulatory actions on cholinergic transmission. Depression is also associated with increased cholinergic drive. Here we report that sildenafil increases muscarinic acetylcholine receptor (mAChR) signaling in human neuroblastoma cells. We also show that fluoxetine (20 mg/kg/day x 7 days), as well as a combination of sildenafil (10 mg/kg/day x 7 days) plus the antimuscarinic atropine (1 mg/kg/day x 7 days) demonstrates significant, comparable antidepressant-like effects in the rat forced swim test (FST) and also reduces cortical beta-adrenergic receptor (beta-AR) density, while sildenafil or atropine alone did not. Importantly, sildenafil did not modify fluoxetine's response. Sildenafil thus demonstrates antidepressant-like effects but only after central muscarinic receptor blockade, providing evidence for cholinergic-nitrergic interactions in the neurobiology of depression.
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PMID:Appearance of antidepressant-like effect by sildenafil in rats after central muscarinic receptor blockade: evidence from behavioural and neuro-receptor studies. 1782 68

Muscarinic autoreceptors regulate cholinergic tone in the striatum. We investigated the functional consequences of genetic deletion of striatal muscarinic autoreceptors by means of electrophysiological recordings from either medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) in slices from single M(4) or double M(2)/M(4) muscarinic acetylcholine receptor (mAChR) knock-out (-/-) mice. In control ChIs, the muscarinic agonist oxotremorine (300 nM) produced a self-inhibitory outward current that was mostly reduced in M(4)(-/-) and abolished in M(2)/M(4)(-/-) mice, suggesting an involvement of both M(2) and M(4) autoreceptors. In MSNs from both M(4)(-/-) and M(2)/M(4)(-/-) mice, muscarine caused a membrane depolarization that was prevented by the M(1) receptor-preferring antagonist pirenzepine (100 nM), suggesting that M(1) receptor function was unaltered. Acetylcholine has been involved in striatal long-term potentiation (LTP) or long-term depression (LTD) induction. Loss of muscarinic autoreceptor function is predicted to affect synaptic plasticity by modifying striatal cholinergic tone. Indeed, high-frequency stimulation of glutamatergic afferents failed to induce LTD in MSNs from both M(4)(-/-) and M(2)/M(4)(-/-) mice, as well as in wild-type mice pretreated with the M(2)/M(4) antagonist AF-DX384 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,1 1-dihydro-6H-pyrido[2,3b][1,4] benzodiazepin-6-one). Interestingly, LTD could be restored by either pirenzepine (100 nM) or hemicholinium-3 (10 microM), a depletor of endogenous ACh. Conversely, LTP induction did not show any difference among the three mouse strains and was prevented by pirenzepine. These results demonstrate that M(2)/M(4) muscarinic autoreceptors regulate ACh release from striatal ChIs. As a consequence, endogenous ACh drives the polarity of bidirectional synaptic plasticity.
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PMID:Loss of muscarinic autoreceptor function impairs long-term depression but not long-term potentiation in the striatum. 1855 Jul 68

In the present study we used electrophysiological techniques in an in vitro preparation of the rat dentate gyrus to examine the effect of muscarinic acetylcholine receptor activation on the intrinsic excitability of hilar neurons. We found that bath application of muscarine caused a direct depolarization in approximately 80% of mossy cells tested, and also produced a clear afterdepolarization (ADP) in nearly 100% of trials. The ADP observed in hilar mossy cells is produced by the opening of a Na(+) permeant and yet largely TTX insensitive ion channel. It requires an increase in postsynaptic calcium for activation, and is blocked by flufenamic acid, an antagonist of a previously identified calcium activated non-selective cation channel (I(CAN)). Further, we demonstrate that induction of an ADP in current clamp causes release of cannabinoids, and subsequent depression of GABAergic transmission that is comparable to that produced in the same cells by a more conventional 5s depolarization in voltage clamp. By contrast, other types of hilar neurons were less strongly depolarized by bath application of muscarinic agonists, and uniformly lacked a similar muscarinic ADP. Overall, the data presented here extend our understanding of the specific mechanisms through which muscarinic agonists are likely to modulate neuronal excitability in the hilar network, and further reveal a mechanism that could plausibly promote endocannabinoid mediated signaling in vivo.
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PMID:Muscarinic receptor activation modulates the excitability of hilar mossy cells through the induction of an afterdepolarization. 2007 44


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