Blockade Of Cholinergic Receptors Research Articles

One-Trial Appetitive Learning Tasks for Drug Targeting.

One-trial appetitive learning developed from one-trial passive avoidance learning as a standard test of retrograde amnesia. It consists of one learning trial followed by a retention test, in which physiological manipulations are presented. As in passive avoidance learning, food- or waterdeprived rats or mice finding food or water inside an enclosure are vulnerable to the retrograde amnesia produced by electroconvulsive shock treatment or the injection of various drugs. In one-trial taste or odor learning conducted in rats, birds, snails, bees, and fruit flies, there is an association between a food item or odorant and contextual stimuli or the unconditioned stimulus of Pavlovian conditioning. The odor-related task in bees was sensitive to protein synthesis inhibition as well as cholinergic receptor blockade, both analogous to results found on the passive avoidance response in rodents, while the task in fruit flies was sensitive to genetic modifications and aging, as seen in the passive avoidance response of genetically modified and aged rodents. These results provide converging evidence of interspecies similarities underlying the neurochemical basis of learning.

Effect of Sinapic Acid on Scopolamine-Induced Learning and Memory Impairment in SD Rats

The seriousness of the diseases caused by aging have recently gained attention. Alzheimer's disease (AD), a chronic neurodegenerative disease, accounts for 60-80% of senile dementia cases. Continuous research is being conducted on the cause of Alzheimer's disease, and it is believed to include complex factors, such as genetic factors, the accumulation of amyloid beta plaques, a tangle of tau protein, oxidative stress, cholinergic dysfunction, neuroinflammation, and cell death. Sinapic acid is a hydroxycinnamic acid found in plant families, such as oranges, grapefruit, cranberry, mustard seeds, and rapeseeds. It exhibits various biological activities, including anti-inflammatory, anti-oxidant, anti-cancer, and anti-depressant effects. Sinapic acid is an acetylcholine esterase inhibitor that can be applied to the treatment of dementia caused by Alzheimer's disease and Parkinson's disease. However, electrophysiological studies on the effects of sinapic acid on memory and learning must still be conducted. Therefore, it was confirmed that sinapic acid was effective in long-term potentiation (LTP) using organotypic hippocampal segment tissue. In addition, the effect on scopolamine-induced learning and memory impairment was measured by oral administration of sinapic acid 10 mg/kg/day for 14 days, and behavioral experiments related to short-term and long-term spatial memory and avoidance memory were conducted. Sinapic acid increased the activity of the field excitatory postsynaptic potential (fEPSP) in a dose-dependent manner after TBS, and restored fEPSP activity in the CA1 region suppressed by scopolamine. The scopolamine-induced learning and memory impairment group showed lower results than the control group in the Y-maze, Passive avoidance (PA), and Morris water maze (MWM) experiments. Sinapic acid improved avoidance memory, short and long-term spatial recognition learning, and memory. In addition, sinapic acid weakened the inhibition of the brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and the activation of prostaglandin-endoperoxide synthase 2 (COX-2) and interleukin 1 beta (IL-1β) induced by scopolamine in the hippocampus. These results show that sinapic acid is effective in restoring LTP and cognitive impairment induced by the cholinergic receptor blockade. Moreover, it showed the effect of alleviating the reduction in scopolamine-induced BDNF and TrkB, and alleviated neuroinflammatory effects by inhibiting the increase in COX-2 and IL-1β. Therefore, we showed that sinapic acid has potential as a treatment for neurodegenerative cognitive impairment.

Mechanisms of the White Sea cod Gadus morhua marisalbi (Gadidae) intestinal smooth muscle cholinergic contraction: the contribution of various subtypes of M-cholinergic receptors and Rho-kinase

The study of the functioning of various body systems in diff erent vertebrates is one of the key tasks of comparative physiology. Teleost fi sh are a large group of vertebrates, however, the mechanisms of functioning of their digestive tract have been studied little and mainly only for such a model object as Danio rerio. The aim of this work was to characterize the participation of various subtypes of M-cholinergic receptors and the enzyme Rho-kinase in the cholinergic contraction of the intestinal smooth muscles of the White Sea cod Gadus morhua marisalbi (Gadidae). A longitudinal strip was excised from the proximal cod intestine and placed in an apparatus for recording contractile responses in the isometric mode. Contractile responses to acetylcholine were ompletely blocked by atropine. Blockade of M3 cholinergic receptors with 4-DAMP resulted in a decrease in acetylcholine-induced contraction compared with the control response. Blockade of M1 receptors with pirenzepine led to a weakening of contraction, less pronounced than with blockade of M3 cholinergic receptors. Blockade of M2-cholinergic receptors with methoctramine did not affect the magnitude of the contractile response. Incubation of preparations with the Rho-kinase inhibitor fasudil was accompanied by a significant decrease in contractile responses compared with the control, as well as a faster decrease in the contraction force after reaching the “peak” of the reaction. Thus, acetylcholine causes contraction of cod intestinal smooth muscle by activating M3- and M1- but not M2-cholinergic receptors. The activity of the Rho-kinase enzyme contributes to the development and maintenance of cod intestinal smooth muscle contraction under the action of acetylcholine. The results obtained are of interest for comparative physiology, may be important for understanding the mechanisms of the damaging effect of environmental factors on the bony fish’ body, as well as for the use of fish as objects of preclinical studies of drugs.

S-13-4: INHIBITORY IMPACTS OF CHLOROGENIC ACID ON ADRENAL CATECHOLAMINE SECRETION

(Objective) Chlorogenic acid (CGA) is one of the most available phenolic acid compounds in foods, such as coffee and tea. Thus, the present study was aimed to determine the characteristics of CGA on secretion of catecholamines (CA) in the perfused model of the rat adrenal medulla, and also to validify its mechanism of action. (Design and Methods) The adrenal gland was isolated and perfused with Krebs-bicarbonate. CA was measured directly by using the fluorospectrophotometer. (Results) CGA (30∼300 μM), administered into an adrenal vein for 90 min, reduced ACh-induced CA secretion in a dose- and time-dependent manner. CGA also time-dependently depressed the CA secretion induced by McN-A-343 (a selective muscarinic M1 receptor agonist), DMPP (a selective neuronal nicotinic receptor agonist), and angiotensin II. CGA itself failed to influence spontaneous CA secretion. Also, During the perfusion of CGA for 90 min, the CA secretory responses induced by high K+ (56 mM, a direct membrane depolarizer), veratridine (a voltage-dependent Na+ channel activator, cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor, Bay-K-8644 (an L-type dihydropyridine Ca2+ channel activator were suppressed. However, in the simultaneous presence of CGA and L-NAME (an inhibitor of NO synthase), the CA secretory responses induced by ACh, Ang II, Bay-K-8644 and veratridine was restored nearly to the control level compared to those of the inhibitory effects of CGA-treatment alone. Virtually, the adrenal NO release was significantly enhanced by CGA-treatment. Also, in the coexistence of CGA and olmesartan, ACh-induced CA secretion was markedly reduced compared to that of olmesartan-treatment alone. (Conclusion) Taken together, we present the first evidence that CGA suppresses the CA secretion induced by activation of cholinergic receptors as well as AT1-receptors. This CGA-induced inhibitory effect seems to be exerted by reducing both the influx of Na+ and Ca2+ through their ionic channels into the adrenomedullary chromaffin cells as well as by suppressing the Ca2+ release from the cytoplasmic calcium store, at least through the elevated NO release by the activation of NO synthase, which is associated to the blockade of neuronal cholinergic receptors and AT1-receptors. Based on these results, the ingestion of CGA may be helpful to alleviate or prevent the cardiovascular diseases, via reduction of adrenal CA secretion and consequent decreased CA level in the circulation. Co-administration of CGA and Olmesartan (ARB) may be clinically beneficial for treatment of cardiovascular diseases, including hypertension and angina pectoris.

The role of age-associated autonomic dysfunction in inflammation and endothelial dysfunction.

Aging of the cardiovascular regulatory function manifests as an imbalance between the sympathetic and parasympathetic (vagal) components of the autonomic nervous system (ANS). The most characteristic change is sympathetic overdrive, which is manifested by an increase in the muscle sympathetic nerve activity (MSNA) burst frequency with age. Age-related changes that occur in vagal nerve activity is less clear. The resting tonic parasympathetic activity can be estimated noninvasively by measuring the increase in heart rate occurring in response to muscarinic cholinergic receptor blockade; animal study models have shown this to diminish with age. Humoral, cellular, and neural mechanisms work together to prevent non-resolving inflammation. This review focuses on the mechanisms underlying age-related alternations in the ANS and how an imbalance in the ANS, evaluated by MSNA and heart rate variability (HRV), potentially facilitates inflammation when the homeostatic mechanisms between reflex neural circuits and the immune system are compromised, particularly the dysfunction of the cholinergic anti-inflammatory reflex. Physiologically, the efferent arm of this reflex acts via the [Formula: see text] 7 nicotinic acetylcholine receptors expressed in macrophages, monocytes, dendritic cells, T cells, and endothelial cells to curb the release of inflammatory cytokines, in which inhibition of NF‑κB nuclear translocation and activation of a JAK/STAT-mediated signaling cascade in macrophages and other immune cells are implicated. This reflex is likely to become less adequate with advanced age. Consequently, a pro-inflammatory state induced by reduced vagus output with age is associated with endothelial dysfunction and may significantly contribute to the development and propagation of atherosclerosis, heart failure, and hypertension. The aim of this review is to summarize the relationship between ANS dysfunction, inflammation, and endothelial dysfunction in the context of aging. Meanwhile, this review also attempts to describe the role of HRV measures as a predictor of the level of inflammation and endothelial dysfunction in the aged population and explore the possible therapeutical effects of vagus nerve stimulation.

The widely used antihistamine mepyramine causes topical pain relief through direct blockade of nociceptor sodium channels.

Mepyramine, a first-generation antihistamine targeting the histamine H(1) receptor, was extensively prescribed to patients suffering from allergic reactions and urticaria. Serious adverse effects, especially in case of overdose, were frequently reported, including drowsiness, impaired thinking, convulsion, and coma. Many of these side effects were associated with the blockade of histaminergic or cholinergic receptors. Here we show that mepyramine directly inhibits a variety of voltage-gated sodium channels, including the Tetrodotoxin-sensitive isoforms and the main isoforms (Nav1.7, Nav1.8, and Nav1.9) of nociceptors. Estimated IC50 were within the range of drug concentrations detected in poisoned patients. Mepyramine inhibited sodium channels through fast- or slow-inactivated state preference depending on the isoform. Moreover, mepyramine inhibited the firing responses of C- and Aβ-type nerve fibers in ex vivo skin-nerve preparations. Locally applied mepyramine had analgesic effects on the scorpion toxin-induced excruciating pain and produced pain relief in acute, inflammatory, and chronic pain models. Collectively, these data provide evidence that mepyramine has the potential to be developed as a topical analgesic agent.

Intrahippocampal blockade of nicotinic or muscarinic receptors fails to impair nonnavigational spatial memory in macaques.

Cholinergic neurotransmission within the hippocampus has long been suggested to play a pivotal role in memory processing, based partly on the assumption that the well-established amnestic effects of systemic cholinergic receptor blockade are mediated by the hippocampus. However, experimental evidence suggests that this may not be the case; a growing number of studies employing selective lesion or pharmacological approaches to disrupt cholinergic transmission within the hippocampus have failed to find robust deficits in either learning or memory, primarily in rodent models. Here, we evaluated the contribution of nicotinic acetylcholine receptor (nAChR)- and muscarinic acetylcholine receptor (mAChR)-mediated neurotransmission in the hippocampus of rhesus macaques for performance in a hippocampal-dependent spatial memory task, the Hamilton Search Task. We infused the nAChR antagonist, mecamylamine, or the mAChR antagonist, scopolamine, and evaluated performance on a within-subject basis. Neither treatment impaired performance under any task conditions. These data demonstrate that the hippocampus is not the critical site for the mnemonic actions of cholinergic neurotransmission, at least in the context of spatial memory. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Sulforaphane enhances long-term potentiation and ameliorate scopolamine-induced memory impairment

Increases in human life expectancy have led to increases in the prevalence of senile dementia and neurodegenerative diseases. This is a major problem because there are no curative treatments for these diseases, and patients with unmanaged cognitive and neurodegenerative symptoms experience many social problems. Sulforaphane is a type of organosulfur compound known as an isothiocyanate. It is derived from glucoraphanin, a compound found in cruciferous vegetables such as broccoli, brussels sprouts, and cabbages, via an enzymatic reaction that is triggered by plant damage (e.g., chewing). Sulforaphane exhibits activity against cancer, inflammation, depression, and severe cardiac diseases. It can also alleviate oxidative stress and neural dysfunction in the brain. However, there is insufficient knowledge about the electrophysiological and behavioral basis of the effects of sulforaphane on learning and memory. Therefore, we evaluated whether acute sulforaphane administration affected long-term potentiation (LTP) in organotypic cultured rat hippocampal tissues. We also measured the effect of sulforaphane on the performance of three behavioral tests, the Y-maze test, the passive avoidance test, and the Morris water maze, which assess short-term memory, avoidance memory, and short and long-term spatial memory, respectively. We found that sulforaphane increased the total field excitatory postsynaptic potential (fEPSP) in a dose-dependent manner after high frequency stimulation and attenuated scopolamine-induced interference of the fEPSP in the hippocampal CA1 area. Sulforaphane also restored cognitive function and inhibited memory impairment as indicated by the alleviation of the negative neurological effects of scopolamine, i.e, a lowered ratio of spontaneous alternation in the Y-maze, a reduced step-through latency in the passive avoidance test, and an increased navigation time in the Morris water maze. These results indicate that sulforaphane can effectively prevent the attenuation of LTP and cognitive abilities induced by cholinergic and muscarinic receptor blockade. Further research is warranted to explore the potential therapeutic and prophylactic utility of sulforaphane for improving learning and memory, especially in those suffering from neurodegenerative disorders.

Effects of Blockage of Peripheral Choline, Serotonin, and Dopamine Receptors on Heart Rhythm Variability in Rats under Conditions of Stimulation of Neurotransmitter Systems.

Stimulation of the serotoninergic system (5-hydroxytryptophan, 50 mg/kg; fluoxetine, 3 mg/kg) induced a significant increase in HR and a reduction in the amplitude of all waves of the heart rhythm variability. Stimulation of the dopaminergic system (L-DOPA and amantadine, 20 mg/kg each) resulted in a moderate increase in HR and amplitudes of low-frequency (LF) and very-low-frequency (VLF) waves of the heart rhythm variability. Successive blockade of nicotinic (hexamethonium, 7 mg/kg) and muscarinic cholinergic receptors (atropine, 1 mg/kg) leads to a significant decrease in the variability of cardiointervals (almost to complete levelling) both under control conditions and after stimulation of the neurotransmitter systems. Serotonin receptor blockade (promethazine, 2 mg/kg) did not affect HR, but reduced the amplitude of LF- and VLF-waves. Under conditions of serotoninergic system stimulation, the blockade of serotonin receptors was followed by a significant HR acceleration without changes in heart rhythm variability; blockade of dopamine receptors (sulpiride, 1 mg/kg) induced HR acceleration and increase in the amplitude of LF- and VLF-waves; blockade of dopamine receptors under conditions of dopamine system stimulation was followed by a significant increase in HR and a decrease in the amplitude of all waves of the heart rhythm variability. It can be hypothesized that serotonin- and dopaminergic systems affect the heart rhythm via cardiomyocyte receptors and via modulation of activity of the adrenergic and cholinergic systems. The effects of serotonin- and dopaminergic systems can be considered as synergic in the CNS, and antagonistic at the periphery.

Losartan Reverses Hippocampal Increase of Kynurenic Acid in Type 1 Diabetic Rats: A Novel Procognitive Aspect of Sartan Action.

Patients with diabetes mellitus (DM) type 1 and 2 are at a higher risk of cognitive decline and dementia; however, the underlying pathology is poorly understood. Kynurenic acid (KYNA), endogenous kynurenine metabolite, displays pleiotropic effects, including a blockade of glutamatergic and cholinergic receptors. Apart from well-known glial origin, kynurenic acid is robustly synthesized in the endothelium and its serum levels correlate with homocysteine, a risk factor for cognitive decline. Studies in an experimental DM model suggest that a selective, hippocampal increase of the kynurenic acid level may be an important factor contributing to diabetes-related cognitive impairment. The aim of this study was to assess the effects of chronic, four-week administration of losartan, angiotensin receptor blocker (ARB), on the brain KYNA in diabetic rats. Chromatographic and rt-PCR techniques were used to measure the level of KYNA and the expression of genes encoding kynurenine aminotransferases, KYNA biosynthetic enzymes, in the hippocampi of rats with streptozotocin-induced DM, treated with losartan. The effect of losartan on KYNA synthesis de novo was also evaluated in vitro, in brain cortical slices. The hippocampal increase of KYNA content occurred in diabetic rats treated and nontreated with insulin. Losartan did not affect KYNA levels when administered per se to naïve or diabetic animals but normalized KYNA content in diabetic rats receiving concomitantly insulin. The expression of CCBL1 (kat 1), AADAT (kat 2), and KAT3 (kat 3) genes did not differ between analyzed groups. Low concentrations of losartan did not affect KYNA production in vitro. The neuroprotective effect of ARBs in diabetic individuals may be, at least partially, linked to modulation of KYNA metabolism. The ability of ARB to modulate synthesis of KYNA in diabetic brain does not seem to result from changed expression of genes encoding KATs. We propose possible involvement of angiotensin AT4 receptors in the observed action of losartan.

Motility Patterns Following Esophageal Pharmacologic Provocation With Amyl Nitrite or Cholecystokinin During High-Resolution Manometry Distinguish Idiopathic vs Opioid-Induced Type 3 Achalasia

In some patients, the type 3 achalasia (A3) motor pattern may be an effect of chronic use of high-dose opioids. No motor findings have been identified to differentiate opioid-induced A3 (OA3) from idiopathic A3 (IA3). We investigated whether OA3 could be distinguished from IA3 on the basis of differences in esophageal motor responses to amyl nitrite, cholecystokinin, or atropine. We performed a retrospective study of patients who received pharmacologic provocation during esophageal high-resolution manometry from 2007 through 2017 at a tertiary referral center. We identified 26 patients with IA3 (9 women; mean age, 68 ± 13 years) and 24 patients with OA3 (15 women; mean age, 59 ± 10 years). We compared pressure topography metrics during deglutition and after administration of amyl nitrite, cholecystokinin, or atropine between patients with OA3 vs IA3. Amyl nitrite induced a similar relaxation response in both groups, but the rebound contraction of the lower esophageal sphincter during amyl nitrite recovery, and the paradoxical esophageal contraction during the first phase of cholecystokinin response, were both significantly attenuated in patients with OA3. The second phase of cholecystokinin response in patients with OA3 was 100% relaxation, when present, in contrast to only 26% of patients with IA3. There was no significant difference between groups in inhibition of lower esophageal sphincter tone or esophageal body contractility by cholinergic receptor blockade. Nearly half of patients with an A3 pattern of dysmotility are chronic, daily users of opioids with manometry patterns indistinguishable from those of patients with IA3. Patients with OA3 differ from patients with IA3 in responses to amyl nitrite and cholecystokinin. These findings might be used to identify patients with dysmotility resulting from opioid use.

Cholinergic Receptor Blockade in the VTA Attenuates Cue-Induced Cocaine-Seeking and Reverses the Anxiogenic Effects of Forced Abstinence

Drug relapse after periods of abstinence is a common feature of substance abuse. Moreover, anxiety and other mood disorders are often co-morbid with substance abuse. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate drug-seeking and anxiety-related behavior in rodent models. However, it is unclear if overlapping VTA cholinergic mechanisms mediate drug relapse and anxiety-related behaviors associated with drug abstinence. We examined the effects of VTA cholinergic receptor blockade on cue-induced cocaine seeking and anxiety during cocaine abstinence. Male Sprague–Dawley rats were trained to self-administer intravenous cocaine (~0.5 mg/kg/infusion, FR1 schedule) for 10 days, followed by 14 days of forced abstinence. VTA infusion of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine (0, 10, and 30 μg/side) or the non-selective muscarinic receptor antagonist scopolamine (0, 2.4 and 24 μg /side) significantly decreased cue-induced cocaine seeking. In cocaine naïve rats, VTA mecamylamine or scopolamine also led to dose-dependent increases in open arm time in the elevated plus maze (EPM). In contrast, rats that received I.V. cocaine, compared to received I.V. saline rats, displayed an anxiogenic response on day 14 of abstinence as reflected by decreased open arm time in the EPM. Furthermore, low doses of VTA mecamylamine (10 μg /side) or scopolamine (2.4 μg /side), that did not alter EPM behavior in cocaine naive rats, were sufficient to reverse the anxiogenic effects of cocaine abstinence. Together, these data point to an overlapping role of VTA cholinergic mechanisms to regulate relapse and mood disorder-related responses during cocaine abstinence.

Regulation of blood flow in the pulmonary and systemic circuits during submerged swimming in common snapping turtle (Chelydra serpentina).

Blood flow patterns and heart rate have rarely been investigated in freely swimming turtles and their regulation during swimming is unknown. In this study, we investigated the blood flow patterns and heart rate in surfacing and during graded, submerged swimming activity in common snapping turtles. We further investigated the effects of beta-adrenergic and cholinergic receptor blockade on blood flow and heart rate during these activities. Our findings illustrate that surfacing is accompanied by an increase in heart rate that is primarily due to beta-adrenergic stimulation. During swimming, this mechanism also increases heart rate while vagal withdrawal facilitates a systemic to pulmonary (left to right) shunt. The results indicate there may be important taxonomic effects on the responses of cardiac function to activity in turtle species.

Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review.

Background: Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are accompanied by a myriad of cardiometabolic side-effects. The specific reasons for clozapine's high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these.Objective: This systematic review summarizes the literature on autonomic dysfunction and related cardiovascular side effects associated with clozapine treatment.Method: A search of the EMBASE, MEDLINE, and EBM Cochrane databases was conducted using the search terms antipsychotic agents, antipsychotic drug*, antipsychotic*, schizophrenia, schizophren*, psychos*, psychotic*, mental ill*, mental disorder*, neuroleptic*, cardiovascular*, cardiovascular diseases, clozapine*, clozaril*, autonomic*, sympathetic*, catecholamine*, norepinephrine, noradrenaline, epinephrine, adrenaline.Results: The search yielded 37 studies that were reviewed, of which only 16 studies have used interventions to manage cardiovascular side effects. Side effects reported in the studies include myocarditis, orthostatic hypotension and tachycardia. These were attributed to sympathetic hyperactivity, decreased vagal contribution, blockade of cholinergic and adrenergic receptors, reduced heart rate variability and elevated catecholamines with clozapine use. Autonomic neuropathy was identified by monitoring blood pressure and heart rate changes in response to stimuli and by spectral analysis of heart rate variability. Metoprolol, lorazepam, atenolol, propranolol, amlodipine, vasopressin and norepinephrine infusion were used to treat tachycardia and fluctuations in blood pressure, yet results were limited to case reports.Conclusion: The results indicate there is a lack of clinical studies investigating autonomic dysfunction and a limited use of interventions to manage cardiovascular side effects associated with clozapine. As there is often no alternative treatment for refractory schizophrenia, the current review highlights the need for better designed studies, use of autonomic tests for prevention of cardiovascular disease and development of novel interventions for clozapine-induced side effects.

0143 CARBACHOL INHIBITS GLUTAMATERGIC INPUT TO MOUSE HYPOGLOSSAL MOTOR NEURONS - A MECHANISM FOR REM SLEEP SUPPRESSION OF GENIOGLOSSUS ACTIVITY

In REM sleep, the genioglossus (GG) muscle undergoes a dramatic suppression of activity. A current hypothesis is that the loss of GG activity during REM sleep is mediated by a combination of 1) monoaminergic disfacilitation and 2) a cholinergic inhibition of hypoglossal motor neurons. Strikingly, blockade of cholinergic receptors in the hypoglossal motor nucleus fully restores REM sleep tonic and inspiratory-modulated components of GG activity (Grace et al., 2013), suggesting that the cholinergic signal is largely responsible for the REM sleep suppression of GG activity. Respiratory rhythm generator neurons of the pre-Bötzinger complex drive the activation of hypoglossal motor neurons through glutamatergic premotor neurons in the parahypoglossal region (PH). In the current study, we investigate how cholinergic signaling affects the PH glutamatergic input to hypoglossal motor neurons. We stereotaxically injected the PH region of vGluT2-cre mice with a cre-dependent AAV-ChR2-mCherry to expressed channelrhodopsin2 (ChR2) in PH glutamatergic premotor neurons. We then performed whole-cell recordings in hypoglossal neurons while photostimulating PH glutamatergic inputs expressing ChR2. Photostimulation of the glutamatergic PH input evoked AMPA-mediated EPSCs in hypoglossal motor neurons. These photoevoked EPSCs were maintained in TTX, indicating direct connectivity between stimulated terminals and recorded hypoglossal motoneurons. Bath application of carbachol strongly inhibited the PH glutamatergic excitation of hypoglossal neurons via muscarinic receptors. The effect of carbachol on photoevoked EPSCs was maintained when 1) we blocked postsynaptic G-mediated effects by adding GDP-β-S in the recording pipette and 2) when we blocked action potential mediated transmission by adding TTX in the extracellular bath solution. These results indicate that carbachol inhibits PH input to hypoglossal motoneurons through a presynaptic mechanism. Our results provide a possible mechanism for cholinergic inhibition of the hypoglossal motor neurons in REM sleep. We propose that the cholinergic presynaptic suppression of the excitatory drive from the PH premotor neurons can be responsible for the reduction in activity of hypoglossal motor neurons in REM sleep. P01HL095491.

Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta-Gamma Coupling during Cue Detection.

The capacity for using external cues to guide behavior ("cue detection") constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta-gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection.SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding ("cue detection") is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination of in vivo neurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection.

Loganin enhances long-term potentiation and recovers scopolamine-induced learning and memory impairments

Although the incidence rate of dementia is rapidly growing in the aged population, therapeutic and preventive reagents are still suboptimal. Various model systems are used for the development of such reagents in which scopolamine is one of the favorable pharmacological tools widely applied.Loganin is a major iridoid glycoside obtained from Corni fructus (Cornusofficinalis et Zucc) and demonstrated to have anti-inflammatory, anti-tumor and osteoporosis prevention effects. It has also been found to attenuate Aβ-induced inflammatory reactions and ameliorate memory deficits induced by scopolamine. However, there has been limited information available on how loganin affects learning and memory both electrophysiologically and behaviorally.To assess its effect on learning and memory, we investigated the influence of acute loganin administration on long-term potentiation (LTP) using organotypic cultured hippocampal tissues. In addition, we measured the effects of loganin on the behavior performance related to avoidance memory, short-term spatial navigation memory and long-term spatial learning and memory in the passive avoidance, Y-maze, and Morris water maze learning paradigms, respectively.Loganin dose-dependently increased the total activity of fEPSP after high frequency stimulation and attenuated scopolamine-induced blockade of fEPSP in the hippocampal CA1 area. In accordance with these findings, loganin behaviorally attenuated scopolamine-induced shortening of step-through latency in the passive avoidance test, reduced the percent alternation in the Y-maze, and increased memory retention in the Morris water maze test.These results indicate that loganin can effectively block cholinergic muscarinic receptor blockade -induced deterioration of LTP and memory related behavioral performance. Based on these findings, loganin may aid in the prevention and treatment of Alzheimer's disease and learning and memory-deficit disorders in the future.

Motor Symptoms While Switching Antipsychotics: Should We Taper or Increase The Dose?

Rebound syndromes are well described among several drugs, not only psychotropics. A key element to suspect them is that full manifestations of this phenomenon occur after a given period that depends on the drug´s half-life. Strictly within antipsychotics and their M1 cholinergic receptor blockade, switching from a high- to a low-affinity drug can induce cholinergic rebound, with symptoms like malaise, nausea, vomiting, diarrhea, sialorrhea, extrapyramidal symptoms and akathisia. We know, for example, that abrupt clozapine withdrawal has been associated with cholinergic rebound as well as with serotonin syndrome. PubMed database (last search on 02/15/2016, search terms “cholinergic rebound AND antipsychotics”, with no time limit) shows 27 results for this topic: 04 case reports, 09 review articles, and 02 randomized controlled trials (only one specifically for cholinergic rebound). In the current case, cholinergic symptoms were observed while switching between typical antipsychotics.

Mechanisms of Discoordination of Contractile Activity in the Gastroduodenal Zone during Psychogenic Stress in Rabbits.

Inhibition of the contractile activity of the stomach induced by psychogenic stress persisted after blockade of muscarinic and nicotinic cholinergic receptors and α2 and β1/β2-adrenergic receptors. Stress-induced increase in contractile activity in the proximal part of the duodenum persisted during blockade of muscarinic and nicotinic cholinergic receptors, β1/β2-adrenergic receptors. At the same time, blockade of the above cholinergic and adrenergic receptors eliminated the stress-induced increase in contractive activity in the distal part of the duodenum.

Combined unilateral blockade of cholinergic, peptidergic, and serotonergic receptors in the ventral respiratory column does not affect breathing in awake or sleeping goats

Previous work in intact awake and sleeping goats has found that unilateral blockade of excitatory inputs in the ventral respiratory column (VRC) elicits changes in the concentrations of multiple neurochemicals, including serotonin (5-HT), substance P, glycine, and GABA, while increasing or having no effect on breathing. These findings are consistent with the concept of interdependence between neuromodulators, whereby attenuation of one modulator elicits compensatory changes in other modulators to maintain breathing. Because there is a large degree of redundancy and multiplicity of excitatory inputs to the VRC, we herein tested the hypothesis that combined unilateral blockade of muscarinic acetylcholine (mACh), neurokinin-1 (NK1, the receptor for substance P), and 5-HT2A receptors would elicit changes in multiple neurochemicals, but would not change breathing. We unilaterally reverse-dialyzed a cocktail of antagonists targeting these receptors into the VRC of intact adult goats. Breathing was continuously monitored while effluent fluid from dialysis was collected for quantification of neurochemicals. We found that neither double blockade of mACh and NK1 receptors, nor triple blockade of mACh, NK1, and 5-HT2A receptors significantly affected breathing (P ≥ 0.05) in goats that were awake or in non-rapid eye movement (NREM) sleep. However, both double and triple blockade increased the effluent concentration of substance P (P < 0.001) and decreased GABA concentrations. These findings support our hypothesis and, together with past data, suggest that both in wakefulness and NREM sleep, multiple neuromodulator systems collaborate to stabilize breathing when a deficit in one or multiple excitatory neuromodulators exists.