Role Of Cholinergic Mechanisms Research Articles

The role of cholinergic mechanisms in the effects of GABA on the small bowel electrical activity

On a sample of 14 rats, the role of cholinergic mechanisms in the effects of GABA on the small bowel electrical activity under the conditions of 18-hour food deprivation in a chronic experiment was studied. Administration of GABA at a dose of 70 mg/kg resulted in stimulation of phase II (irregular activity) and the disappearance of phases I (rest) and III (regular activity) of the migrating myoelectric complex (MMC). The main effect of the M-cholinoblockator — atropine (1 mg/kg) was manifested in the disappearance of phase III MMC. The administration of GABA after the administration of atropine caused the appearance of extraordinary phase III MMC, thereby exerting a release effect on the regular (propulsive) activity of the small intestine. Therefore, one of the mechanisms of GABA action on the electrical activity of the small intestine is cholinergic pathways.

The peculiarities of pulmonary macro- and microhemodynamics changes after treatment with agonists and blockers of cholinoceptors

Background. The pulmonary arterial and venous vessels are innervated by parasympathetic cholinergic nerves. However, the studies, performed on the isolated rings of pulmonary vessels, can not give answer to the question about the role of cholinergic mechanisms in the changes of pulmonary circulation in full measure.
 Aim. The comparative analysis of the changes of the pulmonary macro- and microhemodynamics after acetylcholine, atropine, pentamine and nitroglycerine treatment.
 Materials and methods. The study was carried out on the anesthetized rabbits in the condition of intact circulation with the measurement of the pulmonary artery pressure and flow, venae cavae flows, cardiac output, and also on isolated perfused lungs in situ with stabilized pulmonary flow with measurement of the perfused pulmonary artery pressure, capillary hydrostatic pressure, capillary filtration coefficient and calculation of the pulmonary vascular resistance, pre- and postcapillary resistances.
 Results. In the conditions of intact circulation after acetylcholine, pentamine and nitroglycerine treatment the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance did not change as a result of decreasing of pulmonary artery flow and left atrial pressure due to diminution of venous return and venae cavaе flows. On perfused isolated lungs acetylcholine caused the increasing of pulmonary artery pressure, capillary hydrostatic pressure, pulmonary vascular resistance, pre- and postcapillary resistance and capillary filtration coefficient. After M-blocker atropine treatment the indicated above parameters of pulmonary microcirculation increased, on the contrary, after N-blocker pentamine treatment they decreased. Nitroglycerine infusion caused less decreasing of the parameters of pulmonary microcirculation in comparison with effects of pentamine, but capillary filtration coefficient decreased to a greater extent. These data indicate that nitroglycerine decreases endothelial permeability of pulmonary microvessels.
 Conclusion. After activation or blockade of cholinergic mechanisms in the condition of intact circulation the calculated parameter of pulmonary vascular resistance is depended from the ratio of the pulmonary artery pressure and flow and left atrial pressure, which are determined by the venous return. The different character of the changes of pulmonary microcirculatory parameters after M-blocker atropine and N-blocker pentamine treatment is evidence of reciprocal relations of M- and N-cholinoceptors in the nervous regulation of the pulmonary microcirculatory bed.

Carbachol and Nicotine in Prefrontal Cortex Have Differential Effects on Sleep-Wake States.

The role of the brainstem cholinergic system in the regulation of sleep-wake states has been studied extensively but relatively little is known about the role of cholinergic mechanisms in prefrontal cortex in the regulation of sleep-wake states. In a recent study, we showed that prefrontal cholinergic stimulation in anesthetized rat can reverse the traits associated with anesthesia and restore a wake-like state, thereby providing evidence for a causal role for prefrontal cholinergic mechanisms in modulating level of arousal. However, the effect of increase in prefrontal cholinergic tone on spontaneous sleep-wake states has yet to be demonstrated. Therefore, in this study, we tested the hypothesis that delivery of cholinergic agonists – carbachol or nicotine – into prefrontal cortex of rat during slow wave sleep (SWS) would produce behavioral arousal and increase the time spent in wake state. We show that unilateral microinjection (200 nL) of carbachol (1 mM) or nicotine (100 mM) into prefrontal cortex during SWS decreased the latency to the onset of wake state (p = 0.03 for carbachol, p = 0.03 for nicotine) and increased the latency to the onset of rapid eye movement sleep (p = 0.008 for carbachol, p = 0.006 for nicotine). Although the infusion of 1 mM carbachol increased the time spent in wake state (p = 0.01) and decreased the time spent in SWS (p = 0.01), infusion of 10 or 100 mM nicotine did not produce any statistically significant change in sleep-wake architecture. These data demonstrate a differential role of prefrontal cholinergic receptors in modulating spontaneous sleep-wake states.

Airway constriction and cough induced by breathing warm humidified air in asthmatics: Role of cholinergic mechanisms

Airway constriction and cough induced by breathing warm humidified air in asthmatics: Role of cholinergic mechanisms

Microinjection of carbachol in the supramammillary region suppresses CA1 pyramidal cell synaptic excitability

Previous studies have established that the posterior hypothalamus-supramammillary (SUM) region is involved in the control of the hippocampal theta rhythm and also modulates the synaptic excitation of hippocampal neurons. Particularly, the medial but not lateral SUM region mediates reticular stimulation-induced suppression of CA1 pyramidal cell synaptic excitation to Schaffer collateral stimulation. In the present study using urethane anesthetized rats, we have investigated the effect of direct chemical stimulation of the posterior hypothalamus-SUM region on CA1 pyramidal cell excitability. It was observed that microinjection of the cholinergic muscarinic receptor agonist, carbachol (0.1 microl, concentration of either 0.0052, 0.156, or 0.625 microg/microl), evoked concentration-dependent suppression of CA1 pyramidal cell excitability that was dissociated from theta activation. Further, carbachol microinjection preferentially recruited the lateral SUM region when compared with the medial SUM and the posterior hypothalamic regions. In this context, the shortest latencies to suppression at the lowest concentration of carbachol and the strongest suppression at higher concentrations were observed with lateral microinjections. The carbachol-induced suppression was attenuated by inactivation of the medial septal region by microinjection of procaine (0.5 microl, 20% w/v). These results underscore a possible role for cholinergic mechanisms in the lateral SUM region in modulation of CA1 pyramidal cell synaptic excitation via the medial septal region. Furthermore, the present findings when juxtaposed with the medial SUM mediation of reticularly-elicited suppression suggest a medial-lateral topographic organization of the SUM region in modulation of CA1 excitability.

Acute effects of nicotine on physiological responses of the auditory systems of nonsmokers

The role of cholinergic mechanisms in the auditory system was investigated by assessing the acute effects of nicotine, a cholinergic drug, on aggregate responses within the auditory pathway. In a single-blind procedure, evoked potentials (auditory brainstem, middle-latency, long-latency, steady-state responses) and electroencephalograms were measured from 20 normal-hearing, nonsmokers (10 male) under two conditions (nicotine, placebo). After the drug session, plasma tests indicated a subject’s nicotine concentration. Results indicated that transdermal administration of nicotine to nonsmokers does appear to acutely affect the transmission of acoustic information. The measures most affected by nicotine administration likely originate from the midbrain and cortex and are believed to involve processing of auditory information related to vigilance and the screening of sensory input. The effects of nicotine on evoked potentials or the electroencephalogram do not appear to be dependent on the sex of the subject or the hemisphere from which the responses are measured. [Work supported by AAA and NIDCD.]

Acetylcholine affects the spatial scale of attention: evidence from Alzheimer's disease.

Location precues were used to manipulate the spatial scale of attention in visual search for a target in an array of letters in patients with dementia of the Alzheimer type (DAT) and in age-matched older controls. Cue size varied in the amount of spatial precision conferred. Scopolamine, a muscarinic antagonist, decreased overall arousal and broadened spatial attention after a precise precue (small and valid) to target location for DAT patients but not for controls, suggesting a selective effect for attentional impairment induced by cholinergic blockade. In contrast, physostigmine, a cholinesterase inhibitor, did not alter the distribution of spatial attention relative to no-drug baseline testing for patients. Results support a differential role for cholinergic mechanisms in the modulation of the spatial scale of visual attention.

The Pharmacology of Physostigmine

The Pharmacology of Physostigmine

Enhanced growth hormone responses to pyridostigmine challenge in patients with panic disorder.

Panic disorder is associated with neuroendocrinological abnormalities, some of which overlap with those seen in major depression. To date, there has been little assessment of the role of cholinergic mechanisms in this disorder. Sixteen patients with DSM-III-R panic disorder and an age and gender-matched comparison group were administered 120 mg of the acetylcholinesterase inhibitor pyridostigmine. Growth hormone (GH) responses over a three-hour period were monitored. Mean delta GH, the difference between basal and the maximum pyridostigmine levels, was significantly greater in patients with panic disorder than in the comparison group. This may reflect increased cholinergic responsivity in panic disorder.

Cholinergic factors are not involved in the delayed diet passage from the crop of chicks given medium chain triacylglycerol.

The role of cholinergic mechanisms in the delayed food passage from the crop induced by medium chain triacylglycerol was investigated in the young chicken. Vagotomy altered the crop emptying of chicks given dietary long chain triacylglycerol, but did not alter it in chicks given dietary medium chain triacylglycerol. On the contrary, denervation in the cranial rete and lateral commissure of the gizzard further inhibited the food passage induced by medium chain triacylglycerol. Administration of cisapride, which induces acetylcholine release from the myenteric nerves, and atropine, a muscarinic cholinergic antagonist, both delayed crop emptying of chicks given medium chain triacylglycerol. These results demonstrate that cholinergic factors are not involved in the delayed forward movement of the food containing medium chain triacylglycerol from the crop of chicks.

Nicotine protects cultured striatal neurones against N-methyl-D-aspartate receptor-mediated neurotoxicity.

The role of cholinergic mechanisms in N-methyl-D-aspartate (NMDA)-mediated neuronal death was investigated using mouse striatal neurones in primary culture. A 30 min exposure of striatal neurones to increasing concentrations of NMDA resulted 24 h later in dramatic neuronal degeneration as assessed by MTT staining, crystal violet incorporation and determination of microtubule-associated protein 2. The NMDA-induced neurodegeneration was strongly inhibited by the co-application of two non-selective cholinergic agonists, acetylcholine or carbachol. This protective effect appears to be mediated by nicotinic receptors since it was insensitive to the muscarinic antagonist atropine but mimicked by nicotine, nornicotine and 1,1-dimethyl-4-phenyl-piperazinium. Moreover, the nicotine-evoked neuroprotection was inhibited by the central nicotinic antagonist hexamethonium. Therefore, this study suggests that cholinergic interneurones play an important role in neuronal survival in the striatum.

Antagonism of diazepam's anticonflict effects in rats by nicotine, but not by arecoline

AbstractThe purpose of the present study was to determine the possible role of cholinergic mechanisms in the anticonflict effects of the anxiolytic diazepam. Male Sprague‐Dawley rats were tested with a modified Geller‐Seifter procedure using a multiple reinforcement schedule in which unpunished responding in one component was reinforced according to a fixed‐interval 60‐sec schedule, and punished responding in the other component resulted in both food and a brief electric shock presentation according to a fixed‐ratio 1 schedule. In Experiment 1 (−)‐nicotine antagonized the increase in punished responding that was produced by diazepam. In Experiment 2 diazepam produced selective increases in punished responding that again was antagonized by (−)‐nicotine, a nicotinic cholinergic agonist, whereas arecoline, a muscarinic cholinergic agonist, did not antagonize diazepam's increase in punished responding. Neither drug produced any significant changes in unpunished responding. In Experiment 3 it was shown that the centrally acting nicotinic antagonist, mecamylamine, was able to block nicotine's antagonism of diazepam. These results suggest that there is an interaction between central nicotinic cholinergic mechanisms and diazepam's anticonflict effects in this animal model for anxiolytics, and support clinical observations that smoking can reduce some effects of benzodiazepines. © 1994 Wiley‐Liss, Inc.

Delayed treatment with nerve growth factor improves acquisition of a spatial task in rats with lesions of the nucleus basalis magnocellularis: Evaluation of the involvement of different neurotransmitter systems

Rats received bilateral lesions of the nucleus basalis magnocellularis by infusion of ibotenic acid. Fourteen days later, osmotic minipumps releasing human recombinant nerve growth factor (0.3 μg/day) were implanted subcutaneously. Starting one month after the lesion, spatial learning of the animals was tested using the Morris water maze. Acquisition of the task was impaired by the lesion, but treatment with nerve growth factor reduced the average latency to find the platform by approximately 9 s, which represents 28% of the lesion-induced behavioral deficit. Retention of this task and spatial acuity, tested in a trial in which the platform was not present, did not show a statistically significant improvement. Lesions of the nucleus basalis magnocellularis reduced the choline acetyltransferase activity in the neocortex, but not in the hippocampus. Treatment with nerve growth factor increased the choline acetyltransferase activity in the neocortex but not in the hippocampus. There was no significant difference in the levels of norepinephrine, dopamine, serotonin or their metabolites in the cortex or hippocampus between nerve growth factor-treated animals and lesioned control animals. There was no significant correlation between any of these neurochemical changes and behavioral performance (acquisition and spatial acuity). Treatment with nerve growth factor did not increase the number or the size of nerve growth factor receptor-immunoreactive neurons in the nucleus basalis magnocellularis. These data suggest that delayed treatment with nerve growth factor results in an improvement of spatial learning in rats with lesions of the nucleus basalis magnocellularis. A possible role for cholinergic mechanisms in this effect is discussed.

Effects of atropine on pancreatic response to bethanechol, cholecystokinin, and food intake in rats

Atropine was used to examine the role of cholinergic mechanisms in the pancreatic secretory response to food intake. Unanesthetized rats with gastric, jugular vein, bile-pancreatic, and duodenal cannulas were used; bile-pancreatic juice was recirculated. The maximal response to bethanechol (4 mg.kg-1.h-1) was similar to cholecystokinin (CCK)-8-induced maximal secretion. Atropine (25-200 micrograms.kg-1.h-1) markedly inhibited basal amylase output and caused dose-related inhibition of the incremental response to a maximal dose of bethanechol. Atropine (50 micrograms.kg-1.h-1) shifted the dose-response curve to bethanechol (1-32 mg.kg-1.h-1) to the right but did not alter maximal amylase output. L 364718 (0.5 mg/kg), a CCK receptor antagonist, had no effect on bethanechol-stimulated pancreatic secretion. Atropine (50 micrograms.kg-1.h-1) did not affect the incremental responses to low doses of CCK-8; the maximal response occurred at a higher CCK-8 dose because atropine decreased basal secretion. Atropine (50 or 200 micrograms.kg-1.h-1) did not decrease the amylase response to ingestion of a liquid meal. We conclude that 1) bethanechol is a full agonist for stimulation of pancreatic enzyme secretion and its effects are not mediated by CCK release; 2) atropine is a competitive antagonist of bethanechol-induced pancreatic secretion in vivo but does not directly affect responses to CCK-8; 3) cholinergic mechanisms do not mediate the pancreatic enzyme response to a liquid meal in rats.

Cholinergic mechanisms in learning, memory and dementia: a review of recent evidence

The discovery in the late 1970s that cholinergic neurons in the basal forebrain degenerate in Alzheimer's disease (AD) greatly accelerated research on the role of cholinergic mechanisms in learning and memory. As is often the case in science, the early enthusiasm for the cholinergic hypothesis has been tempered by the results of subsequent research. Although there is substantial pharmacological evidence that unspecified cholinergic systems in the brain play important roles in some forms of learning and memory, recent findings in humans indicate that antimuscarinic drugs do not model the deficits seen in AD. In addition, the goal of elucidating the functions of these basal forebrain neurons in animals has proved to be difficult and is yet to be achieved. Despite substantial effort, therefore, the cognitive and behavioral consequences of cholinergic pathology in AD remain unknown. Under these circumstances, attempts to develop cholinergic pharmacotherapies for these deficits in AD are based on questionable assumptions.

Human Fetal Tracheal Smooth Muscle Produces Spontaneous Electromechanical Oscillations That Are Ca^2+ Dependent and Cholinergically Potentiated

Although the electromechanical properties of, and the cholinergic innervation to adult airway smooth muscle has been extensively studied, the little information is available on developing human airway smooth muscle, and the role of cholinergic mechanisms in regulating bronchomotor tone. A total of 7 tracheae obtained at the time of elective abortion and between 12-16 weeks of gestational development were used in this study. For each trachea, muscle tension and transmembrane potentials were measured simultaneously using an isometric force transducer and a standard 3-M KCl-filled glass microelectrode. All preparations showed spontaneous electrical oscillations approximately 8 mV in amplitude, which could be increased using electrical field stimulation, or exogenously applied acetylcholine. This was accompanied by a corresponding increase in muscle tension. Atropine (0.1 microM) abolished this potentiation, but had no apparent effect on the oscillations. Slow-wave activity was completely suppressed in the absence of extracellular Ca2+, or in the presence of verapamil (1 microM) or quinidine (1 microM). It appears that these oscillations of membrane potential may be potentiated by cholinergic mechanisms which regulate cell membrane ion channels, thus serving to change excitability in a rhythmic manner.

Role of cholinergic mechanisms in alterations of rabbit brain functional activity during sea-sickness

Using the hydrogen-clearance method in chronic experiments on alert rabbits, we investigated the dynamics of changes in local and total cerebral blood-flow, oxygen pressure, bioelectrical activity of the motor, auditory, and visual zones of the cerebral cortex, the heart rate during sea-sickness and the effect of the cholinolytic scopolamine upon changes in these indices. It was found that scopolamine affects the character and direction of changes in both local and overall blood flow in the brain during sea-sickness. Scopolamine does not substantially alter oxygen pressure in the cortical structure of the brain and does not eliminate brachycardia arising during sea-sickness. On the electrocorticogram (ECoG), it does cause an intensification of activational processes and an increase in the total bioelectrical activity, especially in the motor zones of the cerebral cortex. It is suggested that the protective effect of scopolamine during sea-sickness is connected with its central cholinolytic action and with the decrease it brings about in the cerebral hemodynamics and bioelectrical activity of the cerebral cortex arising during "motion sickness."

Oro-facial dyskinesia and the sub-commissural part of the globus pallidus in the cat: role of acetylcholine and its interaction with GABA.

The possible role of cholinergic mechanisms in the sub-commissural part of the globus pallidus (scGP) in the induction of oro-facial dyskinesia (OFD) was studied in cats. Local injections of the cholinergic agonist carbachol into the scGP elicited tongue protrusions in a dose dependent way (100-1000 ng/0.5 microliters). The effect elicited by 1000 ng carbachol was selectively antagonized by the cholinergic antagonist scopolamine (10 micrograms/0.5 microliters); this dose of scopolamine was ineffective when injected alone. The tongue protrusions resulted from both normal and abnormal movements: whereas normal movements simply consisted of protruding the flat tongue, abnormal movements implied a variety of movements, especially curling upwards the lateral side(s) or tip of the tongue inside or outside the oral cavity. The abnormal carbachol-induced tongue protrusions formed part of a syndrome marked by dyskinetic movements of the muscles of the eye, ear and cheek, and were identical to those seen previously after local injections of picrotoxin (250-500 ng). Intra-pallidal injections of the abovementioned dose of scopolamine had no effect on the tongue protrusions induced by local injections of 375 ng picrotoxin. However, local injections of 100 ng muscimol, which was previously found to attenuate significantly the effect of 375 ng picrotoxin and which was ineffective when injected alone, significantly attenuated the tongue protrusions induced by local injections of 1000 ng carbachol. These data suggest that the cholinergic effects are mediated via a GABAergic mechanism, but not vice versa. The results are discussed in view of GABAergic and anti-cholinergic therapies used in oro-facial dyskinesia.

Swallow-evoked peristalsis in opossum esophagus: role of cholinergic mechanisms.

This study examined the role of cholinergic mechanisms in esophageal smooth muscle of anesthetized opossums. Swallow-induced motility was recorded manometrically before and after treatment with physostigmine or metoclopramide. At the 5-cm site above lower esophageal sphincter (LES) the latency, duration, and amplitude of swallow-evoked contractions were 2.1 +/- 0.12 (SE) s, 1.8 +/- 0.31 s, and 74.5 +/- 6.1 mmHg, respectively. At the 1-cm site the respective values were 4.6 +/- 0.38 s, 3.8 +/- 0.24 s, and 42.0 +/- 4.6 mmHg. The calculated speed of peristalsis was 1.72 +/- 0.21 cm/s. After intravenous treatment with the physostigmine (100 micrograms X kg-1 X h-1), each swallow produced contractions that were simultaneous, repetitive, and of long duration. The values of duration and amplitude of contraction at the 5- and 1-cm site after physostigmine treatment were significantly higher than controls (P less than 0.01). There was a significant decrease in the latency of contraction at all sites. This resulted in a significant faster speed of peristalsis. Atropine (30 micrograms/kg iv) reversed the influence of physostigmine, resulting in a significantly slower speed of peristalsis. Metoclopramide (10 mg/kg iv) resulted in several changes in swallow-evoked contractions similar to those observed after physostigmine treatment. These data suggest that alteration in cholinergic mechanisms results in disordered esophageal peristalsis in the opossum.

Neuroendocrine responses in psychiatric and pain patients with major depression

Basal and postdexamethasone concentrations of cortisol and prolactin were studied in three groups of male patients: chronic pain patients with no psychiatric diagnosis ( n = 12). chronic pain patients with coexisting major depression by Research Diagnostic Criteria (RDC) ( n = 24), and pain-free psychiatric patients meeting RDC criteria for major depression ( n = 28). Basal cortisol concentrations were significantly higher in pain-major depression and psychiatric-major depression patients compared to pain patients without psychiatric illness. The frequency of cortisol nonsuppression after dexamethasone was significantly greater in pain patients with major depression (41.7%) compared to pain patients without psychiatric disorder (8.3%), and was comparable to that of psychiatric patients (21.4%). Prolactin concentrations, but not cortisol levels, were significantly correlated with observer-rated severity of depression in pain patients. These findings suggest that cortisol and prolactin abnormalities in chronic pain may be related to psychiatric disorder rather than to pain per se, at least in male patients, and may indicate a role for cholinergic mechanisms in the interface of pain and depression.