Role Of Cholinergic Mechanisms Research Articles

Cholinergic effects on gallbladder emptying in humans

The role of cholinergic mechanisms in the control of gallbladder emptying has not been defined. In this report a scintigraphic technique using 2,6-dimethylphenylcarbamoylmethyl iminodiacetic acid labeled with technetium 99m to visualize the gallbladder and its emptying and diethylenetriamine pentaacetic acid labeled with indium 111 to visualize the stomach and its emptying was used to study 43 normal subjects and 18 patients with vagotomies. Direct cholinergic stimulation with bethanechol induced significant gallbladder emptying. Cholinergic blockade with atropine sulfate decreased the gallbladder emptying responses to a liquid meal, a solid meal, and the infusion of cholecystokinin-octapeptide. In patients with vagotomies, gallbladder emptying was decreased despite accelerated gastric emptying of an ingested liquid meal. The gallbladder emptying response to cholecystokinin-octapeptide was augmented in patients who had undergone vagotomy. These studies suggest that cholinergic receptors may be important in the regulation of human gallbladder emptying.

Cholinesterases in primary affective disorders

Cholinesterase activities were measured in plasma (ChE) and in intact erythrocytes (AChE) in patients suffering from manic-depressive illness, their first degree relatives who were well, and unrelated normal volunteers. All the subjects were in a normal mood state at the time of testing. Plasma cholinesterase activity was found to be significantly lower than normal in bipolar (BP), unipolar (UP), other affective disorder (OA) and well subjects belonging to manic-depressive families. Intact erythrocyte cholinesterase (true cholinesterase) activity was also found to be significantly lower than normal in all the above mentioned patients and their relatives. Half of the BP subjects were on lithium treatment and their cholinesterase activities were similar to those patients not on lithium treatment. The data suggest a significant role of cholinergic mechanisms in the etiology of manic-depressive illness.

Excitatory Transmitters and Epilepsy-Related Brain Damage

Publisher Summary Either systemic or intraamygdaloid administration of cholinergic agonists or cholinesterase inhibitors results in sustained seizure activity and a pattern of acute brain damage resembling what is known to occur in human epilepsy. It is observed that a similar pattern of brain damage occurs because of sustained seizures induced by any of several methods and in each case, the cytopathological changes resemble the excitotoxin type of cellular damage induced by glutamate or aspartate. The chapter discusses kainic acid as an enigmatic excitotoxin. The chapter also discusses some experiments to clarify the possible involvement of specific transmitter systems in seizure-related brain damage phenomena. Since it has been demonstrated that a specific type of cytopathological reaction-namely an excitotoxic type of reaction-results from sustained seizures regardless of the inductory method employed, this type of reaction can reasonably be interpreted as a seizure-mediated phenomenon. Concerning the role of cholinergic mechanisms either in experimental or human seizure-related brain damage syndromes, it is a possibility that cholinergic circuits contribute to the pathophysiology in a manner that glutamate/aspartate circuits cannot. It means that if excessive synaptic release of glutamate or aspartate progresses rapidly to depolarization block, circuits employing these transmitters are an unlikely source of the sustained drive that keeps neurons firing for hours in status epilepticus.

Mechanism of the cardiovascular response to systemic intravenous administration of leucine-enkephalin in the conscious dog

Leucine-enkephalin (Leu 5-ENK) (35 μg/kg) increased heart rate and mean systemic arterial blood pressure following intravenous injection into chronically-instrumented, conscious dogs. Repeated injections at five-minute intervals were not associated with a diminished response. Naloxone (1 mg/kg) pre-treatment inhibited both heart rate and blood pressure increases. Prazosin (1 mg/kg) attenuated the increase in blood pressure but did not influence the heart rate response. Propranolol (1 mg/kg) attenuated the heart rate response but not the pressor response. Clonidine (30 μg/kg) attenuated the positive chronotropic effect of Leu 5-ENK. Atropine (1 mg/kg) plus propranolol (1 mg/kg) blocked the heart rate response but the pressor effect was still present. The attenuation of the heart rate response by propranolol and the pressor response by prazosin suggests an adrenergic component to the enkephalin response; the reduction in the heart rate response by clonidine and atropine-propranolol indicates a role for cholinergic mechanisms in the chronotropic response. Hexamethonium (10 mg/kg) blocked the heart rate response and markedly inhibited the pressor response. Vagal interruption attenuated both heart rate and blood pressure responses. It is concluded that intravenous Leu 5-ENK stimulates afferent pathways located in fibers which are contained in the vagosympathetic trunk to reflexly increase heart rate and blood pressure.

Neuropharmacological Analysis of Mechanisms Controlling Larval Behaviour in the Sea Urchin; 2. Effects of physostigmine and the role of cholinergic mechanisms

The purpose of this paper is to shed some light on the systems controlling the contractile activities in the sea urchin pluteus, their pharmacological properties, the regional organization of the structures involved, their interactions, and their physiological roles. Physostigmine may bring about tetanic celomic activity of long duration. In spite of this it is possible to recognize the two activity patterns elicited by carbachol. The effects of the two agents, together with some histochemical data, suggests the occurrence of two control systems. The main muscular control system may be linked to adjoining cholinergic and mono-aminergic structures close to the mouth and is presumably responsible for the “reciprocal antagonism” between swallowing and celomic movements when the larva is stimulated (activity pattern I). It may involve intricate interactions between the cholinergic and monoaminergic components in the generation of muscular impulses. Another control system is presumably linked to neurons extending from the main ciliated band and responsible for the intestinal cycling and the “non-antagonistic” muscular activity (activity pattern II). After strong stimulation both control systems may become “exhausted” in some respects, but may eventually recover. In comparison with the effects of carbachol, the physostigmine effects are not quickly reversible which indicates that, to a great extent, they are due to inhibition of cholinesterase in deeper parts of the two control systems.

Further studies on the role of cholinergic mechanisms in the development of increased naloxone potency in mice

Using the abdominal constriction response in mice, it was shown that pretreatment with either pilocarpine (5.0 mg/kg, s.c.) or oxotremorine (0.05–0.10 mg/kg s.c.) caused a small but significant potentiation of the antinociceptive effect of morphine and the antagonistic action of naloxone. The potentiation of naloxone was considerably augmented following pretreatment with morphine plus either pilocarpine (2.5–5.0 mg/kg) or oxotremorine (0.05–0.10 mg/kg) as compared with any of these drugs given alone. Pretreatment with atropine sulphate (2.0 mg/kg, s.c.) had no effect on naloxone potency nor on the antinociceptive activity of morphine, but somewhat reduced that of pilocarpine and oxotremorine. Atropine abolished the ability of morphine pretreatment to enhance naloxone potency, and greatly reduced the augmenting effect of morphine plus the muscarinic receptor agonist drugs. It was also shown that oxotremorine reduced the development of dependence on morphine as tested by naloxone-precipitated jumping. These results agreed well with those reported using anticholinesterase drugs and add further evidence that the cholinergic system does play a role in the development of increased naloxone potency caused by morphine pretreatment. The increased naloxone potency does not seem to be related to the development of “acute dependence” on morphine.

The role of cholinergic mechanisms in the corticofugal inhibition of the spinal trigeminal nucleus

A conditioning stimulus to the contralateral coronal gyrus of cats inhibits the response of certain neurons in the spinal trigeminal nucleus to maxillary nerve stimulation. This corticofugal inhibition (CFI) is markedly increased by eserine. The subsequent administration of atropine reverses the effect of eserine. However, atropine has a variable effect when it is given as the initial drug. On the other hand, the simultaneous injection of atropine and D-amphetamine consistently decreases the CFI, even though D-amphetamine alone also has a variable effect. The magnitude of the effect of the combined administration of atropine and D-amphetamine is directly proportional to the magnitude of the CFI prior to the injection. These results indicate that the CFI is modulated by a cholinergic facilitatory and an adrenergic inhibitory pathway. Furthermore, there appears to be a close reciprocal relationship between the cholinergic and adrenergic mechanisms in our experimental model, such that the CFI is consistently decreased only when an anticholinergic and an adrenergic effect are exerted simultaneously. These observations are discussed in relation to the neurotransmitters that may be involved in the production and control of absence seizures, since we have previously found that anti-absence drugs depress the CFI.

Stimulation of phrenic nerve activity by an acetylcholine releasing drug: 4-aminopyridine.

The effect of the acetylcholine releaser 4-aminopyridine on ventilation was studied by recording and quantifying the efferent phrenic nerve activity in 40 paralysed and vagotomized cats; with arterial Po2, PCO2 and pH kept constant. 4-Aminopyridine, given intravenously or in the vertebral artery, stimulates the phrenic nerve activity in a dose dependent manner. The stimulatory effects of 4-aminopyridine on the phrenic nerve activity could be abolished completely by administration of high doses of atropine. We conclude that 4-aminopyridine, which is used clinically for the reversal of a neuromuscular block, stimulates the phrenic nerve activity. Since the role of cholinergic mechanisms in the central chemoreception has been well established, the effect on the phrenic nerve activity is most probably by an increased release of acetylcholine at the site of the central chemoreceptors.

Role of cholinergic mechanisms in the mechanism of action of bicuculline

The hypothesis of a possible role of cholinergic structures in the mechanism of the action of bicuculline was tested by screening and electrophysiological methods. Neither muscarinic (M-) nor nicotinic (N-) cholinolytics (benactyzine, atropine, aprophen,* and pediphen†) abolished convulsions produced in mice by bicuculline. Meanwhile substances inducing the accumulation of γ-aminobutyric acid (GABA) in the brain, such as aminohydroxyacetic acid (AHAA) and depakine, had a well marked protective action against bicuculline convulsions. The electrophysiological experiments also showed that the M-cholinolytic benactyzine does not abolish the effects of bicuculline. Bicuculline was shown to reduce the depression of the test response in the recovery cycle of the primary response of the rat sensomotor cortex when intervals between stimuli measured 40–125 msec, whereas benactyzine reduced the late facilitation of the test response when intervals between stimuli measured 150–300 msec. No interaction could be found between benactyzine and bicuculline by this test. It was concluded from these results that the effects of bicuculline are produced by blockade of postsynaptic GABA receptors and are not connected with the activity of cholinergic structures.

Role of Cholinergic Mechanisms in the Response to Secretin of Isolated Canine Pancreas

The effects of carbamylcholine (CCH, 100 mug per hr) and of atropine (0.25, 1.0, and 10.0 mg per hr) on the response of the exocrine pancreas to secretin (0.1, 0.5, and 5.0 clinic units per hr) were studied using the isolated canine pancreas perfused with whole heparin-treated blood. CCH induced a sharp decrease in D50 (dose of secretin which elicits half the calculated maximal response) but no increase in maximal response to secretin. Experiments performed under different haemodynamic conditions show that this potentiating effect (synergism) is partly due to vasomotor modifications and chiefly to the action of CCH on the receptor of secretin. Although this work indicates that cholinergic tone is not necessary for secretin-induced hydrelatic response to occur, it evidences that this cholinergic tone plays a major role in modulating the pancreatic response to submaximal doses of secretin. It has also been found that large doses of atropine (10 mg per hr) were necessary to achieve a complete inhibition of enzymatic response to CCH. Even at these high doses, however, enzymatic response to secretin and cholecystokinin-pancreozymin were not significantly inhibited.

Morphine withdrawal response and central cholinergic activity

MOST of the different neurotransmitter systems have been implicated in opiate withdrawal. Frederickson and Pinsky1 suggested a primary role for acetylcholine (ACh) in both the development and the expression of dependence on morphine but the specific role of cholinergic mechanisms in opiate withdrawal is not yet clear and deserves further attention. The hypothesis of the role of ACh in the expression of withdrawal phenomena, on which most earlier experiments were based, was that of the ‘cholinergic excess’, first postulated by Paton2. Tests of this hypothesis in various laboratories have, however, produced conflicting results and thus confusion rather than clarification of the role of cholinergic mechanisms in the withdrawal syndrome3–9. Unfortunately, many such studies have neglected to differentiate between peripheral interference with expression and central interference with initiation of the signs of withdrawal by the various drugs studied. Our experiments were designed to eliminate this particular factor, which has contributed to much of the conflict. The results clearly illustrate the confounding effect of failure to separate peripheral from central cholinergic effects and suggest that the exact opposite of the cholinergic excess theory is the actual nature of the central cholinergic role in the morphine withdrawal syndrome.

Role of cholinergic mechanisms in the genesis of some cortical responses

The dynamics of evoked potentials during blocking of cholinergic cortical structures was investigated in unanesthetized cats. Application of the anticholinergic drug benactyzine inhibits the negative phases of cortical responses to stimulation of the reticular formation and non-specific thalamic nuclei and also of responses to direct cortical stimulation. Direct cortical responses (DCRs), inverted by γ-aminobutyric acid, are also depressed, indicating the role of cholinergic mechanisms in the genesis of these responses. During blocking of cholinergic synapses, negative phases of the primary response (PR) and response to stimulation of the specific thalamic nucleus are facilitated. A tendency is then observed toward grouping of spontaneous unit discharges and abolition of inhibition of cortical neurons produced by high-frequency stimulation of the reticular formation. One cause of the increase in amplitude of the primary response (PR) to the action of anticholinergic drugs may be widening of the zone of cortical neurons involved in the response because of abolition of the localizing effect of inhibitory neurons.

Role of Cholinergic Mechanisms in States of Wakefulness and Sleep

Publisher Summary Pharmacological data on the importance of cholinergic mechanisms in electroencephalogram (EEG) activation and behavioral arousal as well as sleep are impressive. The gross behavioral consequence of the initial EEG activation is clearly a wake-up or arousal state. This chapter summarizes some research on the hypothesis that cholinergic mechanisms are involved in states of wakefulness and sleep. It has previously been reported by Wikler, Bradley and Elkes, Bradley and Nicholson, and others, that cholinergic agonists and antagonists produce EEG dissociation from gross behavior. Similar findings have been made by us using large doses of atropine and physostigmine. However, it should be pointed out that effective doses of physostigmine and other cholinergic agonists produce initial behavioral arousal that is associated with neocortical and limbic activation. The emphasis in the literature on EEG dissociation from gross behavior may have been overstated, particularly in relationship to the awake–sleep cycle of the chronic cat. The findings of Bradley and Elkes and others with cholinergic agonists were made at a time when the stage of fast wave sleep as described by Dement and Jouvet was not generally known. It would appear that in some instances investigators may have been observing fast wave sleep and did not recognize it as such.