Cholinergic Inhibitory Mechanism Research Articles

Fasting and postprandial serum gastrin levels before and after highly selective gastric vagotomy, truncal vagotomy with pyloroplasty and truncal vagotomy with antrectomy: Is there a cholinergic antral gastrin inhibitory and releasing mechanism?

Fasting serum gastrin levels and postprandial gastrin response were measured before and 1 month after highly selective vagotomy, truncal vagotomy with pyloroplasty and truncal vagotomy with antrectomy. The three groups of patients, 12 in each group, were closely matched for age, sex, maximum acid output and completeness of vagotomy. After highly selective and truncal vagotomy an identical and significant increase in fasting gastrin was observed, whereas after truncal vagotomy with antrectomy the pre- and postoperative fasting gastrin levels were not different. The net postprandial gastrin output over basal value was significantly increased after highly selective vagotomy, unchanged after truncal vagotomy and significantly lowered after truncal vagotomy with antrectomy. These results suggest the presence in the intact subject of a cholinergic inhibitory mechanism in the gastric body and fundus for the release of antral gastrin in the fasting and postprandial states and a possible cholinergic facilitatory mechanism for the release of antral gastrin after meals.

Effects of cisapride on gallbladder emptying and pancreatic polypeptide and cholecystokinin release in humans

We investigated the effects of cisapride on gallbladder motility and on the release of pancreatic polypeptide and cholecystokinin in the fasting and postprandial states. Cisapride (7.5 mg) and/or a test meal was administered intraduodenally to seven healthy volunteers with or without atropine pretreatment (0.5 mg, i.m.). In the fasting state, cisapride increased gallbladder volume to 154% of the basal level, and significantly elevated plasma pancreatic polypeptide levels. The effects of cisapride were inhibited by atropine. In the postprandial state, integrated pancreatic polypeptide and cholecystokinin responses were increased by cisapride to 180% and 192%, respectively, of control values. Atropine inhibited the integrated gallbladder and pancreatic polypeptide response to about 60% of the control value, but did not affect the cholecystokinin response. These observations suggest that: (1) fasting gallbladder tone is influenced by cholinergic inhibitory mechanisms, (2) acetylcholine (ACh) is the final mediator for about 40% of the postprandial gallbladder emptying and pancreatic polypeptide response, and (3) coordination between the ACh-independent cholecystokinin response and ACh-dependent pancreatic polypeptide response may be important in the regulation of postprandial gallbladder emptying.

Acetylcholine induces burst firing in thalamic reticular neurones by activating a potassium conductance

Recent studies have emphasized the role of acetylcholine (ACh) as an excitatory modulator of neuronal activity in mammalian cortex and hippocampus. Much less is known about the mechanism of direct cholinergic inhibition in the central nervous system or its role in regulating neuronal activities. Here we report that application of ACh to thalamic nucleus reticularis (nRt) neurones, which are known to receive a cholinergic input from the ascending reticular system of the brain stem, causes a hyperpolarization due to a relatively small (1-4 nS) increase in membrane conductance to K+. This cholinergic action appears to be mediated by the M2 subclass of muscarinic receptors and acts in conjunction with the intrinsic membrane properties of nucleus reticularis neurones to inhibit single spike activity while promoting the occurrence of burst discharges. Thus, cholinergic inhibitory mechanisms may be important in controlling the firing pattern of this important group of thalamic neurones.

Effect of atropine on plasma gastrin and somatostatin concentrations during sham feeding in man

The purpose of these studies was to measure circulating gastrin and somatostatin concentrations during sham feeding in humans and to evaluate the effect of two doses of intravenous atropine on circulating concentrations of these peptides. Gastric acid and bicarbonate secretion and pulse rate were also measured. Sham feeding increased plasma gastrin concentrations by approximately 15 pg/ml but had no effect on plasma somatostatin-like immunoreactivity (SLI). A small dose of atropine (5 μg/kg) augmented plasma gastrin concentrations during sham feeding significantly ( P < 0.01), but did not affect plasma SLI. Atropine also significantly inhibited gastric acid secretion and gastric bicarbonate secretion (by 62% and 52%, respectively), but pulse rate was not affected. A larger dose of atropine (15 μg/kg intravenously) suppressed plasma gastrin concentrations significantly compared to the smaller 5 μg/kg atropine dose ( P < 0.02), so that plasma gastrin concentrations when 15 μg/kg atropine was given were not significantly different from those during the control study. 15 μg/kg atropine reduced gastric acid and bicarbonate secretion by 81% and 66%, respectively, and also increased pulse rate by 15 min −1. These studies indicate that small doses of atropine enhance vagally mediated gastrin release in humans, probably by blocking a cholinergic inhibitory pathway for gastrin release. Although the nature of this cholinergic inhibitory mechanism is unclear, we found no evidence to incriminate somatostatin. Our finding that the larger dose of atropine reduced serum gastrin concentrations compared with the smaller dose suggests that certain vagal-cholinergic pathways may facilitate gastrin release.

Bombesin: A vagally independent stimulator of gastrin release

In this study we demonstrate that bombesin is a potent stimulant of canine gastrin and gastric acid secretion. Bombesin was shown to release almost fourfold more gastrin than a meal by a mechanism which is independent of vagal integrity. An exogenously administered cholinomimetic agent released only minimal amounts of gastrin after vagotomy and virtually none in the intact canine model. The combination of bombesin and bethanechol caused a significant increase in acid secretion compared with bombesin alone and was associated with a marked inhibition of gastrin release both before and after vagotomy. Gastric acid secretion in response to bombesin was not significantly altered by vagotomy. We interpret these data to reflect the sensitivity of bombesin-stimulated gastrin release to gastric luminal pH, although they also suggest the existence of a cholinergic inhibitory mechanism for gastrin release. The data provided by this study are consistent with the hypothesis that bombesin might function as a paracrine neuromodulator of gastrin release. In view of its presence in the nerves and mucosa of human stomach and its potent actions on gastrin release and gastric acid secretion, bombesin may play a role in gastric physiology.

Effect of strychnine on cardiac vagal inhibition

Strychnine blocked the vagal-induced cardiac inhibition in both perfused frog heart and dog's heart in situ. This effect was antagonized by eserine. The present results are consistent with our previous findings that strychnine blocks the cholinergic inhibitory mechanisms both in the central nervous system as well as in the peripheral autonomic nervous system.

Deficits in passive-avoidance learning following atropine in the developing rat

The maturation of cholinergic inhibitory mechanisms that may be involved in passive-avoidance learning was studied in rats 14, 17, 21, 25, 28, and 34 days of age. Acquisition and extinction of the conditioned response were examined under saline and atropine sulfate (5 mg/kg). Learning was also tested following scopolamine hydrobromide injections (1, 4, 8 mg/kg) in rats 17 days of age and following alpha-methylatropine (5 mg/kg) in 17- and 34-day-old groups. In normal animals the rate of acquisition increased during ontogenesis, with a significant improvement between postnatal days 17 and 21, whereas the rate of extinction did not vary with age. Acquisition was impaired by atropine sulfate at all ages and even totally prevented in younger groups (14 and 17 days of age). It was also completely disrupted by scopolamine in 17-day-old rats. Extinction following acquisition under atropine was more rapid than after normal acquisition. Methyl-atropine was without effect. These results support the hypothesis of central cholinergic mechanisms involved in response suppression, already functioning in the rat 14 days of age and maturing mainly between the 17th and the 21st postnatal days.

Disinhibitory effects of intrahippocampal or intrahypothalamic injections of anticholinergic compounds in the rat

The effects of intrahippocampal or intrahypothalamic injections of anticholinergic compounds on operant responding were observed in a multiple schedule paradigm consisting of reinforced, punished, and nonreinforced components and on a punished ingestive passive avoidance task. The pattern of results suggests that cholinergic components of the hippocampus and hypothalamus mediate responding suppressed by nonreinforcement but not by punishment. The data are discussed with reference to Carlton's proposed central cholinergic inhibitory mechanisms.

Effect of atropine on behavioral arousal in the developing rat.

Atropine-induced changes in behavioral arousal were examined in the developing rat between 21 and 40 days of age using a single exploratory trial on an elevated T-maze. Under atropine (10 mg/kg, i.p.) spontaneous activity as measured by numbers of errors, rearing responses, and stereotyped responses was significantly decreased in animals less than 25 days of age. It was significantly increased, however, between 26 and 30 days, with maximal action on the 28th day. After 30 days the effect of atropine was negligible. These results support the hypothesis of a cholinergic inhibitory mechanism controlling behavioral arousal and becoming efficient after the 25th day of life.

Blockade by eserine of the cerebral cortical effects of alloferin: a further evidence of cholinergic inhibitory mechanism

In rats anaesthetised with pentobarbitone, somatosensory evoked potentials, produced by stimulation of contralateral or ipsilateral forepaws were used to measure the activity in different neuronal pathways. Computer derived averages of 32 consecutive responses yielded a stable and consistent measurement of the evoked potentials. The drugs were applied to the cerebral cortex by using cortical cup technique and changes were measured in evoked potentials. Cortical application of alloferin increased the amplitude of the early negative wave of the cortical evoked potentials. This effect of alloferin was blocked by prior treatment of the cortex with eserine. It appears that the excitant effect of alloferin on the cortex was the result of disinhibition of cortical cholinergic inhibitory mechanism.

Blockade by eserine of the cerebral cortical effects of alloferin: a further evidence of cholinergic inhibitory mechanism.

In rats anaesthetised with pentobarbitonc, somatosensory evoked potentials, produced by stimulation of contralatcral or ipsilateral forepaws were used tc measure the activity in different neuronal pathways. Computer derived averages of 32 consecutive responses yielded a stable and consistent measurement of the evoked potentials. The drugs were applied to the cerebral cortex by using cortical cup technique and changes were measured in evoked potentials. Coriical application of alloferin increased the amplitude of the early negative wave of the cortical evoked potentials. This effect of alloferin was blocked by prior treatment of the cortex with eserine. It appears that the excitant effect of alloferin on the cortex was the result of disinhibition of cortical cholinergic inhibitory mechanism.

Ontogenetic aspects of central cholinergic involvement in spontaneous alternation behavior.

AbstractFour studies are reported examining the development of spontaneous alternation behavior in rats. Spontaneous alternation was found to increase from a rate of around 20% in 15‐16 day old rats to around 90% in 100‐day olds. Increasing the length of confinement in the 1st chosen goal arm did not affect alternation rats. Spontaneous alternation could be disrupted or facilitated in mature animals by the administration of either scopolamine hydrobromide or physostigmine sulphate, drugs which had no effect on the typical alternation pattern of 16‐day olds, but appeared to begin to have an effect at around 24 days. Dose response curves revealed certain age‐dose level interactions which were consistent with the hypothesis that cholinergic inhibitory mechanisms in the brain develop gradually in the rat.

Effects of physostigmine and scopolamine on operant brightness discrimination in the rat

Performance in an operant brightness discrimination was facilitated through the mid-range of training by injections of 0.3 mg/kg physostigmine. Performance was facilitated, compared to saline injected controls, due to lower response rates during SΔ while SD response rates were not affected. Injection of 0.5 mg/kg scopolamine suppressed both SD and SΔ response rates proportionally and thus did not affect discrimination performance as reflected in the discrimination ratio. The facilitation of discrimination performance produced by physostigmine was interpreted as due to facilitation of inhibitory precesses and as consistent with the hypothesis of a central cholinergic inhibitory mechanism.

Effects of some sympathomimetic drugs and their antagonists on afterdischarges elicited in chronically isolated slabs of cerebral cortex.

1. The role of sympathomimetic agents in the maintenance and termination of induced cortical epileptiform activity was studied in chronically neuronally isolated slabs of cerebral cortex in the suprasylvian gyrus of unanaesthetized, unrestrained cats.2. The administration of the sympathomimetic agents (+)-amphetamine, methamphetamine, tyramine, and ephedrine resulted in a highly significant decrease in the duration of epileptiform afterdischarge (EADs).3. The alpha-adrenoceptor blocking drugs phenoxybenzamine, phentolamine and tolazoline did not significantly alter the duration of EADs but prevented the decrease in duration of EADs produced by the sympathomimetic drugs.4. The effect of atropine and arecoline on the duration of EADs, previously described, were not modified by the alpha-adrenoceptor blocking drugs, but atropine prevented and reversed the inhibitory action of amphetamine.5. It is suggested that (1) in the chronically neuronally isolated cortical slab there is normally no spontaneous adrenergic activity, (2) a cortical, cholinergic inhibitory mechanism, previously described, is modulated by ascending adrenergic influences, (3) adrenergic cholinergic linkages might be arranged in the cortex in an alternating network, as proposed by Feldberg.

Ontogeny of adrenergic arousal and cholinergic inhibitory mechanisms in the rat.

With spontaneous activity as a measure of arousal, dose response curves were established for scopolamine and amphetamine administered to 10-, 15-, 20-, 25-, and 100-day-old rats. Amphetamine always increased activity, but scopolamine had no efect on younger rats, which suggests that adrenergic excitatory areas in the brainstem mature more rapidly than cholinergic inhibitory areas in the forebrain.

Anticholinergic drugs and neuronal mechanisms of reticulo-cortical interaction

It was shown in cats that anticholinergic drugs inhibit the spontaneous activity of some cortical neurons and facilitate that of others. Intravenous injection as well as the application of anticholinergic drugs to the cortex abolished both EEG arousal and inhibition of cortical neurons produced by reticular stimulation. It is suggested that the blocking of cholinergic inhibitory mechanisms in the cortex promotes interactions between cortical neurons. This provides conditions for grouping of neuronal discharges and increasing of cortical slow potentials.