Effects Of Cholinomimetics Research Articles

Role of the adenylate cyclase system in cholinergic modulation of synaptic transmission in the hippocampus

The adenylate cyclase system has been studied from the standpoint of its significance in cholinergic modulation of the synaptic transmission in the CA1 field of the rat hippocampal slices. Microionphoretic application of ACh as well as addition of either carbachol or tolbutamide (an inhibitor of cAMP-dependent protein kinase) blocked the transmission in synapses formed by the Schaffer collaterals and commissural fibres with dendrites of carbacholine both the number of releasing quanta of the neurotransmitter and the probability of their release decreased. Atropine eliminated the inhibitory effect of carbacholine on synaptic transmission. Dibutyryl cAMP and forskolin increased the amplitude of synaptic potentials and completely or partially prevented the inhibitory effect of cholinomimetics on synaptic potentials. The results obtained revealed opposite effects of cholinomimetics and activators of the adenylate cyclase system on neurotransmission in synapses formed by the Schaffer collaterals/commissural fibres and dendrites of pyramidal neurons of the hippocampal CA1 field.

Restoration of cholinomimetic activity by clonidine in cholinergic plus noradrenergic lesioned rats

The effects of combined lesions of forebrain cholinergic and noradrenergic systems on memory and responsitivity to the memory enhancing effects of cholinomimetics were investigated in rats. Forebrain noradrenergic deficits produced by the injection of 6-hydroxydopamine into the ascending noradrenergic bundle (ANB) blocked the ability of cholinomimetics such as physostigmine and oxotremorine to enhance retention test performance in nucleus basalis of Meynert lesioned rats. Low doses of the noradrenergic receptor agonist clonidine, when administered in conjunction with cholinomimetics reversed this blockade. These results suggest that combined cholinergic/noradrenergic therapy may be of value in the treatment of some Alzheimer's disease patients.

Involvement of a steroidal component in the mechanism of action of piracetam-like nootropics

Since adrenalectomy abolishes the memory-enhancing effects of piracetam and its derivatives, oxiracetam, aniracetam and pramiracetam, the question arises whether endogenous steroids play a role in their mechanism of action. We show that inhibition of steroid biosynthesis by aminoglutethimide and blockade of the aldosterone receptors by epoxymexrenone completely suppress the memory-improving effects of the nootropics. These results indicate that steroids, or more precisely, activities mediated by the aldosterone receptors, might be involved in the mechanism of action of this class of nootropics. Blockade of aldosterone receptors, however, does not block the effects of cholinomimetics on memory, indicating the involvement of another mechanism of action.

Comparison of the effects of four cholinomimetic agents on cognition in primates following disruption by scopolamine or by lists of objects

The ability of four central cholinomimetics to reverse a scopolamine-induced spatial memory impairment or to improve visual recognition memory in primates was examined. Physostigmine (0.04-0.08 mg/kg IM) fully reversed the effects of scopolamine (0.03 mg/kg). Coadministration of pilocarpine (3.0-5.0 mg/kg) caused partial reversal of the scopolamine impairment after intermediate or long retention intervals (10 or 20 s). Treatment with arecoline (0.1-1.8 mg/kg) or nicotine (1.0-2.0 mg/kg) generally did not reverse the effects of scopolamine. A task in which memory could be taxed by increasing the number of visual stimuli presented appeared more sensitive to the effects of cholinomimetics on cognition than the scopolamine reversal model. In this paradigm treatment with physostigmine (0.001, 0.01 or 0.03 mg/kg) increased choice accuracy from about 55 to 70% correct. Arecoline improved performance at one dose only (0.1 mg/kg) which also induced marked adverse side-effects (salivation and tremor). Pilocarpine improved performance in the dose range 0.125-0.35 mg/kg, but not at higher doses which also induced marked salivation. Treatment with nicotine (0.001-2.0 mg/kg tended to improve performance but this did not reach statistical significance. The relevance of these findings for studies in man and for animal models of dementia is discussed.

The relative potencies of cholinomimetics and muscarinic antagonists on the rat iris in vivo: effects of pH on potency of pirenzepine and telenzepine.

The effects of cholinomimetics and muscarinic antagonists were compared following topical administration to the eyes of anaesthetized rats. For tests with cholinomimetics, clonidine (0.3 mg/kg) was used to induce mydriasis via central inhibition of parasympathetic tone. Full, dose-dependent miosis was induced by acetylcholinesterase inhibitors [physostigmine greater than neostigmine greater than tetrahydroaminoacridine (THA)] and by membrane channel blockers (4-aminopyridine greater than 3,4-diaminopyridine). Oxotremorine was the most potent direct agonist tested [oxotremorine greater than arecaidine propargylester (APE) greater than arecoline greater than carbachol greater than ethoxyethyltrimethyl-ammonium iodide (EOE) greater than RS 86]. Some putative M1 selective agonists were weakly active or behaved as partial agonists (pilocarpine greater than AH6405 greater than Mc-A-343 greater than isoarecoline). Of the antagonists, compared in non-clonidine treated rats, scopolamine hydrochloride was the most potent. Of the receptor selective antagonists the M2 (ileal) selective compounds hexahydrosiladifenidol and 4-DAMP were more potent than either M1 selective (pirenzepine, telenzepine) or M2 (atrial) selective (AF DX 116) drugs. These data tentatively suggest the involvement of an M2 (ileal) type muscarinic receptor. Potency was lower for quaternary structures, probably due to impaired corneal penetration. The potency of pirenzepine and telenzepine was increased 60-fold at low pH following topical administration. Acid induced corneal damage does not appear to account for this potency shift as the effects of scopolamine and several agonists (oxotremorine, pilocarpine and McNA-343) were not substantially altered by acid media. For pirenzepine the potency shift appears to be related to protonation of the second amino group (N1) in the piperazine tail (pKa = 2.05).(ABSTRACT TRUNCATED AT 250 WORDS)

P-459 - Studies on the colonic longitudinal muscle responses mediated by neuronal connections between mucosal tissue and smooth muscle layers. The 6-th report — on the effects of cholinomimetics and pyrenzepine

P-459 - Studies on the colonic longitudinal muscle responses mediated by neuronal connections between mucosal tissue and smooth muscle layers. The 6-th report — on the effects of cholinomimetics and pyrenzepine

Acetylcholine and affective disorder.

We reviewed the evidence for involvement of central cholinergic neurons in affective disorder. Cholinomimetics inhibit speech, thought, and activity in most subjects, decrease manic symptoms and, in some affective disorder patients, produce depressive symptoms. Cholinomimetics also cause ACTH and cortisol secretion and decrease latency to REM sleep. It is unclear whether cholinomimetics are specifically "antimanic" or "depressogenic" or whether their fundamental effect is nonspecific behavioral inhibition; whether the observed effects of cholinomimetics are mediated largely through cholinergic pathways, are secondary to changes in other neurotransmitters or are part of a nonspecific stress response. The suggestion that anticholinergic agents have mood elevating properties has not yet been subjected to controlled investigation. Although the proposal that affective disorders involve cholinergic neurons has received some support from clinical investigation further research is required to substantiate the intriguing observations to date and to clarify the physiologic and psychologic processes mediating them.

Evidence against an acetylcholine releasing action of cisapride in the human colon.

The effect of cisapride (R51619) on intrinsic cholinergic nerve activity of human sigmoid taenia coli muscle strips (taenia) was assessed using radiolabelling techniques. Taeniae previously incubated with [3H]-choline were exposed to cisapride (0.41 and 4.1 microM), placebo solution and electrical field stimulation (EFS; 10 Hz, 1 ms, 200 mA for 480 pulses). Cisapride did not affect unstimulated (basal) release of radioactive material nor the release evoked by EFS. It was concluded that cisapride did not demonstrate a cholinomimetic effect in human sigmoid taenia coli muscle strips.

Effect of ranitidine on ileal myenteric plexus preparation and on acetyl- and butyrylcholinesterase

Ranitidine at concentrations from 1 μM to 0.1 mM brought about a dose-dependent potentiation of the twitch responses elicited by electrical stimulation of the ileal myenteric preparation. At higher concentrations (0.3-3 mM) ranitidine also caused irregular slow contractions of the unstimulated ileal preparation which were potentiated by eserine and blocked by atropine and tetrodotoxin. In order to identify the mechanism of these apparently cholinomimetic actions, the effects of ranitidine on AChE and BuChE were studied. Ranitidine showed an instantaneous and promptly reversible inhibitory action at concentrations between 0.5 and 30 μM. Double reciprocal plots were prepared and equilibrium dissociation constants calculated. It appears that ranitidine exerts an inhibition of the “mixed” type on both AChE and BuChE, but the dissociation constants for BuChE were markedly higher than those for AChE. Since AChE inhibition occurs in the same concentration range potentiating the twitch responses on the ileal myenteric preparation, it may explain the cholinomimetic effect of ranitidine.

Presence of cholinoceptors in mesencephalic raphe nuclei concerned in thermoregulation in rabbits.

The thermal effects of cholinomimetics and cholinoceptor blocking agents microinjected into mesencephalic nucleus raphe medianus (NRM) were investigated in rabbits to determine the nature and role of these cholinoceptors in thermoregulation. Microinjection of cholinoceptor agonists, carbachol and pilocarpine, into NRM resulted in significant hyperthermia which could be blocked by local pretreatment with chlorisondamine (a nicotinic receptor blocker) as well as by ethybenztropine (a muscarinic receptor blocker). Intracerebroventricular pretreatment with LM 5008 (serotonin reuptake blocker) significantly inhibited the carbachol-induced hyperthermia. Both nicotinic and muscarinic cholinoceptors are present in mesencephalic NRM which may be involved in thermoregulation in rabbits. Activation of these cholinoceptors in NRM results in hyperthermia which seems to be due to an inhibition of a serotonin sensitive hypothalamic heat loss mechanism.

Effect of arecoline on posterior hypothalamic unit activity in rabbits with experimental fever

In fever caused by endogenous (leukocytic) pyrogen hypothalamic unit activity is modified, mainly in its preoptic region [i, ii]. The hyperthermic effect of prostaglandins (PG) of the E group also is connected with changes in activity of certain neurons in this region [i0]. The development of hyperthermia under the influence of PG and pyrogen is inhibited by cholinomimetics [3-5]. However, the problem of relations between synaptically active substances and pyrogens has received little study. In particular, the hypothesis on antagonistic effects of cholinomimetics and pyrogenic substances on unit activity in the posterior hypothalamus, which performs integrative functions in the formation of a controlling signal to effectors of the temperature regulating system, requires experimental verification.

Effects of cholinomimetics on glucose utilization in rat brain optic systems

Physostigmine and oxotremorine effects on local cerebral glucose utilization (LCGU) in rat brain optic systems were examined by the [ 14C]2-deoxy-D-glucose procedure. Both drugs significantly stimulated LCGU in the superior colliculus (superficial layer) and nucleus of the optic tract, but not in the visual cortex. Physostigmine, but not oxotremorine, stimulated LCGU in components of the accessory optic system. The effects in the accessory optic system apparently result from nicotinic actions of physostigmine.

Ionic regulation of antagonist binding to the human muscarinic cholinergic receptor of caudate nucleus

In this in vitro study we investigated the effects of a variety of cations on binding of the cholinergic antagonist, ( 3H)-quinuclidinyl benzilate, to the human caudate. Physiologic sodium concentrations induced a state of positive cooperativity upon the human muscarinic cholinergic receptor ( n Hill =1.41). Lithium at therapeutic equivalency (1 mM) was unique in increasing the dissociation constant ( K D ) for this antagonist from 35.9 to 72.4 pM. This implies a lithium-induced cholinomimetic effect at the human muscarinic receptor consistent with reports of the reversal of mania by physostigmine. These findings are also relevant to previous cholinergic receptor studies in which various cations have been employed.

Contractile effect of prolactin on guinea pig isolated ileum

Prolaction (PRL) at high concentrations contracted the guinea pig isolated ileum. The maximum response elicited by PRL was 44% of that of histamine-induced responses. There was no significant difference in potency between PRL preparations obtained from two different sources. PRL responses were nullified by denaturation or proteolytic digestion of the hormone. The contractile response was antagonised by atropine and potentiated by neostigmine, but unaffected by the prostaglandin antagonist SC-19220. The pA 2 values of atropine against PRL and ACh were similar. Preincubation with morphine, which inhibits ACh release, produced slight inhibition of PRL-evoked contractions. Even high concentration of PRL failed to produce any response in neostigmine-treated frog rectus muscle preparations. This suggests that PRL may produce contractions through a cholinergic mechanism involving muscarinic receptors. Enhanced gut motility reported earlier for hyperprolactinemic states may be attributed to this cholinomimetic effect of PRL on the intestinal tract.

The nature of the membrane potential of glial cells associated with the medial giant axon of the crayfish

Electrophysiological, pharmacological and electron microscopic methods were used to characterize the satellite glial (Schwann-like) cells associated with the medial giant axon of the crayfish, Procambarus clarkii. The satellite glial cell layer surrounding the axon is formed by 15–20 cells deeply interdigitated into each other, forming a vast system of intercellular channels which communicate the axo-glial space with the external medium. The satellite cell layer varies from 0.2–3 μm in thickness. Membrane potentials of the giant axon and the satellite glial cells were monitored before, during and after treatment with ouabain and a variety of cholinergic agonists and antagonists. The membrane potentials of 63 control satellite cells averaged−42.6 ± 0.6 mV. The intracellular localization of the glial cell potential difference was corroborated by lithium carminate marking of the microelectrode tip recording site. Superfusion of satellite cells with 10 −7 m carbachol, nicotine or acetylcholine caused a 15 to 20 mV hyperpolarization from resting level. Muscarine (10 −6 m) had no effect on the glial cell potential. The effect of nicotine was prevented or reversed by-tubocurarine (10 −9 m). The effects of cholinomimetics were reversed by washing the cells in drug-free solution. None of these agents had an obvious effect on axon membrane potential or action potential generation at the concentration used in this study. Ouabain (10 −3 m) also caused a rapid hyperpolarization of the glial cells. The effect lasted 15–18 min after which the membrane rapidly depolarized. The results suggest that (1) the satellite glial cell of the crayfish giant axon system may be studied simultaneously with the axon using electrophysiological techniques; (2) the satellite glial cell membrane appears to have typical acetylcholine receptors of the nicotinic type; (3) the membrane potential of the glial cell is sensitive to ouabain and (4) properties of the glial cell associated with the giant axon of the crayfish are similar to those of the Schwann cell of the tropical squid Sepioteuthis sepioidea.

Memory Deficits in Aged Cebus Monkeys and Facilitation With Central Cholinomimetics

Cebus monkeys of 3 different age groups were trained to perform an automated behavioral task (delayed response), intended to measure recent memory ability. In in initial study, the aged monkeys (18 years and older) exhibit prprogressively greater performance impairments (relative to young monkeys) as they were required to remember the location of a visual stimulus for increasingly longer durations (0 to 20 sec). This deficits replicated previously published results from aged Rhesus monkeys and appeared similar to the primary memory deficits reported in elderly humans and demented patients. In subsequent studies, the effects of three different cholinomimetics were evaluated for their ability to improve the aged monkey's performance on this task. Each monkey was tested under several acute doses of the cholinergic precursor, choline, the anticholinesterase, physostigmine, and the cholinergic muscarinic receptor agonist, arecoline. The results revealed clear differences in the ability of these drugs to improve performance on this task. Choline exerted no apparent effects in the aged monkeys at any dose tested. Physostigmine clearly enhanced performance in certain aged monkeys, but the optimal dose varied dramatically between subjects, replicating previously published results with aged Rhesus monkeys and humans. Arecoline produced clear improvement within a restricted dose range, with little variation in optimal dose between subjects. In addition to demonstrating differences in the effects of different cholinomimetics on memory performance in aged primates, these data also suggest a possible rationale for future investigations. Assuming that each of these drugs primarily affected cholinergic function in the manner conventionally attributed, these data suggest that, within the cholinergic system, the more directly one stimulates the receptor, the more one might expect robust and consistent effects on memory performance in aged subjects.

Effects of oxotremorine demonstrate presynaptic muscarinic and dopaminergic receptors on motor nerve terminals

THERE has been little conclusive evidence about the presynaptic effects of acetylcholine (ACh) and cholinomimetics on mammalian motor nerve terminals1,2 which may have functional implications in motor abnormalities3,4. We now report the existence of dopaminoceptive muscarinic receptors on motor nerve terminals which participate in the local release of ACh from motor nerve terminals.

Effects of parachlorophenylalanine and 5,6-dihydroxytryptamine on aggressive behaviour evoked by cholinomimetics and anticholinesterases injected into the cerebral ventricles of conscious cats

Carbachol, muscarine, eserine and neostigmine injected into the cerebral ventricles of conscious cats, evoked emotional behaviour with aggression and autonomic and motor phenomena with clonic-tonic convulsions. The main and the most impressive feature of the gross behavioural effects of intraventricular cholinomimetics and anticholinesterases was an affective type of aggression. After 5,6-dihydroxytryptamine and parachlorophenylalanine, intraventricular carbachol, muscarine, eserine and neostigmine elicited aggression and autonomic and motor phenomena with clonic-tonic convulsions. The affective type of aggressive behaviour was modified with biting attack predominant, while hissing and snarling (i.e. vocalization) were depressed or absent. The manifestations of affective aggressive behaviour caused by muscarine were most resistent to 5,6-dihydroxytryptamine and parachlorophenylalanine. When 5-hydroxytryptophan was given to parachlorophenylalanine treated-cats, intraventricular carbachol, muscarine and eserine evoked emotional behaviour with aggression and autonomie and motor phenomena with clonic-tonic convulsions. Hissing and snarling reappeared, but they were less intense and shorter in duration than in control animals. Based on these experiments, it is concluded that an intact central 5-hydroxytryptamine network is required for the expression of emotional behavioural phenomena, especially vocalization in the appearance of the affective type of aggression. On the other hand, intact central 5-hydroxytryptamine pathways are not essential for the performance of the motor act for the attack and biting.

The action of smooth muscle stimulators studied by correlation analysis

Correlation between the maximal effects of acetylcholine and other cholinomimetics and also of serotonin, barium chloride, and a depolarizing solution on an isolated strip of rat stomach was studied. The effect of acetylcholine correlates closely with the effects of cholinomimetics, less closely with the effects of barium chloride and depolarizing solution, and less closely still with the effects of serotonin. It is suggested that the degree of correlation be used to analyze the points of action of drugs and the paths linking receptor stimulation with the observed effect. The point of convergence of the linking paths for the last three stimulators was shown to precede the convergence of their common path with the linking path of the effects of cholinomimetics.

Comparison of the effects of the intranigral injections of cholinomimetics with systemic injections of the dopamine receptor stimulating and blocking agents in the rabbit

The cholinergic stimulation of the substantia nigra of the rabbit, induced by intranigral injections of acetylcholine, methacholine or neostigmine, produced behavioural and EEG alerting, various forms of stereotyped behaviour and autonomic symptoms, followed by a pre-epileptic EEG pattern (sharp waves, spike and waves, and multispike complexes) and an epileptic EEG pattern accompanied in most of cases by clonico-tonic convulsions. The EEG and behavioural effects were similar to those observed after systemic injections of amantadine or apomorphine, although they produced more intensive stereotypy and no convulsions. The effects of cholinomimetics were abolished by intranigral injections of atropine, or by subcutaneous injections of spiroperidol. The catalepsy produced by spiroperidol was abolished by intranigral neostigmine injections. The relationship between the cholinergic stimulation of the nigra and dopaminergic stimulation of the striatum is discussed.