Effects Of Cholinomimetics Research Articles

In vivo acute toxicity, laxative and antiulcer effect of the extract of Dryopteris Ramose.

Dryopteris ramosa (D. ramosa) is one of the most traded medicinally important plants of Himalayan region. Apart from other uses, D. ramosa is traditionally also used to treat gastric ulcers and as a laxative. The present study was designed to investigate the role of methanolic crude extract of Dryopteris Ramosa (MEDR) in acute toxicity, against loperamide induced constipated mice model, antiulcer effect of methanolic extract of D. Ramosa and cholinomimetic like effect of methanolic extract of D. Ramosa. The crude extract was investigated for the presence of active compounds (secondary metabolites) such as alkaloids, flavonoids, carbohydrates, glycosides, terpenoids, phenolic compounds, saponins, and tannins following the standard methods. The antiulcer effect was investigated in mice using the ethanol induced ulcer model at various doses i.e. 50 mg/kg, 100 mg/kg and 200 mg/kg doses. Constipation was induced in the mice via loperamide (3mg/kg body weight). The control group received normal saline. Different doses of plant extracts (50, 100, 150 and 200 mg/kg body weight/day) were administered for 7 days. Various parameters like feeding characteristics, gastrointestinal transit ratio, body weight, fecal properties and the possible mechanism of action of D. Ramosa on intestinal motility were monitored. Various Phytochemicals like saponins, glycosides, flavonoids, tannins, phenols, carbohydrate, alkaloids and triterpenes were found in D. Ramosa. The acute toxicity study showed that MEDR was associated with no mortality except mild and moderate sedation at the highest tested doses (1500 and 2000 mg/kg). MEDR also showed significant antiulcer activity against ethanol-induced ulcerogenesis. The extract enhanced the intestinal motility, normalized the body weight of constipated mice and increased the fecal volume which are indications of laxative property of the herb. The 200 mg/kg body weight dose of the extract was found effective. The presence of various Phytochemicals such as flavonoids, glycosides and tannins might be responsible for the antiulcer activity of D. Ramosa. This study provides the scientific background for the folkloric use of D. Ramosa as antiulcer agent. The laxative action of the extract compares positively with Duphalac, (standard laxative drug). These findings have therefore evidence scientific background to the folkloric use of the herb as a laxative agent.

LUEM PUA RICE EXTRACT ATTENUATES THE SEVERITY OF DEXTRAN SULFATE SODIUMINDUCED ULCERATIVE COLITIS IN RATS THROUGH CHOLINOMIMETIC EFFECTS

Objective: The objective of the study was to investigate the effect of aqueous extract of unpolished dark purple glutinous Thai rice variety Luem Pua(LP) in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in rat and the possible cholinomimetic effects of the extract.Methods: The effect of LP extract (0.5, 1, or 1.5 mg/ml final concentration) on ileum contraction was tested using isolated guinea pig ileum. Certainagonists (acetylcholine, tetramethylammonium, and clonidine) and antagonists (hexamethonium chloride and atropine) were studied to determinethe cholinomimetic effect of the extract. The effects of LP extract (5 g/kg/day) in DSS-induced UC model (drinking water was replaced with 3%DSS in water for 7 days) in rat were evaluated. On each day of treatment, the change of disease activity index (DAI) was recorded. At the end of theexperiments, rats were terminated and disease severity expressed as DAI, colon length, and spleen weight were determined.Results: LP extract at the concentration of 0.5, 1, and 1.5 mg/ml (final concentration) could contract the ileum in a dose-dependent manner and beblocked completely by atropine. Oral administration of LP extract could significantly attenuate the severity of DSS-induced UC as seen by the reductionof DAI, colon length, and spleen weight.Conclusion: Results in isolated guinea pig ileum suggest that LP might contain active substance that could activate muscarinic receptors. In additionto antioxidant activity, through activation of muscarinic receptor, might explain the protective effects of LP extract against DSS-induced UC in rats.

Prospects of application of acetyl-L-carnitine in neurology and psychiatry (the treatment of polyneuropathy and depressive states)

Acetyl-L-carnitine (ALA) is a biologically active form of L-carnitine, which is a readily available substrate for triggering energy-dependent metabolic processes in the mitochondria. The mechanism of the protective effect of ALA on brain tissue is a significant reduction in the amount of oxygen consumed for energy supply of the needs of the nervous system. ALA also has antioxidant and antiapoptotic activity. In addition, ALK plays a neuromodulating effect on both synaptic morphology and synaptic transmission. The similarity in structure with acetylcholine allows to have a cholinomimetic effect, as well as to show neuroprotective and neurotrophic properties. ALK has an antidepressant and analgesic effect in painful neuropathies. Therefore, ALA is a promising drug for the treatment of polyneuropathy of various origins. Compared with antidepressants efficacy and a minimum of side effects open up wide possibilities of using ALA in the treatment of depression with a low risk of developing NLR.

Comparative effects of different fractions of crude aqueous extract of Ficus exasperata leaves on blood pressure

Ficus exasperata has been extensively used in folk medicine for the treatment of many ailments. The aqueous extract of leaves of this herb reduced blood pressure through its cholinomimetic effect. In this study, different fractions of the crude extract of F. exasperata leaves (FEFIX) were evaluated on blood pressure. Fractionated extracts were obtained by successive use of different solvents on the total crude extract. Phytochemical analysis was performed for each fraction and increasing doses (0.25 to 40 mg / kg b.w.) were administered intravenously. The phytochemical screening showed that alkaloids and phenols were found in ethanol fraction (FE-FEFIX) and methanol fraction (FM-FEFIX). Saponins and tannins have been identified only in the aqueous fraction (FA-FEFIX). Decreases in blood pressure were 40.02 ± 3.08 mm Hg for the ethanol fraction (FE-FEFIX), 9.95 ± 2.09 mm Hg for the methanol fraction (FM-FEFIX) and 5.26 ± 1.46 mm Hg in the aqueous fraction (FA-FEFIX). Hypotension induced by ethanol fraction is found to be greater than those induced by the other two fractions. In conclusion, this study showed that the hypotensive effect of F. exasperata leaves was greater with its ethanol extract. Alkaloids and phenols present in this extract may be involved in the hypotensive effect.DOI: http://dx.doi.org/10.3329/icpj.v2i11.16534 International Current Pharmaceutical Journal, October 2013, 2(11): 193-195

Oral tremor induced by galantamine in rats: A model of the parkinsonian side effects of cholinomimetics used to treat Alzheimer's disease

Anticholinesterases are the most common treatment for Alzheimer's disease, and, in recent years, a new group of cholinesterase inhibitors (i.e. rivastigmine, galantamine, and donepezil) has become available. Although these drugs improve cognitive symptoms, they also can induce or exacerbate parkinsonian symptoms, including tremor. The present studies were conducted to determine if galantamine induces tremulous jaw movements, a rodent model of parkinsonian tremor, and to investigate whether these oral motor impairments can be reversed by co-administration of adenosine A2A antagonists. The first experiment demonstrated that systemic injections of galantamine (0.75–6.0mg/kg I.P.) induced a dose-related increase in tremulous jaw movements in rats. In a second study, co-administration of the muscarinic antagonist scopolamine (0.0156–0.25mg/kg I.P.) produced a dose dependent suppression of tremulous jaw movements induced by a 3.0mg/kg dose of galantamine, indicating that galantamine induces these tremulous oral movements through actions on muscarinic acetylcholine receptors. In two additional studies, analyses of freeze-frame video and electromyographic activity recorded from the lateral temporalis muscle indicated that the local frequency of these galantamine-induced jaw movements occurs in the 3–7Hz frequency range that is characteristic of parkinsonian tremor. In the final experiment, the adenosine A2A antagonist MSX-3 significantly attenuated the tremulous jaw movements induced by the 3.0mg/kg dose of galantamine, which is consistent with the hypothesis that co-administration of adenosine A2A antagonists may be beneficial in reducing parkinsonian motor impairments induced by anticholinesterase treatment.

Chironomus (diptera) polytene chromosomes functional activity under the influence of cholinotropic preparations

Morphometric analysis of nucleolar organizer (NO), Balbiani rings (BR) - BRsubB/sub, BRsub1G/sub, BRsub2G/sub, chromosome I arm puff B, chromosomes compactness activity change under the influence of cholinotropic preparations was carried out. Most sensitive criterion - chromosomes compactness is, most stable under the influence of stress - NO is. Atropine and pilocarpine antagonistic effect on the polytene chromosomes (PC) sites activity pilocarpine manifested itself in functional activity and restoration period duration change: on cholinoblocker effect activity decreased, while on cholinomimetic effect activity increased.

A Study Of The Cardiovascular Toxic Effects Of Zingiber Officinale (Ginger) In Adult Male Albino Rats And Its Possible Mechanisms Of Action

Ginger is a world known food plant which is equally reputed for its medicinal properties. The aim of the work is to study the acute and subacute cardiovascular toxicity of ginger in adult male albino rats and its possible mechanisms of action. The in- vivo studies included eighty four adult male albino rats for the acute and subacute toxicity experiments. The rats were divided into 7 groups each one consisted of 12 rats. All rats received ginger orally in saline. Each of the in- vivo studies included 2 control groups, the negative and positive control rats. In the acute toxicity study, rats received ginger in a single dose of 2500 mg/ kg. In the subacute toxicity study group VI and VII received ginger in a daily dose of 50 mg/ kg and 500 mg/ kg respectively for 28 days. After 24 hours of the acute toxicity and 28 days of the subacute experiments six rats of each group were used for blood pressure and heart rate recording. The other 6 rats were used for histopathological study of the cardiac tissue. The in- vitro experiments included 6 rabbits each weighing 1.5- 2 kg. Ginger (5mg/ml) was incubated with the aortic spiral strip of each rabbit to investigate the possible mechanisms of action of Ginger. It was concluded that; single dose of 2500 mg/ kg ginger can be a toxic by causing severe hypotension and bradycardia with induction of prenecrotic changes in cardiac tissue. The administration of ginger in a dose of 50 mg/ kg for 28 days produced bradycaria with waviness in cardiac muscle fibers. Ginger in a dose of 500 mg/ kg produced both hypotension and bradycardia with degenerative changes in cardiac myocyte tissue. The hypotensive and bradycardic effects of ginger may be partially due to induction of vasodilatation by increasing nitric oxide release or synthesis and partially due to a calcium channel blocking effect. Also, a cholino-mimetic effect could be contributed in the cardiovascular effects of ginger. While the In-vitro results revealed that ginger is a partial vasorelaxant as it produced a relaxant effect on rabbit's aortic strip procontracted with phenylephrine, while preincubation with L-nitroarginine methyl ester (L-NAME) significantly attenuated the ginger-induced relaxation indicating that the vasodilator effect of ginger is partially mediated through nitric oxide synthesis or release from L-NAME.

On the Physiological Relevance of Muscarinic Acetylcholine Receptors in Alzheimers Disease

The loss of cholinergic neurons, particularly in the forebrain, plays an important role in the pathophysiology of Alzheimer's disease (DAT). This concept has lead to the effective treatment of DAT by means of acetylcholine (Ach) esterase inhibitors. G-protein-coupled muscarinic acetylcholine receptors (mAchR) are classified in 5 subtypes, the M1 receptor stimulation and M2 inhibition being especially associated with cognitive skills. Modified cerebral muscarinic receptor profiles in patients with Alzheimer's disease in addition to loss of Ach releasing neurons help us to understand the pathophysiology of dementia and offer potential therapeutic approaches. Specific agonists and antagonists of muscarinic receptors are discussed as possible treatment options in DAT. Experimental results postulate a positive long lasting modulation of the pathological neuronal protein pattern in addition to their cholinomimetic effect.

Concurrent administration of donepezil HCl and levodopa/carbidopa in patients with Parkinson's disease: assessment of pharmacokinetic changes and safety following multiple oral doses

The use of acetylcholinesterase inhibitors for the treatment of comorbid Alzheimer's disease in Parkinson's disease (PD) patients stabilized on a levodopa regimen may potentially disrupt cholinergic balance. This randomized, double-blind, crossover study investigated the safety of, and possible drug-drug interaction between, donepezil HCl and levodopa/carbidopa. Twenty-five patients with PD who were taking physician-optimized doses of levodopa/carbidopa (with daytime dosing intervals of 4-8 h) were administered once-daily doses of either donepezil HCl (5 mg) or placebo for 15 days, in two treatment periods, separated by a washout of at least 2 weeks. Some patients took a second dose of levodopa/carbidopa after 4 h, therefore subanalysis of the levodopa/carbidopa data was conducted up to 4 h and 8 h after dosing. Twenty-six healthy matched controls received open-label donepezil HCl only, for a single 15-day period. Blood samples were collected before, during and after the 15 doses of donepezil HCl for pharmacokinetic (PK) assessments. Pharmacokinetic parameters included maximum attained plasma drug concentration (C(max)), time at which C(max) is attained (t(max)), plasma drug concentration at steady state (C(ss)), and area under the drug concentration-time curve over the dosing interval. Safety assessments included monitoring adverse events, and the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. The mean age of all subjects was 72.6 +/- 1.3 years. Donepezil PK assessments of PD patients receiving levodopa/carbidopa were similar to the PK results from healthy controls who received donepezil HCl only (mean AUC(0-12 h)= 281.6 +/- 17.6 and 268.6 +/- 19.9 ng.h ml(-1), respectively). Carbidopa PK were not significantly altered by the concomitant administration of multiple doses of donepezil HCl, compared with when PD patients received placebo (mean AUC(0-8 h)= 921.8 +/- 160 and 821.8 +/- 113 ng.h ml(-1), respectively). Four hours after administration of donepezil HCl in PD patients, AUC(0-4 h), C(max) and C(ss) of levodopa were higher than when PD patients received placebo (P < 0.05). Eight hours after donepezil HCl, however, only C(max) and t(max) were observed to change compared with when PD patients received placebo (mean C(max) = 2652 +/- 429 and 2077 +/- 276 ng ml(-1), respectively; mean t(max) = 1.7 +/- 0.4 and 2.9 +/- 0.5 h, respectively; P< or = 0.05). The number of PD patients who experienced at least one adverse event during the study (13/25) was higher when they received donepezil HCl than when they received placebo (5/25), but was the same as healthy subjects who received donepezil HCl only (13/26). There were no significant differences in change from baseline on the UPDRS motor examination parameters in PD patients when they took donepezil HCl and when they took placebo. No clinically significant drug-drug interactions between donepezil HCl and levodopa/carbidopa were observed at steady state. The small changes in the pharmacokinetics of levodopa did not result in any change in motor symptoms. Co-administration of the two drugs led to a small increase in adverse events compared with administration of levodopa/carbidopa alone in PD patients. These adverse events, however, were consistent with donepezil's cholinomimetic effect, and their incidence was comparable to that observed following the administration of donepezil HCl alone.

Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in heart failure

Background Increased ventricular arrhythmia density and reduced heart rate variability are associated with risk of death in patients with heart failure. Cholinesterase inhibition with pyridostigmine bromide increases heart rate variability in normal subjects, but its effect on patients with heart failure is unknown. In this study, we tested the hypothesis that short-term administration of pyridostigmine bromide, a cholinesterase inhibitor, reduces ventricular arrhythmia density and increases heart rate variability in patients with congestive heart failure. Methods Patients with heart failure and in sinus rhythm participated in a double-blind, cross-over protocol, randomized for placebo and pyridostigmine (30 mg orally 3 times daily for 2 days). Twenty-four hour electrocardiographic recordings were performed for arrhythmia analysis and for the measurement of time domain indices of heart rate variability. Patients were separated into 2 groups, according to their ventricular arrhythmia density. The arrhythmia group (n = 11) included patients with >10 ventricular premature beats (VPBs) per hour (VPBs/h), and the heart rate variability group (n = 12) included patients with a number of VPBs in 24 hours not exceeding 1% of the total number of R-R intervals. Results For the arrhythmia group, pyridostigmine resulted in a 65% reduction of ventricular ectopic activity (placebo 266 ± 56 VPBs/h vs pyridostigmine 173 ± 49 VPBs/h, P = .03). For the heart rate variability group, pyridostigmine administration increased mean R-R interval (placebo 733 ± 22 ms vs pyridostigmine 790 ± 33 ms, P = .01), and in the time domain indices of heart rate variability root-mean-square of successive differences (placebo 21 ± 2 ms vs pyridostigmine 27 ± 3 ms, P = .01) and percentage of pairs of adjacent R-R intervals differing by >50 ms (placebo 3% ± 1% vs pyridostigmine 6% ± 2%, P = .03). Conclusion In patients with heart failure, pyridostigmine reduced ventricular arrhythmia density and increased heart rate variability, most likely due to its cholinomimetic effect. Long-term trials with pyridostigmine in heart failure should be conducted.

Selective blockade of muscarinic receptor subtypes in the brain stem reticular formation in rats: effects on anesthetic requirements

Muscarinic involvement in the modulation of general anesthesia was examined in the rat with a cannula implanted in the pontine reticular formation. Atropine microinjected into the reticular formation reversed the minimum alveolar concentration (MAC) reducing effect of carbachol on halothane anesthesia, but M 1 or M 3 antagonist had no effect. An M 2 antagonist reduced the MAC of halothane following saline and carbachol. The results suggest that any of the muscarinic receptor subtypes in this region do not independently mediate the cholinomimetic effect on halothane anesthesia.

Possible involvement of nitric oxide in pilocarpine induced seminal emission in rats

Intraperitoneal injection of pilocarpine (0.75–3.0 mg/kg) caused a dose-related seminal emission in adult male rats. The seminal emission response to 3 mg/kg of pilocarpine was greatly reduced in atropinized (5 and 10 mg/kg, SC) animals, suggesting a cholinomimetic effect. N w-nitro-L-arginine methyl ester (5, 10, and 20 mg/kg, SC), a nitric oxide synthesis inhibitor, also inhibited the pilocarpine-induced seminal emission, which was reversed by L-arginine (600 mg/kg, SC) or by coinjection of sodium nitroprusside (0.5 mg/kg, SC). Urine analysis for levels of nitric oxide metabolites, nitrate/nitrite (NO 3 −/NO 2 −), showed marked alterations in accordance with the drug treatments. The results suggest that nitric oxide mediates the inhibitory neurotransmission responsible for seminal emission in pilocarpine stimulated rats.

The Pharmacology of Physostigmine

The Pharmacology of Physostigmine

Enhanced performance of spatial and visual recognition memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys

Hepatotoxicity limits the clinical utility of the cholinesterase inhibitor tacrine as a palliative therapy for Alzheimer's disease. The present studies examined the effects of E2020, a selective acetylcholinesterase inhibitor not associated with liver toxicity in man, on cognitive performance in rhesus monkeys using tasks employed previously to evaluate tacrine and other cholinomimetic agents. The ability of E2020 to prevent the induction of a cognitive impairment by the muscarinic receptor antagonist scopolamine was assessed using an automated spatial delayed response task. Coadministration of E2020 (0.5-1.75 mg/kg) caused a dose-dependent reversal of the scopolamine (0.03 mg/kg) induced impairment observed after retention intervals of 10 and 20 s. At the highest dose of E2020 examined (1.75 mg/kg), choice accuracy approached normal control levels. In this dose range, E2020 was well tolerated, but at the higher dose of 2 mg/kg, cholinergic side-effects were apparent. The effect of E2020 on choice accuracy in a visual recognition task was also assessed as this task does not require the use of scopolamine to disrupt performance and beneficial effects of cholinomimetics can therefore be detected at lower doses than in the spatial memory paradigm. In this task, administration of E2020 increased choice accuracy from 59 +/- 1% correct to up to 71 +/- 2% at doses of 0.03 and 0.05 mg/kg. No observable adverse effects were induced by E2020 in this dose range. The ability of E2020 to improve performance in these cognitive tasks resembles the profile of other cholinesterase inhibitors, including tacrine, that also improve cognitive function in Alzheimer's disease patients. Because of its more favourable clinical safety profile, E2020 may provide a significantly improved palliative therapy for dementia.

The Post-training Memory Enhancement Induced by Physostigmine and Oxotremorine in Mice Is Not State-Dependent

Immediate post-training subcutaneous administration of either the centrally acting anticholinesterase physostigmine (35, 70, or 150 μg/kg) or the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 μg/kg) significantly enhanced retention of male Swiss mice tested 48 h after training in a one-trial step-through inhibitory avoidance task (0.8 mA, 50 Hz, 1 s footshock). Neither physostigmine nor OTM affected latencies to step through in mice not given the footshock on the training trial, suggesting that the effects of both cholinomimetics on retention performance were not due to nonspecific actions on response test latencies. The peripherally acting anticholinesterase neostigmine (35, 70, or 150 μg/kg) did not significantly influence retention latencies of either shocked or unshocked mice. The influences of physostigmine (150 μg/kg) and OTM (100 μg/kg) on retention were time-dependent, which suggests that the drugs facilitated memory storage. Administration of physostigmine (150 μg/kg) or OTM (100 μg/kg) 30 min prior to the retention test did not affect the retention performance of mice given post-training injections of either saline, physostigmine (150 μg/kg), or OTM (100 μg/kg). Considered together, these findings indicate that the memory-enhancing effects of post-training administration of physostigmine or OTM are not state-dependent and are consistent with the view that the behavioral effects of the cholinomimetics drugs are mediated through an interaction with the neural processes underlying the storage of acquired information.

Effects of cholinomimetics on cocaine-induced hypotension and apneusis at a ventral brainstem cardiorespiratory control site

The current study was undertaken to evaluate the effects of cholinomimetic drugs on cocaine-induced central cardiorespiratory depression. Cats anesthetized by urethane (2.0 g/kg) were subjected to topical application at the caudal ventrolateral medullary surface (cVMS) of cocaine and two cholinomimetic pretreatment drugs. The following drug regimens were tested: 37 mM cocaine 1) given alone; 2) given 5 min after 2.7 mM carbachol pretreatment; and 3) given 5 min after 3.6 mM physostigmine pretreatment. In 7 of 11 cats, pretreatment with physostigmine decreased the incidence of cocaine-induced apneusis and hypoventilation significantly (p < 0.05); these animals showed no significant change in the mean arterial blood pressure during the 5-min pretreatment before administration of cocaine. In 4 of 11 cats, the physostigmine pretreatment produced a significant decrease in mean arterial blood pressure followed by lethal cardiorespiratory arrest when cocaine was administered. Pretreatment with carbachol resulted in cardiorespiratory responses which were not significantly different from those produced by cocaine alone. In anesthetized cats not exhibiting hypotensive responses to physostigmine, pretreatment may ameliorate cocaine-induced respiratory failure by ventral brainstem control mechanisms.

Evidence for a central cholinergic effect of high‐dose thiamine

In vitro animal studies have suggested that thiamine is involved in the presynaptic release of acetylcholine. Total thiamine content in cholinergic nerve terminals is comparable with that of acetylcholine, and the phosphorylation state of thiamine changes with release of acetylcholine. Thiamine binds to nicotinic receptors and may exhibit anticholinesterase activity. Based on these observations, we investigated the effects of pharmacological doses of thiamine on the cognitive deficits induced by the anticholinergic scopolamine in healthy young adults using a randomized, double-blind, placebo-controlled, double-crossover design. Drug effects were assessed by P3 event-related potential, quantitated electroencephalography, and free recall memory. Conditions included (1) baseline, (2) thiamine 5 gm p.o. and scopolamine 0.007 mg/kg IM, and (3) lactose PO and scopolamine 0.007 mg/kg IM. Thiamine significantly reduced adverse effects of scopolamine on P3 latency, spectral components of electroencephalography, and memory recall. The results are consistent with a cholinomimetic effect of thiamine in the central nervous system. Additional studies are needed to delineate the basic mechanisms and possible therapeutic efficacy of thiamine at pharmacological dosages.

Actions of cholinergic agonists and antagonists on the efferent synapse in the frog sacculus

Intracellular recordings were made from hair cells in the frog saccular epithelium isolated with its innervating nerves. Inhibitory post-synaptic potentials (IPSPs) were recorded from hair cells when the efferent fibers were activated by electrical stimulation. The effects of acetylcholine (ACh), cholinomimetics, and cholinergic antagonists on the efferent synapse were studied in a preparation where the IPSPs can be observed directly. ACh or carbachol (CCh) produced a transient membrane hyperpolarization with a decrease in input resistance followed by an abolition or reduction of the IPSP. In a low Ca 2+ medium where efferent synaptic activity was abolished, ACh or CCh still induced hyperpolarization, though the response appeared to be smaller than that in normal medium. Neither nicotinic (dimethyl-4-phenyl-piperazinium (DMPP), phenyltrimethylammonium (PTMA) and nicotine) nor muscarinic (muscarine, methacholine, bethanechol and oxotremorine) agonists induced the membrane hyperpolarization, but the former drugs inhibited the IPSPs while the latter drugs did not. Both d-tubocurarine and atropine inhibited the IPSP, but the d-tubocurarine was more potent, causing inhibition even at a dose of 0.5 μM while 2 μM or more atropine was needed. The ACh- or CCh-induced hyperpolarization was inhibited completely by d-tubocurarine (5 μM), but only slightly by atropine (5 μM). These results may indicate that the IPSP and the effects of ACh or CCh are based a direct interaction between ACh or CCh and ACh receptors on the hair cells.

Elevated corticosteroid levels block the memory-improving effects of nootropics and cholinomimetics.

Oral pretreatment of mice with aldosterone or corticosterone blocked the memory-enhancing effects of piracetam, pramiracetam, aniracetam and oxiracetam in a dose-related manner, without, however, impairing the animals' learning performance. The improvement of memory induced by physostigmine, arecoline, and tacrine (THA) was similarly inhibited. The fact that elevated steroid levels suppress the memory-enhancing effects of entirely different substances could indicate that these substances have a common site of action. In the light of new observations showing increased cortisol concentrations in Alzheimer patients, this steroid dependency of the effects of memory enhancers might explain why only a limited number of these patients respond to therapy with nootropics or cholinomimetics.

Evaluation of a cholinomimetic drug, 9-amino-2,3,5,6,7,8-hexahydro-1h-cyclopenta [b] quinoline (NIK-247), as an enhancer of endogenous efflux of acetylcholine from brain slices

Basal and high K +-stimulated efflux of endogenous ACh from slices of brain was measured to evaluate the cholinomimetic effect of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b] quinoline monohydrate HC1 (NIK-247) on the central nervous system. The drug NIK-247 dose-dependently accelerated the efflux of ACh from slices of striatum. The maximum increase produced by 1.0 × 10 −4 M of NIK-247 was 329% in basal and 1332% in 30 mM K +-stimulated efflux. This drug was nearly twice as potent as THA (9-amino-l,2,3,4-tetrahydroacridine HC1) but had the same potency as physostigmine, in enhancing basal efflux, although there was no significant difference between the efficacy of these drugs in enhancing the K +-stimulated efflux. Both basal and 50 mM K +-stimulated efflux of ACh were increased by NIK-247, not only from the striatum but also from slices of frontal cortex and hippocampus. The activity was more effective in the striatum than in other tissues, and more effective on K +-stimulated than on basal efflux, regardless of the region of the brain. These effects of NIK-247 may be a result mainly of its inhibition of cholinesterase and its other biological characteristics, such as K + channel blockade, capable of modulating release of ACh, may not be of major importance.