Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Picrotoxin, 2 mg/kg i.p., a GABA receptor blocking agent, increased rat striatal acetylcholine content by approximately 70% without altering the levels of this amine in the cerebral hemispheres, mesencephalon, diencephalon, hippocampus and cerebellum. Striatal choline levels were concomitantly decreased by about 25%. This dose of picrotoxin also increased striatal homovanillic acid levels by about 30%, an effect which was not antagonized by pretreatment with the dopamine receptor stimulating agent, piribedil. Picrotoxin did not affect striatal choline-O-acetyltransferase or cholinesterase activity after in vitro incubation. The action of picrotoxin on striatal acetylcholine levels was partially antagonized by pimozide and completely blocked by alpha-methyl-para-tyrosine pretreatment while the intraventricular injection of 6-hydroxydopamine was without effect. Convulsions were not prevented by any of these treatments. The results are interpreted as follows: picrotoxin released dopamine through disinhibition of the dopaminergic neurons as a result of blockade of gabergic receptors. The increased dopaminergic activity inhibited cholinergic neurons and lead to an increase in acetylcholine content. The data thus provide evidence for a possible gabergic (inhibitory)--dopaminergic (inhibitory)-cholinergic link terminating in the striatum.
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PMID:Increase in striatal acetylcholine by picrotoxin in the rat: evidence for a gabergic-dopaminergic-cholinergic link. 94 12

The behavioral effects of GABAergic manipulation of the basal forebrain were investigated using two behavioral tasks, which previous studies have shown to yield dissociable effects following quisqualate-induced lesions of the basal forebrain: a five-choice serial reaction time task, involving approaching the location of a brief visual stimulus that is associated with reward; and a conditional visual discrimination task, requiring retrieval of information about a discriminative stimulus that stays constant over time. Following acquisition of the tasks, chronic guide cannulae were stereotaxically implanted into the basal forebrain. Those animals trained on the conditional visual discrimination task showed a dose-dependent reduction in choice accuracy and a lengthening of latency to respond correctly to the visual stimulus following administration of the GABA-A agonist, muscimol (1, 2, 3 ng/microliters/hem). While certain of these deficits, for example response latency, could be restored to control levels by co-administration of the GABA-A antagonist, bicuculline, none of the behavioural impairments could be significantly attenuated by systemic by systemic co-administration of the cholinesterase inhibitor, physostigmine (0.05, 0.1, 0.2 mg/kg, IP). Similarly, a dose dependent effect of muscimol (1, 1.5, 2 ng/microliters/hem) on choice accuracy and correct response latency was observed on performance of the five-choice attentional task. However, in contrast to the conditional task, significant attenuation of the impairment in choice accuracy was obtained following administration of physostigmine (0.05 and 0.1 mg/kg). Attenuation of muscimol-induced deficits by administration of bicuculline was also observed. It is therefore evident that although manipulation of GABAergic activity in the region of the basal forebrain produces profound deficits in different tasks of cognitive function, only some of these may be due to modulation of the magnocellular cholinergic projection to the neocortex.
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PMID:Disruptive effects of muscimol infused into the basal forebrain on conditional discrimination and visual attention: differential interactions with cholinergic mechanisms. 160 98

Heritable neurodegenerative diseases may be associated with one or more endogenous neurotoxins whose actions on neurons lead to the degenerative changes. One metabolite of tryptophan, the amino acid L-kynurenic acid (L-KYN), was chronically injected into the striatum of the male rat to test its potential as an endogenous neurotoxin. L-KYN, at concentrations of approximately five times its normal brain levels, produced a large lesion with relative selective neuron sparing. The L-KYN-induced lesion presented three concentric regions: a central necrotic zone, a thin pyknotic zone, and an outermost spongiose zone. The number of GABA-ergic neurons were markedly reduced (approximately 76%), while cholinesterase-positive neurons were also lost. The NADPH diaphorase-positive neurons were the most resistant to L-KYN neurotoxicity and were spread throughout the spongiose zone. The brain levels of L-KYN are abnormal in patients with the neurodegenerative disorder Huntington's disease and as a neurotoxin L-KYN may play a role in the etiology of this disease. Of further significance, the fact that L-KYN is neurotoxic contraindicates the use of this excitatory amino acid receptor antagonist as a therapeutic agent in the treatment of neurodegenerative disorders.
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PMID:Chronic intrastriatal injection of the excitatory amino acid receptor antagonist L-kynurenic acid in rat produces selective neuron sparing lesions. 173 68

The hypothesis that the cognitive decline in senile dementia is related to the loss of cortical cholinergic afferent projections predicts that pharmacological manipulations of the remaining cholinergic neurons will have therapeutic effects. However, treatment with cholinesterase inhibitors or muscarinic agonists has been, for the most part, largely unproductive. These drugs seem to disrupt the normal patterning of cholinergic transmission and thus may block proper signal processing. An alternative pharmacological strategy which focuses on the amplification of presynaptic activity without disrupting the normal patterning of cholinergic transmission appears to be more promising. Such a strategy may make use of the normal GABAergic innervation of basal forebrain cholinergic neurons in general, and in particular of the inhibitory hyperinnervation of remaining cholinergic neurons which may develop under pathological conditions. Disinhibition of the GABAergic control of cholinergic activity is assumed to intensify presynaptic cortical cholinergic activity and to enhance cognitive processing. Although the extent to which compounds such as the benzodiazepine receptor antagonist beta-carboline ZK 93,426 act via the basal forebrain GABA-cholinergic link is not yet clear, the available data suggest that the beneficial behavioral effects of this compound established in animals and humans are based on indirect cholinomimetic mechanisms. It is proposed that an activation of residual basal forebrain cholinergic neurons can be achieved most physiologically via inhibitory modulation of afferent GABAergic transmission. This modulation may have a therapeutic value in treating behavioral syndromes associated with cortical cholinergic denervation.
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PMID:Activating the damaged basal forebrain cholinergic system: tonic stimulation versus signal amplification. 216 Jun 62

The effects of intracerebroventricular injection of gamma-Aminobutyric acid, muscimol, or picrotoxin have been studied on butyrylcholinesterase (BuChE) activities in the serum and several hypothalamic nuclei using biochemical, histochemical, and cytophotometric techniques, respectively. The blood samples were withdrawn from indwelling catheters in jugular vein 1, 15, 30, 45, 60, 90, and 120 min after injection of the drugs. Biochemical estimations demonstrated a significant inhibition of BuChE after GABA and muscimol injections, whereas a pronounced stimulation of BuChE was observed after injection of picrotoxin. The peak changes were observed within 30 min of drug injection. Cytophotometric studies have appeared to dovetail the biochemical findings. Only a marginal decrease was observed after injection of GABA in all nuclei, while muscimol induced a very conspicuous decrease of BuChE. On the contrary, intracerebroventricularly administered picrotoxin markedly increased the levels of BuChE activity. Thus it could be concluded that probably GABA and muscimol along with picrotoxin appear to alter BuChE.
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PMID:Butyrylcholinesterase fluctuation in male albino rats with intracerebroventricular injection of gamma aminobutyric acid, muscimol, and picrotoxin. 232 58

This study sought to determine whether release of acetylcholine (ACh) within the C1 area of nucleus reticularis rostroventrolateralis (RVL) contributes to the tonic maintenance of arterial pressure (AP) in the rat. The activity of choline acetyltransferase (ChAT), the biosynthetic enzyme for ACh, varied 5.5-fold in micropunches of the 6 medullary regions examined. ChAT activity in the C1 area (179 +/- 35 nmol [14C]ACh formed/mg protein/60 min; n = 4) was intermediate between that of the hypoglossal nucleus (249 +/- 38; highest) and the pyramids (45 +/- 11; lowest) and equivalent to that found in the parietal cortex (147 +/- 15). Release of [3H]ACh from C1 area micropunches was increased by raising extracellular K+ concentrations (5-55 mM) and was entirely Ca2(+)-dependent. Muscarinic receptor binding density was assessed using [3H]quinuclidinyl benzylate ([3H]QNB) as ligand and a recently developed 'electronic micropunch' technique which allows measurement of quench-corrected [3H]QNB binding within corresponding cylinders of tissue obtained by the mechanical micropunch cannula. [3H]QNB binding density varied 2.6-fold: lateral reticular nucleus pars lateralis greater than C1 area greater than nucleus ambiguus = hypoglossal nucleus = pyramid = oral spinal trigeminal nucleus. In urethane-anesthetized rats, inhibition of ACh synthesis by hemicholinium-3 (HC-3, 3 nmol/50 nl), or blockade of muscarinic receptors by scopolamine (SCOP, 3 nmol/50 nl), reduced resting mean AP by 18-24 mm Hg following bilateral microinjection into the C1 area. These concentrations of HC-3 and SCOP were sufficient to attenuate by 70-80% the increase in local cholinergic neurotransmission elicited by the cholinesterase inhibitor physostigmine given systemically. High concentrations of SCOP (30-150 nmol/50 nl) lowered AP by 46-60 mm Hg. Similarly, bilateral microinjections of GABA (10 nmol/50 nl) into the C1 area markedly reduced mean AP by 51 +/- 6 mm Hg to levels normally found after transection of the spinal cord. Thus, a substantial portion of tonic sympathetic activity may be driven by activation of muscarinic receptors in the C1 area. In the spontaneously hypertensive rat (SHR), a genetic model of hypertension, neither spontaneous nor K(+)-evoked release of [3H]ACh from the C1 area differed from that of normotensive Wistar-Kyoto rats (WKY).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synthesis, release and receptor binding of acetylcholine in the C1 area of the rostral ventrolateral medulla: contributions in regulating arterial pressure. 233 21

Effect of injection in third ventricle of GABA, the GABA agonist muscimol, and the GABA antagonist picrotoxin on the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidase (MAO) in serum and succinic dehydrogenase (SDH) in plasma has been studied. Surprisingly, the AChE, BuChE, MAO and SDH enzymes activity were inhibited by GABA and muscimol, while they were enhanced by picrotoxin.
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PMID:Effect of GABA, muscimol and picrotoxin given in third ventricle on serum cholinesterases and monoamine oxidase and on plasma succinic dehydrogenase in rats. 262 Sep 59

In the present study, the effect of intracerebroventricular (icv) injection of GABA, its agonist--muscimol, and antagonist--picrotoxin, has been studied on histoenzymological alterations of acetylcholinesterase (AChE). butyrylcholinesterase (BuChE), monoamine oxidase (MAO), and succinic dehydrogenase (SDH) by cytophotometric technique. This study was conducted on medial preoptic area (mPOA), nucleus paraventricularis hypothalami (PVH), area lateralis hypothalami (LHA), nucleus dorsomedialis hypothalami (DMH), and nucleus ventromedialis hypothalami (VMH). Results showed that GABA and muscimol inhibited AChE, BuChE, MAO, and SDH in all the areas while picrotoxin stimulated these enzymes. These changes in enzyme activity by GABA, muscimol, and picrotoxin and their possible mode of action are discussed.
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PMID:Centrally administered GABA and GABA-selective agonist and antagonist in rats: histoenzymological cytophotometric study. 280 37

The pharmacologic effects of benzodiazepines may be counteracted either by functional antagonists like physostigmine acting via cholinergic mechanisms or by competitive antagonists like flumazenil (Ro 15-1788) acting via GABAergic mechanisms (GABA = Gamma-AminoButyric Acid). The lipophilic choline esterase inhibitor physostigmine adjusts a relatively or absolutely decreased concentration of acetylcholine at central cholinergic synaptic sites. As the neuronal network is very complex, many lipophilic compounds may cause a central anticholinergic syndrome even if they primarily do not affect cholinergic but, like benzodiazepines, GABAergic synaptic sites. Prolonged and/or adverse effects of such drugs may therefore be treated with 1-2 mg physostigmine at a maximal rate of 1 mg/min. The onset of physostigmine action can be expected within 2-20 min. Furthermore, the benzodiazepine action can very effectively be counteracted by the specific antagonist flumazenil. It could be demonstrated in volunteer and clinical studies that the hypnotic effect of benzodiazepines could be antagonized within 1-2 min. However, the minimal duration of action proved to be about 2 h as could be demonstrated by clinical observations, EEG-studies and psychometric tests. In clinical practice, a flumazenil dose of 0.3-0.8 mg proved to be the optimal dose range. The indication to treat unwanted central effects of benzodiazepines either with flumazenil or with physostigmine after anaesthesia should be restricted to cases of distinctly prolonged sedation after adequate dosage or adverse side effects. In intensive care, special indications for flumazenil and/or physostigmine may result after high benzodiazepine dosage or to differentiate a coma of undefined origin if centrally acting drugs including benzodiazepines are involved.
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PMID:Flumazenil (Ro 15-1788) and physostigmine. 284 77

The role of cholinergic and GABAergic neuronal systems on the cycloheximide (CXM)-induced amnesia was investigated using the step-down-type passive avoidance task in mice. CXM (7.5-120 mg/kg, SC) given just after the training caused amnesia (indicated by short latency to step down from the platform on the grid floor) in the retention test conducted 24 hr later in a dose-dependent fashion. In the CXM (60 mg/kg)-treated mice, a choline esterase inhibitor, physostigmine (PHY; 0.125 and 0.25 mg/kg, IP), or GABA agonists, muscimol (1 and 2 mg/kg, IP) and baclofen (6 and 12 mg/kg, IP), given just after training markedly prolonged step down latency (SDL), indicating reversal of amnesia. The antiamnesic action of PHY (0.125 mg/kg) was almost completely antagonized by a central acetylcholine antagonist, scopolamine (3 mg/kg, SC), but not by a peripheral acetylcholine antagonist, butylscopolamine (3 mg/kg, SC). Furthermore, the antiamnesic action of muscimol (2 mg/kg) was reversed by GABA antagonists, picrotoxin (0.5 mg/kg, SC) and bicuculline (0.5 mg/kg, SC), while the effect of baclofen (12 mg/kg) was reversed by picrotoxin (0.5 mg/kg), but not by bicuculline (0.5 mg/kg). These results suggest that the dysfunction of cholinergic and GABAergic neuronal systems play an important role in the CXM-induced memory impairment on the passive avoidance task.
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PMID:Role of cholinergic and GABAergic neuronal systems in cycloheximide-induced amnesia in mice. 285 64


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