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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is known that quinuclidinyl benzilate (QNB) binds specifically and with high affinity to the cholinergic muscarinic receptor and that behaves as a potent antagonist of this receptor. We have analysed L-[3H]QNB binding to rat CNS membranes after the administration of the convulsant 3-mercaptopropionic acid (MP) (150 mg.kg-1, i.p.). The studies were done in rats killed at two stages: during and after seizures. No changes in [3H]QNB binding to hippocampus and cerebral cortex membranes were found. [3H]QNB binding increased about 40 and 80% in striatum and cerebellum membranes, respectively. The changes were observed both in seizure and postseizures states. The study was extended to the assay of [3H]QNB binding kinetic constants in the anatomical areas modified by the convulsant. The analysis of the saturation curves indicated an increase in the binding affinity but no change in the number of binding sites. Hill number values were near the unit suggesting a non-cooperative interaction between the ligand and the receptor, and the labelling of a homogeneous population of receptor sites. The results suggest the participation of some cholinergic pathways in the development and maintenance of MP-induced seizures.
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PMID:3-mercaptopropionic acid administration increases the affinity of [3H]quinuclidinyl benzilate binding to membranes of the striatum and cerebellum. 130 74

Several model systems have been used to test the hypothesis that the release of FFA in the brain is regulated by depolarization of neurons. This FFA release is likely the result of the activation of phospholipase A2. The increased neuronal activity that occurs due to synchronous depolarization during seizures causes activation of phospholipase A2. Decreasing neuronal activity by administering the anxiolytic, diazepam, appears to decrease the activity of phospholipase A2. The GABA antagonist, bicuculline, which causes depolarization by negating the hyperpolarizing tone imposed on neurons by GABA, causes FFA release in synaptosomes and in neurons in tissue culture. Likewise, the glutamate agonist, kainic acid, which depolarizes neurons by opening sodium channels, increases the activity of phospholipase A2. PC-specific phospholipase C, another enzyme important in the generation of the second messenger, DG, is also activated by depolarization. Several important questions remain to be answered. The site of FFA release, in terms of the pre-vs. postsynaptic membrane, is not clear, although the experiments with synaptosomes support the hypothesis that activation of phospholipase A2 may be an important regulator of presynaptic events. This idea has also been suggested by studies on the phenomenon of long-term potentiation, where free 20:4 or its metabolites may be involved in presynaptic facilitation of neurotransmitter release (Freeman et al., 1990; Massicotte et al., 1990; Williams et al., 1989; also see Dorman, this volume). The activation of the PI cycle and subsequent stimulation of protein kinase C may be a postsynaptic event important in the integration of inputs at the dendrite and soma or a presynaptic event involved in the modulation of neurotransmitter release (Taniyama et al., 1990; El-Fakahany et al., 1990; also see Nishizuka, this volume). Therefore the stimulation of a PC-specific phospholipase C, which is capable of generating large amounts of DG over a prolonged period of time (Exton, 1990; Martinson et al., 1990; Diaz-Laviada et al., 1990), could occur at either site. Another important question is the role of FFA and DG in affecting cell-cell signaling events, particularly with regard to ion fluxes. Modulation of an acetylcholine-linked K+ channel in the heart by FFA and their oxygenation products has been reported (Kim and Clapham, 1989). The cardiac muscarinic receptor is linked to a hyperpolarizing K+ channel via a G protein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Reciprocal regulation of fatty acid release in the brain by GABA and glutamate. 135 87

Recent studies in this laboratory have demonstrated that intramuscular injection of the irreversible acetylcholinesterase (AChE) inhibitor, soman (pinacolylmethylphosphonofluoridate), produces a rapid (1-2 h) and profound depletion (70% of control) of norepinephrine (NE) in the olfactory bulb and forebrain. NE is decreased only in convulsing animals. As NE-containing locus coeruleus (LC) neurons provide the only NE input to the olfactory bulb and the major NE innervation of the forebrain, the reduction of NE suggests that soman may cause tonic activation of LC neurons leading to rapid depletion of NE. Activation of LC may result from: (i) facilitation of cholinergic transmission in LC; (ii) soman-induced activation of excitatory inputs to LC; or (iii) generalized activation of LC neurons due to seizures. The present experiments were designed to assess these alternatives. We examined whether LC neuronal activity, c-fos expression, and AChE staining are altered after peripheral (systemic) or direct intracoerulear injection of soman in anesthetized rats. Both modes of soman administration rapidly and potently increase the spontaneous discharge rate of LC neurons. This activation was associated with a desynchronization of the electroencephalogram, but not with seizures. The discharge of LC neurons remained elevated at all postsoman intervals examined (up to 2 h) and was rapidly and completely reversed by systemic injection of the muscarinic receptor antagonist scopolamine hydrochloride, but not by the nicotinic receptor antagonist mecamylamine. Both systemic and intracoerulear soman administration completely inhibited AChE staining in LC and rapidly induced the expression of c-fos in LC neurons. These results demonstrate that soman potently and tonically activates LC neurons. This effect appears to be mediated by direct inhibition of AChE in LC leading to a rapid accumulation of ACh. Unhydrolyzed ACh tonically activates LC neurons via muscarinic receptors. Soman-induced activation of LC neurons does not require seizures. We conclude that depletion of forebrain and olfactory bulb NE after systemic administration of soman results from tonic hypercholinergic stimulation of LC.
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PMID:Tonic activation of locus coeruleus neurons by systemic or intracoerulear microinjection of an irreversible acetylcholinesterase inhibitor: increased discharge rate and induction of C-fos. 138 4

The binding of [3H] quinuclidinyl benzilate (QNB) to rat striatum membranes after diisopropylfluorophosphate (DFP) induced seizures was characterized. There was a 36% decrease in Kd and a 33% decrease in the number of muscarinic receptors. Paraoxon caused inhibition fo [3H] QNB binding to the striatal membranes of intact rats. It is possible that a direct action of DFP on the muscarinic receptor is not the cause of anti-cholinesterase-induced changes in [3H] QNB binding.
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PMID:[Effects of diisopropylfluorophosphate, paraoxon and dichlophos on [3H] quinuclidinyl benzylate binding to the rat striatum synaptic membranes]. 147 63

Acetylcholine activates both nicotinic and muscarinic receptors in the central nervous system. Although the action of acetylcholine at muscarinic receptor has been well characterized, relatively little is known at the cellular level concerning nicotinic receptor stimulation in brain. Central nicotinic receptors have been implicated in Alzheimer's disease, seizure activity, the generation of slow-wave theta rhythm in the hippocampus and the potential abuse liability of nicotine. At the neuronal level, nicotinic agonists have been most often associated with postsynaptically mediated excitation and membrane depolarization at various sites, including Renshaw spinal motoneurons, locus coeruleus and the medial habenular nucleus. Nicotine acting presynaptically can produce either excitation or inhibition indirectly through the release of endogeneous transmitters or modulators. Whereas a direct inhibitory effect of nicotine has been suggested by one in vivo extracellular recording study in rat cerebellar Purkinje neurons, the mechanism(s) underlying this action is not yet known. We now report our findings obtained using in vitro intracellular methods in a submerged brain slice preparation in which application of nicotinic agonists to rat dorsolateral septal neurons reveal a direct membrane hyperpolarization mediated by an increase in potassium conductance.
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PMID:A direct nicotinic receptor-mediated inhibition recorded intracellularly in vitro. 279 67

This chapter reviews the chemical kindling model of epilepsy and speculates on its significance. Both human and experimental epilepsies are extremely heterogeneous, and it is unlikely that a single molecular or cellular mechanism can account for such a diversity of behavioral manifestations. Recent studies of chemical kindling favor the view that in this model, epilepsy is a property of neuronal networks that can take place in a structurally intact brain and does not depend on the presence of gross or microscopic brain damage. Kindling can be obtained by daily injections of nanomolar amounts of multiple muscarinic agonists in selective brain regions such as the amygdala and, once acquired, it is very persistent and frequently accompanied by spontaneous seizures. No evidence exists for creation of a novel pathway, and studies of seizure threshold suggest the need for a critical mass of neurons even on initial stimulation. The amounts of muscarinic agents injected are small enough to have little recordable effect initially, and the number of stimulations needed varies directly with the dose and inversely with the interstimulus interval. Carbachol kindling is inhibited by picomolar amounts of muscarinic antagonists, and the relative potencies of drugs on the kindling behavior in vivo parallel their affinity for muscarinic receptors in vitro. The (+) isomer of acetyl-beta-methylcholine, with good affinity for the muscarinic receptor, can induce kindling, whereas the (-) stereo isomer with poor affinity for the receptor cannot. No morphological differences are observed between animals injected with the (+) or the (-) isomer. These experiments suggest that the development of chronic focal epilepsy can take place in a structurally intact brain, be independent of the production of brain damage, and totally dependent on synaptic excitation. In other words, in this model, epilepsy may be a disease of cell-cell communication in which structurally normal neurons develop epileptiform responses as their interactions are modified through synaptic activation. A study of the relationships between carbachol and electrical kindling of the same site gave different results depending on the site of stimulation. In the amygdala, no interaction was found, but when both stimuli were aimed at the cholinoceptive hippocampal cells, a strong facilitation in both directions was observed. Thus, it appears that chemical and electrical kindling share similar mechanisms and that cross-facilitation depends on the existence of a common anatomy. The same anticonvulsants that block electrical kindling also inhibit chemical kindling.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synaptic mechanisms in the kindled epileptic focus: a speculative synthesis. 287 22

Seizure-experienced Genetically Epilepsy-prone Rats (GEPRs) have increased acetylcholine content and choline acetyltransferase activity in the thalamus and striatum. These cholinergic differences are accompanied by a slight but statistically significant reduction in acetylcholinesterase activity in the midbrain. In addition, no abnormalities were found in the numbers of specific 3H-QNB binding sites in the striatum, hippocampus, inferior colliculi or cortex. Other work has shown no difference in muscarinic receptor function as measured by carbachol-stimulated inositol-1-phosphate formation. These data suggest a possible presynaptic defect in the striatal and thalamic cholinergic system which may play some role in the seizure-prone state of the GEPR. However, caution must be used in interpreting these cholinergic derangements since more recent findings show no differences in thalamic acetylcholine content in seizure-naive GEPRs. Thus, the original cholinergic abnormalities detected in the seizure-experienced GEPR may be an enduring response to seizure activity.
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PMID:Abnormalities in the central cholinergic transmitter system of the genetically epilepsy-prone rat. 301 14

The generation of the spike-wave activity of Phase III of ECT seizures is attributed to the recurrence of synchronized, prolonged periods of intense inhibitory current flow (hyperpolarization), and associated rebound spike bursts, produced by the inhibitory circuit relationships and intrinsic electrophysiological properties of thalamic neurons. An anatomical and neurophysiological model of the development of generalized, synchronous 3-Hz spike-wave seizure activity is proposed which outlines the origin, maintenance, slowing, and termination of this fundamental seizure rhythm. Phase III inhibitory current flow (delta energy) and/or spike bursts may bring about therapeutic benefit by initiating a chain of agonist-independent and agonist-dependent events which results in long-term augmentation of serotonergic and noradrenergic neurotransmission and diminution of cholinergic neurotransmission in the forebrain. A specific anatomical and functional model of the mechanism of action of ECT is proposed, in which: (1) adrenergic and cholinergic pathways in the forebrain are assumed to be massively stimulated during ECT seizures, whereas serotonergic pathways are assumed to be inhibited during these seizures; (2) the beneficial effects of ECT are considered to be more dependent upon ECT-induced changes in 5-HT neurotransmission than upon alteration of noradrenergic function; (3) these beneficial effects involve up-regulation of 5-HT2 and down-regulation of M1- and M2-muscarinic receptor densities by both agonist-independent and agonist-dependent mechanisms, coupled with functional augmentation of noradrenergic neurotransmission; and (4) these effects may be brought about by Phase III inhibitory current flow- and/or spike burst-induced alteration of the function of second-messenger generator systems.
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PMID:The electroencephalographic pattern during electroconvulsive therapy: V. Observations on the origins of phase III delta energy and the mechanism of action of ECT. 306 Feb 88

The tottering mouse (tg/tg) is a single-locus mutant, phenotypically characterized by the development of epilepsy associated with distinct electroencephalographic abnormalities. Because of reported alterations in muscarinic receptor (mAChR) number in various seizure states, mAChR density was examined in discrete brain regions of tottering (tg/tg) and coisogenic wild-type (+/+) mice. Saturation binding experiments revealed a widespread decrease in membrane mAChR density in the CNS of adult tottering (tg/tg) mice as compared with age-matched control wild-type (+/+) mice. The decrease was most pronounced in the hippocampus, where tg/tg mice exhibited a 40-60% reduction in mAChR density with no change in the affinity of the receptor for antagonists or agonists. At postnatal day 10, before the reported onset of electroencephalographic abnormalities, 114 and 65% increases in mAChR density were observed in the tg/tg hippocampus and cortex, respectively. Following the development of seizure activity at postnatal day 22, mAChR density in the tg/tg hippocampus was reduced by 29%. No change in brain mAChR density was seen in adult heterozygotes (+/tg), which do not develop electroencephalographic or seizure abnormalities. These results indicate that the development of reduced mAChR number in the CNS of the tg/tg mouse is secondary to abnormal neuronal activity, providing further support for the hypothesis that membrane depolarization can cause a decrease in neuronal mAChR density.
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PMID:Decreased muscarinic acetylcholine receptor number in the central nervous system of the tottering (tg/tg) mouse. 395 Jun 15

Variables confounding efforts to interpret data on lithium's effects in laboratory animals in vivo and from in vitro muscarinic receptor binding studies are discussed. After accounting for the effects of these variables, the author concludes that it is of theoretical interest and heuristic value to hypothesize that lithium renders cholinergic systems more stable or less perturbable in the face of mono-aminergic overdrive. Thus lithium may diminish the propensity of cholinergic systems to undergo up-regulation and supersensitization consequent to exogenous and endogenous events apt to induce these changes. Lithium's antidepressant, antimanic, and anticycling efficacy may depend on its cholinotropic properties. The potential significance of lithium's cholinergic effects is highlighted by findings that seizures and verapamil induce similar cholinotropic effects. The author hypothesizes that with further investigation anticycling agents will come to be regarded as unique among psychotropics by virtue of their effects on cholinergic-monoaminergic interactions and mechanisms.
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PMID:Lithium's effects on muscarinic receptor binding parameters: a relationship to therapeutic efficacy? 609 11


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