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

The intracerebral microdialysis technique has been used to monitor extracellular levels of noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat hippocampus in vivo in response to focal and generalized seizures induced by hippocampal kindling stimulation. In fully kindled animals a stimulus-induced generalized seizure gave rise to a three-fold increase of noradrenaline levels in the stimulated hippocampus as compared to baseline levels (15-min samples). The maximal increase of noradrenaline levels occurred within the first minutes after onset of seizure activity, as assessed in 2-min sample fractions with the noradrenaline uptake blocker desipramine added to the perfusion medium. After the peak increase, the noradrenaline levels tapered off, reaching baseline after 8-10 min. In 6-hydroxydopamine-treated animals, baseline noradrenaline levels were markedly reduced and there was no significant increase in noradrenaline release in response to a generalized seizure. These data support the hypothesis that the high extracellular levels of noradrenaline measured in seizures are of neuronal origin. There were no significant changes in extracellular 5-hydroxytryptamine or 5-hydroxyindoleacetic acid levels after a generalized seizure. In non-kindled animals the steady state noradrenaline levels during uptake blockade were two-three times higher than in the kindled rats. However, the peak noradrenaline levels measured in both hippocampi after the first two electrical kindling stimulations giving rise to focal epileptiform activity (afterdischarge) were similar to those observed in the kindled animals in response to generalized seizures. The increase of noradrenaline release in the non-kindled animals was significantly correlated to the duration of afterdischarge. In conclusion, the present study demonstrates the usefulness of the intracerebral dialysis technique for monitoring noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid release during seizures. The results indicate that both focal and generalized hippocampal seizures evoked by electrical kindling stimulation lead to a marked increase of transmitter release from noradrenergic but not from serotonergic neurons in the hippocampus. The ability of the noradrenergic system to respond by increased transmitter release to epileptic seizures is thus retained also in the kindled state.
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PMID:Noradrenaline and 5-hydroxytryptamine release in the hippocampus during seizures induced by hippocampal kindling stimulation: an in vivo microdialysis study. 248 Dec 43

The effect of clonidine, an alpha 2-agonist, on ischemia-induced alterations in brain catecholamine and metabolite levels was studied in Mongolian gerbils subjected to 180 min of unilateral cerebral ischemia. The gerbils were randomly assigned to four treatment groups: sham-operated or unilateral carotid lesion; each pretreated with clonidine 0.4 mg/kg IP, or untreated. All animals were neurologically assessed and categorized as asymptomatic, neurological deficit or seizure activity at the time of sacrifice. Hemispheric levels of noradrenaline (NA), dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured using high pressure liquid chromatography with electrochemical detection. No changes from control were found in animals that remained asymptomatic regardless of treatment. In untreated gerbils that exhibited neurological deficits, marked reductions in both NA and DA and increases in HVA occurred in the ischemic hemisphere. These alterations were greater in gerbils that developed seizures during the observation period. Ischemic animals pretreated with clonidine did not show any significant alterations in catecholamine or metabolite levels from clonidine-treated, sham-operated controls in spite of the presence of neurological deficits. Although significant reductions in NA and DA still occurred in pretreated animals that developed seizures, the changes were markedly less than in untreated gerbils. These results indicate that alpha 2-adrenoceptor stimulation is an effective approach for inhibition of ischemia-induced brain catecholamine alterations, and thus may provide a useful method for assessing the role of catecholamine release in the production of acute ischemic neuronal damage.
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PMID:Inhibition of ischemia-induced brain catecholamine alterations by clonidine. 253 95

We have reported previously an increase in the number of beta-adrenoceptors in mouse cerebral cortex 7 days after kindling of seizures by repeated once-daily administration of the benzodiazepine receptor inverse agonist, FG7142. In subsequent experiments, an even larger increase in beta-adrenoceptor number was found 7 days after a single injection of this compound. The present experiments investigated whether FG7142-induced changes in adrenoceptor binding are also found in the rat and whether the effects of a single and repeated injections of this drug differ quantitatively. In view of the anxiogenic effects of FG7142, we have also tested for parallel changes in behaviours associated with anxiety and exploration. Nine days after a single injection of FG7142, the number of beta-adrenoceptors in the cerebral cortex was greater than that found after repeated administration of this compound; this difference was statistically significant. There was no difference in beta-adrenoceptor binding to tissues from chronically FG7142-treated and vehicle-injected animals and there were no changes in alpha 2-adrenoceptor binding or noradrenaline levels after either a single or repeated FG7142 treatment. Neither single nor repeated FG7142 treatment modified spontaneous behaviour in either the elevated plus-maze test of anxiety or the holeboard test of exploration. The behavioural effects of yohimbine and clenbuterol in these tests were also unaffected by FG7142. We discuss the possibility that the difference in the effects of a single and repeated administration of FG7142 on beta-adrenoceptor binding is related to the expression of kindled seizures.
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PMID:Effects of a single or repeated administration of the benzodiazepine inverse agonist FG7142 on behaviour and cortical adrenoceptor binding in the rat. 254 72

Rats were subjected to hippocampal kindling with short interstimulus intervals (5 min), so-called rapid kindling. Severe depletion of forebrain noradrenaline (NA) with intraventricular 6-hydroxydopamine or blockade of alpha 2 adrenergic receptors with idazoxan markedly reduced the number of stimulations needed to induce the first severe limbic seizure and increased the total number of such seizures during 40 stimulations. Intracerebral microdialysis demonstrated a 3-fold increase of extracellular NA levels in response to the first kindling stimulations in both the stimulated and the non-stimulated hippocampus. The NA levels then gradually tapered off reaching baseline levels after 14 stimulations. We conclude that central noradrenergic neurons exert a powerful suppressant action, most probably mediated via an alpha 2 adrenergic receptor, on seizure development in rapid hippocampal kindling.
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PMID:Noradrenergic mechanisms in hippocampal kindling with rapidly recurring seizures. 256 12

We have investigated the influence of central noradrenergic and dopaminergic systems on the susceptibility of rats to seizures in the kainic acid (KA)-model of epilepsy. In the dose range of 0.75 to 10 mg/kg s.c., KA dose-dependently induced characteristic behavioural changes. Partial depletion of noradrenaline (NA) and dopamine (DA) in the brain by pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT; 250 mg/kg, i.p.) markedly potentiated KA-induced epileptic symptoms. A low dose of KA (1.5 mg/kg s.c.), which was ineffective in normal rats, triggered in AMPT-pretreated rats a high incidence of wet dog shakes (WDS) and a seizure activity (seizure rating: 3.17 +/- 0.31) which was comparable in degree to that resulting from 10 mg/kg KA in rats with normal catecholamine synthesis (seizure rating: 3.33 +/- 0.28). In AMPT-pretreated rats a higher dose of KA (10 mg/kg) further enhanced seizure activity and was associated with a mortality rate of up to 80%. Within 6.5 h after AMPT-pretreatment the levels of NA and DA in amygdala/pyriform cortex declined from 0.56 +/- 0.02 (control) to 0.23 +/- 0.01 ng/mg tissue and from 0.21 +/- 0.03 to 0.05 +/- 0.01 ng/mg tissue, respectively. At a dose of 1.5 mg/kg KA was ineffective on the levels of NA and DA in normal rats, but further reduced these levels in AMPT-pretreated rats to 0.08 +/- 0.02 and 0.020 +/- 0.004 ng/mg tissue, respectively. Induction of seizure activity and decline in NA and DA levels in amygdala/pyriform cortex after AMPT/KA (1.5 mg/kg) treatment was antagonized by the alpha-adrenoceptor agonist clonidine (0.1 mg/kg, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kainic acid-induced seizures: potentiation by alpha-methyl-p-tyrosine. 276 30

The anticonvulsant affects of bifemelane hydrochloride, a novel therapeutic drug for cerebrovascular dementia, were investigated in the kindling model of epilepsy in rats. The results obtained were as follows. (i) Both the seizure stage and afterdischarge duration of kindled seizures from the amygdala and hippocampus were significantly suppressed following systemic injection of bifemelane hydrochloride (5-30 mg/kg) in a dose-dependent manner. (ii) The efficacy of anticonvulsant action on kindled seizures from the hippocampus was more potent than from the amygdala. (iii) The maximum anticonvulsant effects were observed between 1 and 4 h after injection, and this time course was very similar to that of the previously reported increasing effects of bifemelane hydrochloride on noradrenaline levels in the rat brain. Thus, it is suggested that these anticonvulsant effects in kindling may be mediated by central noradrenergic systems. These results indicate that bifemelane hydrochloride has a potent anticonvulsant action on kindled seizures and may be useful for dementia patients with epilepsy or other seizure disorders.
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PMID:[Anticonvulsant effects of bifemelane hydrochloride on kindled seizures from the amygdala and hippocampus in rats]. 281 97

The influence of various substances modulating the activity of central noradrenergic, serotonergic or dopaminergic neurotransmission systems on the anticonvulsant effectiveness of phenobarbital (phenytoin, carbamazepine) was investigated in mice using the maximal electroshock seizure test (MES). The results demonstrated that especially the noradrenergic system might play a predominant role in modulating the efficiency of the standard antiepileptics tested. In general, pharmacological stimulation with different sympathomimetic drugs (e.g. methamphetamine, maprotiline, tranylcypromine, yohimbine) increased the anticonvulsant activity significantly. Conversely, pharmacological suppression of the noradrenergic system (e.g. 6-OHDA, phenoxybenzamine) reduced the activity of the antiepileptics. In contrast, some beta-receptor blockers with local anesthetic properties (e.g. propranolol, alprenolol, pindolol) were also able to enhance the protective effect of phenobarbital in higher concentrations. The influence of manipulations of serotonergic mechanisms was not so pronounced. However, substances such as 5-HTP, clomipramine, citalopram, zimelidine, showed also additive anticonvulsive effects. On the other hand, the dopaminergic system seemed to exert no significant influence in this respect. These findings give further support to the view that the noradrenergic system may play a remarkable role via the inhibitory function of noradrenaline in the CNS in suppression of epileptic activity and reveal also interesting aspects for a possible comedication in convulsive disorders.
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PMID:Pharmacological modulation of central monoaminergic systems and influence on the anticonvulsant effectiveness of standard antiepileptics in maximal electroshock seizure. 284 28

The purpose of this paper was to study the relationship between different neurotransmitter systems and seizure susceptibility in Mongolian gerbils with genetically determined epilepsy. In these animals, generalized tonic-clonic seizures were induced by stimulation with a blast of compressed air. A variety of drugs that specifically manipulate inhibitory or excitatory neurotransmitter systems proved capable of dose dependently blocking these seizures, i.e., the anticholinergic drug biperiden (ED50 12 mg/kg i.p.), the excitatory amino acid antagonist (+/-)-2-amino-7-phosphonoheptanoic acid (120 mg/kg), the gamma-aminobutyric acid (GABA) agonists muscimol (0.66 mg/kg), 4,5,6,7-tetrahydroisoxazolo(5,4-c) pyridine-3-ol (1.3 mg/kg), progabide (50 mg/kg) and its acidic metabolite SL 75102 (45 mg/kg), the GABA aminotransferase inhibitors aminooxyacetic acid (0.9 mg/kg), gamma-acetylenic GABA (2.1 mg/kg) and ethanolamine-O-sulfate (1000 mg/kg), the GABA uptake inhibitor (-)-nipecotic acid ethyl ester (21 mg/kg), the dopamine agonist apomorphine (approximately 5 mg/kg), the dopamine precursor 3,4-dihydroxy-L-phenylalanine (34 mg/kg), and the alpha-adrenoceptor agonists clonidine (0.38 mg/kg) and xylazine (approximately 10 mg/kg). The anticonvulsant effect of 3,4-dihydroxyl-L-phenylalanine was not significantly affected by pretreatment with the dopamine-beta-hydroxylase inhibitors disulfiram and diethyldithiocarbamate, thus strongly indicating that 3,4-dihydroxyl-L-phenylalanine was acting through increase in dopamine rather than noradrenaline levels in the brain. The (+)-isomer of nipecotic acid ethyl ester, the glycineamide derivative milacemide, the indirect 5-hydroxytryptamine agonist fenfluramine and the 5-hydroxytryptamine antagonist ketanserin exerted no anticonvulsant action. The 5-hydroxytryptamine precursor L-5-hydroxytryptophan and the dopamine agonist lisuride were only weakly active but exerted pronounced side effects in the animals. Weak anticonvulsant effects were also determined for atropine, the noradrenaline precursor DL-threo-3,4-dihydroxyphenylserine and the excitatory amino acid antagonist (+/-)-2-amino-5-phosphonopentanoic acid. Comparison of anticonvulsant potencies of the various drugs in gerbils with potencies reported in other genetic animal models of epilepsy, such as audiogenic seizure-susceptible mice, indicated that drugs that increase GABA and dopamine levels in the brain are strikingly more effective in gerbils than in other species in blocking generalized seizures.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Influence of pharmacological manipulation of inhibitory and excitatory neurotransmitter systems on seizure behavior in the Mongolian gerbil. 285 79

Norepinephrine concentrations and tyrosine hydroxylase activity were determined in the brains of moderate-seizure and severe-seizure genetically epilepsy-prone rats (GEPRs) and in nonepileptic control rats. Both moderate-seizure (GEPR-3) and severe-seizure (GEPR-9) animals had widespread abnormalities in brain norepinephrine concentrations. Abnormalities in tyrosine hydroxylase activity were restricted to the midbrain. The state of abnormal seizure susceptibility, but not severity, in the GEPR may be determined by noradrenergic deficits in the hypothalamus/thalamus. Both seizure severity and susceptibility may be determined by noradrenergic deficits in the telencephalon, midbrain, and pons-medulla. Seizure severity but not susceptibility may be determined by noradrenergic abnormalities in the cerebellum.
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PMID:Indices of noradrenergic function in the central nervous system of seizure-naive genetically epilepsy-prone rats. 287 67

From the data discussed in this review it appears that GABA receptor agonists exhibit a variety of actions in the central nervous system, some of which are therapeutically useful (Table V). GABA receptor agonists, by changing the firing rate of the corresponding neurons accelerate noradrenaline turnover without changes in postsynaptic receptor density and diminish serotonin liberation with an up-regulation of 5HT2 receptors. These effects differ from those of tricyclic antidepressants which primarily block monoamine re-uptake and cause down-regulation of beta-adrenergic and 5HT2 receptors. The GABA receptor agonist progabide has been shown to exert an antidepressant action which is indistinguishable from that of imipramine in patients with major affective disorders. The fact that: (a) GABA receptor agonists and tricyclic antidepressants affect noradrenergic and serotonergic transmission differently; and (b) tricyclic antidepressants alter GABA-related parameters challenges the classical monoamine hypothesis of depression and suggests that GABA-mediated mechanisms play a role in mood disorders. Decreases in cellular excitability produced by GABAergic stimulation leads to control of seizures in practically all animal models of epilepsy. GABA receptor agonists have a wide spectrum as they antagonize not only seizures which are dependent on decreased GABA synaptic activity but also convulsant states which are apparently independent of alterations in GABA-mediated events. These results in animals are confirmed in a wide range of human epileptic syndromes. GABA receptor agonists decrease dopamine turnover in the basal ganglia and antagonize neuroleptic-induced increase in dopamine release. On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics. Behaviorally, GABA receptor agonists diminish the stereotypies induced by apomorphine or L-DOPA suggesting that GABAergic stimulation results also in an antidopaminergic action which is exerted beyond the dopamine synapse. These effects of GABA receptor agonists may represent the basis of the antidyskinetic action of these compounds which, however, remains to be fully confirmed. GABA receptor agonists reduce striatal acetylcholine turnover, an effect which occurs at doses much lower than those which affect dopamine neurons. Since hyperactivity of cholinergic neurons plays a determinant role in the pathogenesis of some parkinsonian symptoms, it is conceivable that GABAergic stimulation is effective in ameliorating Parkinson's disease.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:GABA receptor agonists: pharmacological spectrum and therapeutic actions. 298 90


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