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

The development of tolerance to hyperactivity produced by L-5-hydroxytryptophan (5-HTP) was studied in mice pretreated with the peripheral decarboxylase inhibitor MK-486. The results of Experiment I indicated that partial tolerance developed to 5-HTP given twice daily (i.p.) at a dose of 400 mg/kg, but not at a dose of 800 mg/kg. Sustained hyperactivity at the greater dose (800 mg/kg) apparently resulted from the induction of seizures and stereotypy rather than increased locomotor activity. When 5-HTP (400 mg/kg) or saline was administered three times daily (Experiments II and III), the locomotor activity of saline control groups did not differ significantly from chronic 5-HTP-treated groups, but both differed significantly from that of acute 5-HTP-treated animals. Cessation of treatments resulted in a recovery of 5-HTP-induced hyperactivity for experimental animals when later retested. These findings suggest that mice develop tolerance to the effects of 5-HTP on locomotor activity and agree with the hypothesis that behavior change is more closely correlated with the rate of change in concentration of neurotransmitters than the absolute concentrations.
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PMID:Tolerance to the increased locomotor activity produced by L-5-hydroxytryptophan following peripheral decarboxylase inhibition in mice. 41 44

1 The behavioural effects induced by histidine were studied in two species. In rabbits, sedation was assessed by the presence of blepharospasm, loss of righting reflex, and loss of response to painful stimuli. In mice, sedation and arousal were assessed by changes in the locomotor activity, exploratory activity, and minimal electroshock seizure threshold.2 The administration of histidine to normal rabbits or mice, in doses of 800 mg/kg and 1000 mg/kg respectively, had no apparent effect on behaviour. Moreover, it did not affect the behavioural excitation induced by L-DOPA (100 mg/kg i.v. in rabbits and 750 mg/kg i.p. in mice) in these animals.3 The administration of histidine with or after L-DOPA in reserpine-treated rabbits (2.5 mg/kg i.v.) or mice (5 mg/kg, i.p.) produced sedation. This sedative effect was dose-dependent.4 The sedative effects induced by histidine after DOPA-induced arousal in reserpine-treated rabbits and mice were prevented by prior injection of the histamine H(1)-receptor blockers, chlorpheniramine (2.5 mg/kg) or diphenhydramine (5 mg/kg).5 Imipramine (7 to 10 mg/kg, i.v.)-induced arousal in reserpine-treated rabbits was also reversed by histidine infusion.6 The infusion of 5-hydroxytryptophan (100 mg/kg, i.v.) with L-DOPA, or of arginine (450 mg/kg, i.v.) with or after L-DOPA, or of histamine (100 mug/kg), i.v.) after L-DOPA, did not affect the DOPA-induced arousal in reserpine-treated rabbits.7 These findings indicate that histamine, formed centrally from exogenous histidine, and released in increased amounts at the synapses in reserpine-treated animals, possesses a central sedative effect. This effect may be sufficient to antagonize the behavioural excitation induced by high levels of catecholamines in the brain of these animals when aroused by L-DOPA administration.8 It is concluded that in addition to the other monoamines, histamine may also be implicated in the regulation of brain excitability.
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PMID:Reversal of DOPA-induced arousal in reserpine-treated rabbits and mice by histidine. 76 Sep 4

1. The literature, both clinical and experimental, suggests that tricyclic antidepressants are potentially epileptogenic. Using the experimental model of epilepsy provided by the photosensitive baboon, Papio papio, the epileptic potential of four antidepressant drugs, two of which are tricyclic, has been assessed. The drugs used were imipramine 1, 10 and 20 mg/kg, chlorimipramine 1, 10 and 20 mg/kg, maprotiline 1 and 10 mg/kg and nomifensine 10 and 20 mg/kg. In a second series of experiments the 5-hydroxytryptamine (5-HT) precursor 5-hydroxytryptophan (5-HTP) 10 and 25 mg/kg has been administered before administration of imipramine 10 mg/kg and chlorimipramine 10 mg/kg. 2. The results of the experiments indicate that at 10 mg/kg imipramine, chlorimipramine and maprotiline all induce seizures and lower the seizure threshold. In contrast nomifensine at this dose did not alter the seizure threshold. 5-HTP 25 mg/kg administered before the antidepressants, abolished seizures. These results are discussed in the light of other experiments which have attempted to explain the pathophysiology of epileptic seizures following antidepressants, and it is concluded that dopaminergic mechanisms are probably responsible for the differing effect noted with nomifensine.
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PMID:Effect of nomifensine on brain amines and epilepsy in photosensitive baboons. 91 46

The degree of audiogenic seizure was measured in DBA/2J (phenylalanine hydroxylase deficient) mice as a function of dietary phenylalanine (Phe) and injected 5-hydroxytryptophan (5-HTP), the precursor of serotonin (5-HT). Phe was shown to exacerbate seizures significantly, and seizure severity was found to be directly related to dietary concentration when animals were not treated with exogenous 5-HTP. 5-htp was observed to significantly ameliorate seizures. The seizure-intensifying effect of Phe was reversible by 5-HTP injection and protection against seizures was directly related to 5-HTP concentration for animals on a high Phe diet. The results of this study indicate that Phe and 5-HTP are mutually antagonistic in modulating audiogenic seizure suceptibility.
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PMID:Effects of phenylalanine and 5-hydroxytryptophan on seizure severity in mice. 108 44

Mice with a genetically determined susceptibility to audiogenic seizures were utilized to analyze the ontogeny of central monoamine neurotransmission in relation to a behavior with age-specific properties. Levels of noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) were measured in forebrain and hindbrain regions at 14, 21, 28, and 42 days postnatal age in genetically sensitive or resistant strains of mice. An in vivo estimate of tyrosine and tryptophan hydroxylase activity was obtained at the same ages by following the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) respectively, after the administration of a centrally effective L-amino acid decarboxylase inhibitor (R04-4602, 800 mg/kg). At 14 days, there was a faster rate of accumulation of DOPA in both the forebrain and hindbrain of the sensitive mice compared to mice of the nonsensitive strain. At 21 days, the age of maximal sensitivity in the sensitive mice, the levels of NA were significantly lower in both regions of the sensitive mice, but the accumulation of DOPA was similar between strains at this age. There was also a slightly lower level of 5-HT in the forebrain of sensitive mice at 21 days accompanied by a slower rate of accumulation of 5-HTP in this region. In the hindbrain of the sensitive animals however, the rate of accumulation of 5-HTP was faster than in the sensitive strain. At 28 days, some impairment in mechanisms within NA-containing neurons in the sensitive mice was still apparent (including lower NA levels). At 42 days, there were no differences in amine levels, however, the levels of accumulated DOPA and 5-HTP were significantly lower in the sensitive strain. The results suggest that in the sensitive mice, developmental differences in mechanisms of monoamine storage and/or synthesis may exist which could contribute to deficient amounts of physiologically releaseable transmitter.
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PMID:Audiogenic seizures: relation to age and mechanisms of monoamine neurotransmission. 108 62

A myoclonic syndrome consisting of tremor, myoclonus, and seizures was produced following the systemic administration of 5-hydroxytryptophan to adult rats previously given intracisternal injections of 5,7-dihydroxytryptamine and systemic desmethylimipramine, but not in their controls. This behavioral response was blocked by pretreatment with the putative serotonin receptor blocking agents methysergide, lysergic acid diethylamide, and bromolysergic and diethylamide, as well as centrally effective doses of the aromatic amino acid decarboxylase inhibitor Ro4-4602. Blockers of receptors of other neurotransmitters had little effect. This neurologic response in the adult rat may be relevant to some forms of clinical myoclonus and may be useful in testing potential agonists and antagonists of serotonin receptors in the mammalian central nervous system.
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PMID:Myoclonus after 5-hydroxytryptophan in rats with lesions of indoleamine neurons in the central nervous system. 108 96

Tryptophan hydroxylase (TPH) activity was determined in whole brain from male C57BL/10/Bg and DBA/1Bg mice at 14 different ages between postnatal days 4 and 33. Brain TPH activity was higher at every age in C57BL/10/Bg than in DBA/1/Bg mice, the difference being 30-50% after day 20. The apparent Km of the enzyme for substrate was identical (1.4 X 10(-5) M) in both strains. The reciprocal F1's between DBA/1/Bg and C57BL/10/Bg strains were similar in TPH activity, being slighlty lower than the predicted midparental value. At 30 days of age, C57BL/6/Bg males also had high TPH activity, indistinguishable from the C57BL/10/Bg strain. Audiogenic seizure susceptibility in these strains and their hybrid F1's was inversely correlated with their brain TPH activities. These results indicate that seizure susceptibility and aggression in mice may be related to the serotonergic activity in the brain. In the case of seizures, ethanol-induced susceptibility to audiogenic seizures in mice was enhanced by reserpine, and the effect of reserpine could be reversed by 5-HTP but not by DOPA. Furthermore, p-chlorophenylalanine also enhanced such susceptibility, whereas alpha-methyltyrosine had no effect. In the withdrawal audiogenic seizures in mice during chronic ethanol treatment, adrenalectomy blocked the ethanol-induced increase of brain TPH activity and also prevented the withdrawal seizures. Our results are consistent with the hypothesis that the serotonergic system is among the components regulating excitability in the brain.
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PMID:Pharmacogenetic studies of the serotonergic system in association with convulsive seizures in mice. 124 14

Serotonin (5-HT) has been considered to possess an inhibitory action against the kindling development, but the role of 5-HT in kindled seizures is unclear. Furthermore, most previous studies have dealt with amygdaloid kindling. To clarify the role of the 5-HT system in epilepsy, we examined the effects of 5-hydroxytryptophan (5-HTP), a precursor which elevates brain 5-HT, and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT 1 a receptor agonist, on seizures kindled from the feline hippocampus (HIP). Following the completion of HIP kindling, five cats received 0.9% saline, 5-HTP (20 or 40 mg/kg, i.p.) or 8-OH-DPAT (0.1 or 1.0 mg/kg, i.v.). Drugs were administered 15 min (8-OH-DPAT) or 1 hr (5-HTP) prior to electrical stimulation at the generalized seizure triggering threshold, and the anticonvulsant effects were assessed by the behavioral seizure stage and afterdischarge (AD) duration. Both 5-HTP and 8-OH-DPAT suppressed dose-dependently HIP-kindled seizures. The administration of 5-HTP at 40 mg/kg and of 8-OH-DPAT at 1.0 mg/kg produced a marked or complete suppression of HIP-kindled seizures in most of the cats tested, and was found to significantly reduce the seizure stage when compared with the saline control. Both drugs tended to shorten the AD duration, but this effect did not reach statistically significant levels. The present data suggest that the 5-HT system plays an important role in HIP-kindled seizures, and that the 5-HT 1 a receptors have an inhibitory effect on the kindled focal epileptic activity of the HIP.
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PMID:[Serotonergic mechanisms in hippocampal kindled seizures--inhibitory effects of L-5-hydroxytryptophan and 8-hydroxy-2-(di-n-propylamino)tetralin]. 129 23

Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with benzodiazepines, and the discovery that many convulsants inhibited its synthesis, gamma-aminobutyric acid (GABA) has often appeared to be the key to epilepsy. Many assumed that "primary" or "genetic" epilepsy must be a disorder of GABA synapses and that GABA agonists would be universal anticonvulsants if permeability and drug metabolism were controlled. The GABA synthetic gene was a logical "candidate gene" for epilepsy. However, the GABA-deficiency theory of epilepsy is less convincing today. GABA agonists were found to intensify seizures in some rodent and human cases. Absence and other generalized seizures in humans often worsened when treated with GABA transaminase inhibitors such as gamma-vinyl-GABA. Surprisingly, the GABA transaminase inhibitors appear to be more useful in partial than in generalized epilepsies. Neuronal GABA uptake blockers are proconvulsant. GABA agonists aggravate seizures in several mutants, ranging from the photosensitive baboon to the genetically epilepsy-prone rat. How can this be understood? Muscimol injections into the pedunculopontine nucleus increase seizures due to systematically administered convulsants, while the receptor blocker bicuculline suppresses seizures after injection into several brain regions, including the striatum. The result of inhibiting inhibitory circuits is excitation. Studies with GABA uptake blockers and the GABAB agonist baclofen are presented in which their combined administration provoked seizures in rats. Baclofen was shown also to increase the incidence of seizures evoked by pentylenetetrazole without increasing seizures due to local injections of excitatory amino acids. Baclofen antagonized the myoclonic effect of 5-hydroxytryptophan in rats with serotonin lesions. Baclofen augments some seizures and inhibits others. Selective inhibition of a particular tract, whether GABAergic or not, may have convulsant or anticonvulsant effects, depending on its connections and the state of the organism. GABAA receptor stimulation is usually but not always anticonvulsant. GABAB receptor stimulation may facilitate absence seizures and related primary generalized seizures. GABAB receptors may be abnormal in some forms of nonfocal epilepsy seen in childhood. It is likely that mutations of GABA transporter and GABAA receptor genes will be found in humans but they will probably not be patients with "pure epilepsy."
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PMID:GABA and epilepsy: their complex relationship and the evolution of our understanding. 131 57

Tyrosine, tryptophan, and their metabolites in the brain of ddY, non-stimulated El (El (-)), and stimulated El (El (+)) mice were measured using the three dimensional HPLC. The tryptophan content was lower in El (+) than ddY and El (-) mice. The 5-hydroxytryptophan content was much higher in both El groups. The serotonin content of El (+) was higher than that of ddY and El (-) mice. The kynurenine content was remarkably high in the El mice. The dopamine content was lower in El (-) than in ddY mice, whereas it was greater in El (+) than in El (-) mice. The norepinephrine showed higher levels in El (+) mice. These facts suggest that El mice possess congenital metabolic abnormalities of tryptophan and tyrosine and that kynurenine may play an important role as convulsant in El mice seizures along with changes in serotonin, dopamine, and norepinephrine that are inhibitory agents and responded to the repetitive convulsions.
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PMID:Regional distribution of tyrosine, tryptophan, and their metabolites in the brain of epileptic El mice. 140 65


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