Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of chronic ethanol treatment to alter CNS membrane lipids was tested. Adult C57/BL6 mice were given a liquid diet containing ethanol for eight days. This regimen produced strong physical dependence as judged by withdrawal seizures, tremors and concomitant hypothermia. Analyses were performed on cholesterol, total phospholipid content and total phospholipid acyl composition of myelin, crude (P2), light and heavy synaptosomes as well as synaptosomal plasma membranes. Chronic ethanol treatment had no effect on total phospholipid levels nor phospholipid acyl composition in any of the above subcellular fractions. In ethanol dependent mice, significant increases in cholesterol content and cholesterol/phospholipid ratios were observed in synaptosomal plasma membranes.
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PMID:Alterations in brain lipid composition of mice made physically dependent to ethanol. 689 Jun 13

The periodic administration of convulsive agents, even at doses or intensities that initially have no convulsive effect, can lead to a progressive and enduring increase in the susceptibility to subsequent convulsive stimulation. This kindling effect has contributed to the understanding of the convulsive effects of alcohol withdrawal in three ways. First, rats kindled by the periodic application of electroconvulsive shock, local brain stimulation, or pentylenetetrazol were found to be hypersusceptible to the convulsive effects of subsequent alcohol withdrawal, thus raising the possibility that some forms of electrical or pharmacological therapy can potentiate the alcohol withdrawal syndrome in humans. Second, the duration of seizures elicited in kindled rats has been used as a sensitive index of convulsive withdrawal effects; increases in the duration of kindled motor seizures and afterdischarges can be detected following the metabolism of a single intoxicating injection of ethanol. Third, it was suggested that the potentiation of the convulsive effects of alcohol exposure and withdrawal by prior episodes of alcohol withdrawal may reflect a kindling-like process rather than an increase in physical dependence.
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PMID:Alcohol withdrawal seizures: implications of kindling. 701 61

This study was designed to assess the strain differences in pentobarbital toxicity, narcosis, the development of tolerance and physical dependence, the half-life of pentobarbital and the activities of hepatic microsomal electron transfer chain in DBA/2J, C57BL/6J and ICR mice. The comparisons of responses to acute pentobarbital-induced narcosis with two different doses revealed that DBA was most sensitive among these strains. When continuous administration of pentobarbital by pentobarbital pellet implantation is concerned, four criteria were used to assess strain differences: 1) determination of the duration of the loss of righting reflex during pentobarbital pellet implantation; 2) cumulative mortality after pentobarbital pellet implantation; 3) degree of tolerance development after 3 days of s.c. implantation of a 75-mg pentobarbital pellet by the relative decrease in the pentobarbital sleeping time; and 4) assessment of hyperexcitability by pentylenetetrazol- and audiogenic-induced seizures after pellet removal. The order of susceptibility to continuous pentobarbital pellet implantation was found to be as follows: DBA/2J > C57BL/6J > ICR. The biochemical data also revealed that the half-life of pentobarbital in DBA/2J mice was significantly longer than that of C57BL/6J or ICR mice in both brain and serum. Further studies also showed that DBA/2J mice have lower hepatic cytochrome P-450 and cytochrome b5 levels and NADPH dehydrogenase and NADPH-cytochrome c reductase activities as compared with the other strains of mice. However, these parameters were markedly induced in DBA/2J mice after the development of tolerance to pentobarbital. It appears that the differences in genetic variation could be of importance for further studies in gaining insight of the mechanism of barbiturate tolerance and dependence.
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PMID:Pharmacological responses to pentobarbital in different strains of mice. 719 35

Tests were performed on 60 HS mice to determine preference for ethanol before and after a period of forced ethanol ingestion via a liquid diet treatment. Seizure scores measured 4, 5 and 6 h after the end of the liquid diet treatment showed that moderate degrees of physical dependence had developed. Statistical analyses revealed a significant sex difference only for the amount of ethanol consumed during the liquid diet treatment, with females drinking more than males (on a g/kg basis). Correlation analyses indicated that preference for ethanol was not related to seizure severity or to amount consumed during the liquid diet treatment. A significant drop in preference after ethanol withdrawal was observed when pre- and post-withdrawal preference ratios were compared. These findings are discussed in the context of the usefulness of preference for ethanol as a predictor of alcoholism.
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PMID:Lack of association between preference for and dependence on ethanol. 720 79

The use of benzodiazepines (BDZs) in the long-term treatment of epilepsy is greatly restricted by their capacity to induce tolerance and dependence. Thus, the development of new BDZ-related therapeutic agents should be directed by strategies that minimize tolerance- and dependence-inducing properties. Experimental procedures used to determine the success of such strategies often rely on a single assay procedure (e.g., one seizure model), which might lead to false predictions. Furthermore, the different types of tolerance, i.e., "pharmacological" (metabolic or functional) and "behavioral" ("learned" or "contingent"), are often not dealt with in such studies. This prompted us to compare the chronic anticonvulsant efficacy and withdrawal characteristics of diazepam and two novel BDZ receptor ligands, i.e., the partial agonist bretazenil and the subtype-selective agonist abecarnil, in different seizure models in mice. Myoclonic, clonic and tonic seizures were induced by i.v. infusion of pentylenetetrazol and by transcorneal or transauricular application of electrical stimuli. Prolonged administration of diazepam (5 mg/kg twice daily for 6 days) resulted in marked anticonvulsant effects on myoclonic, clonic and tonic seizure thresholds at the onset of treatment, but pronounced tolerance developed rapidly during subsequent treatment. The time course and extent of tolerance was similar with most seizure models. Tolerance characteristics were not affected by study design, i.e., use of separate or the same animals for each seizure induction, indicating that learned or contingent tolerance was not significantly involved under these experimental conditions. After termination of treatment with diazepam, significant seizure threshold decreases were determined, indicating withdrawal hyperexcitability in response to physical dependence. During prolonged administration of abecarnil (10 mg/kg twice daily for 6 days), some anticonvulsant tolerance was seen with electroshock seizures, but not with pentylenetetrazol seizures; no withdrawal hyperexcitability was determined upon termination of treatment. Bretazenil (10 mg/kg twice daily for 6 days) produced no tolerance in any of the seizure models, but a significant decrease in electroshock seizure threshold was seen in the withdrawal period. The data indicate that tolerance and withdrawal characteristics of BDZ receptor partial and subtype-selective agonists in mice depend on the experimental model used, whereas the influence of the experimental protocol is less critical in the case of a full BDZ receptor agonist such as diazepam.
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PMID:Anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. Comparison of diazepam, bretazenil and abecarnil. 747 56

The rates of in vitro release of flunitrazepam (FN), nordiazepam (ND) and diazepam (DZ) from silastic capsules were compared and found to be in the following order: DZ > FN > ND. Rats that were implanted subcutaneously with capsules filled with FN or ND for 5 to 7 weeks before administering flumazenil (FLU) (40 mg/kg, i.v.) showed precipitated abstinence as measured by the Precipitated Abstinence Score (PAS) which included a rapid onset of clonic and tonic-clonic convulsions. Rats implanted with DZ also demonstrated significant PAS and seizures. Implantation of similar doses of DZ, FN and ND resulted in different plasma levels of parent benzodiazepines and their metabolites that corresponded with their in vitro release: DZ > FN > ND. These data indicate that, as for DZ, the capsule implantation is an effective method of producing physical dependence on FN and ND in the rat.
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PMID:Flunitrazepam and nordiazepam slowly released from silastic capsules induce physical dependence in rat. 758 76

The effects of calcium channel inhibitors on ethanol intake and dependence in Wistar rats were studied. Nifedipine and isradipine were suspended in 1% Tween 40 saline solution and administered ip 60 min prior to testing. Audiogenic seizure response evaluation was performed after 5 days of ethanol treatment. Both nifedipine and isradipine significantly reduced the intensity score of convulsions and, in doses of 2.5 and 5.0 mg/kg, respectively, abolished them. Both drugs significantly reduced ethanol preference and intake in the high preference group of animals. Our results support the observations that certain dihydropyridine derivatives are capable of attenuating both ethanol preference and physical dependence.
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PMID:Comparative study of nifedipine and isradipine in animal models of ethanol dependence. 811 82

We have shown previously that the dihydropyridine calcium channel antagonist nitrendipine, given chronically, prevents the development of ethanol tolerance and physical dependence. The present study examines the effects on barbiturate tolerance and physical dependence. Nitrendipine, given acutely during withdrawal, provided little protection against barbiturate withdrawal, as measured by convulsive behaviour on handling. When nitrendipine was given chronically concurrently with the barbiturate, a prolonged protection against the withdrawal syndrome was seen. Acute nitrendipine significantly increased the latency of seizures in response to the partial benzodiazepine inverse agonist FG7142 during barbiturate withdrawal, but there was no effect on the seizure incidence in response to bicuculline. Chronic treatment with nitrendipine did not alter the development of tolerance to the ataxic or general anaesthetic actions of barbiturates, but evidence was found of a possible interaction between nitrendipine and pentobarbitone, which may have been pharmacokinetic. The results suggest that neuronal calcium channels may be involved to some degree in the development of the changes responsible for barbiturate withdrawal, but to a less extent than found previously for ethanol dependence.
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PMID:Dihydropyridine-sensitive calcium channels and barbiturate tolerance and withdrawal. 820 88

Physical dependence was produced in the rat by exposure to continuous release of diazepam from silastic capsule implants (recrystallized diazepam) or by dosing through a gastric fistula. The precipitated abstinence syndrome induced by the IV infusion of flumazenil was characterized by clonic and tonic-clonic seizures, retropulsion, digging, rearing, head, limb and body tremors, twitches and jerks of the body, and ear twitches. This abstinence syndrome differed both qualitatively and quantitatively from the milder syndrome induced in previous experiments by the intragastric administration of flumazenil in the diazepam-dependent gastric fistula rat. Capsule-implanted rats had free plasma and extraneuronal brain levels of diazepam, oxazepam, and nordiazepam in the 10(-3) and 10(-4) mg/ml range, and their brain: plasma ratios were not significantly different from 1. The diazepam capsules had a sustained release of over 28 days. These studies show that the capsule implantation technique is an efficacious way of maintaining plasma levels of diazepam and its metabolites, and producing a high level of physical dependence in the rat.
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PMID:Precipitated abstinence in the diazepam-dependent rat. 827 46

A series of imidazo[1,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the gamma-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying efficacies ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Many of these compounds were also effective in antagonizing metrazole-induced seizures in accordance with anticonvulsant and possible anxiolytic activity. Selected quinoxalines displayed limited benzodiazepine-type side effects such as ethanol potentiation and physical dependence in animal models. Dimethylamino urea 41 emerged as the most interesting analog, having a partial agonist profile in vitro while possessing useful activity in animal models of anxiety such as the Vogel and Geller assays. In accordance with its partial agonist profile, 41 was devoid of typical benzodiazepine side effects.
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PMID:High-affinity partial agonist imidazo[1,5-a]quinoxaline amides, carbamates, and ureas at the gamma-aminobutyric acid A/benzodiazepine receptor complex. 856 3


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