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)

Selective breeding was used to produce lines of mice which differ markedly in their genetically-mediated vulnerability to handling-induced convulsions (HIC) associated with the ethanol withdrawal syndrome. These are known as the ethanol withdrawal seizure prone (WSP) and withdrawal seizure resistant (WSR) selection lines. As a result of 5 generations of selective breeding with ethanol, a 3.4-fold difference between WSP and WSR mice was seen in HIC associated with ethanol withdrawal. When diazepam was used as the dependence-producing drug, a 2.4-fold difference emerged. After 6 more generations of selective breeding with ethanol, an approximate 10-fold difference was seen with ethanol, while with diazepam, this difference in HIC scores was also about 10-fold. This close parallel between ethanol and diazepam indicates that physical dependence on both drugs, as indexed by handling-induced convulsions, is extensively codetermined by the same genes, and thus by the same mechanisms, in these selectively-bred mice.
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PMID:Ethanol and diazepam withdrawal convulsions are extensively codetermined in WSP and WSR mice. 250 7

Studies with ethanol have indicated that dihydropyridine-sensitive calcium (Ca++) channels may be involved in the adaptation to prolonged exposure to ethanol. This study investigated the effects, in mice, of the dihydropyridine Ca++ antagonist, nitrendipine, on acute tolerance to nitrous oxide after 60 min exposure to anesthetizing concentrations, and also the withdrawal syndrome which occurred following removal from nitrous oxide. Control mice were anesthetized by nitrous oxide concentrations in the range 1.28-1.51 atmospheres. Nitrendipine 10, 50, and 100 mg.kg-1, i.p., produced a dose-dependent potentiation of nitrous oxide anesthesia (P less than 0.05 for nitrendipine 50 and 100 mg.kg-1). Tolerance to nitrous oxide anesthesia developed over 60 min (13% increase in ED50, P less than 0.05). Concurrent administration of nitrendipine at all doses prevented the development of nitrous oxide tolerance. After 60 min exposure to nitrous oxide 1-1.5 atmospheres, all control mice showed handling seizures. Nitrendipine diminished or prevented nitrous oxide withdrawal seizures, in a dose-dependent manner (P less than 0.05 for nitrendipine 50 and 100 mg.kg-1). These results support the importance of the role of dihydropyridine-sensitive Ca++ channels in the mechanism of tolerance and dependence to central depressant drugs. They also suggest that acute and chronic tolerance to sedative drug action may share some common pathways, and that tolerance and physical dependence may share a common mechanism through voltage-operated Ca++ channels.
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PMID:Effects of "nitrendipine" on nitrous oxide anesthesia, tolerance, and physical dependence. 252 37

1. The effects of the benzodiazepine receptor antagonists Ro 15-1788 (flumazenil) and the beta-carboline ZK 93426 were compared in dogs before and after chronic treatment with diazepam. 2. In diazepam-naive dogs, the most prominent behavioural alterations occurring during or after i.v. infusion of Ro 15-1788 up to a dose of 20 mg kg-1 were transient sedation, ataxia, and 'hot foot' behaviour, whereas behavioural alterations observed after ZK 93426 were not different from those observed after i.v. infusion of vehicle alone. This indicates that, in contrast to Ro 15-1788, ZK 93426 did not exert partial agonistic activity at benzodiazepine receptors. 3. In dogs treated 3 times daily with diazepam, 1 mg kg -1 orally, for 1 week, both benzodiazepine antagonists precipitated abstinence symptoms but the number and severity of withdrawal signs induced by Ro 15-1788 were greater than with ZK 93426. 4. In dogs treated 3 times daily with diazepam, 2 mg kg-1 orally, for 2 weeks, severe abstinence symptoms were precipitated in all animals by infusion of either antagonist but differences were found in the type of the symptoms: Ro 15-1788 induced rigid postures or rigid walking with increased muscle tone, tremor, twitches and jerks, whereas ZK 93426 did not alter motility but induced generalized myoclonic jerks and tonic-clonic seizures. A generalized tonic-clonic seizure was also observed in one dog of the trial with infusion of Ro 15-1788. 5. Plasma level determinations during chronic treatment diazepam showed marked accumulation of the major active metabolite desmethyldiazepam, whereas diazepam levels were at least 15 times lower, which might suggest that desmethyldiazepam was responsible for the development of physical dependence on diazepam.
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PMID:Physical dependence on diazepam in the dog: precipitation of different abstinence syndromes by the benzodiazepine receptor antagonists Ro 15-1788 and ZK 93426. 256 47

In amygdala-kindled rats, single-dose administration of primidone did not reduced seizure activity 2 h after i.p. injection, i.e. when plasma levels of the drug were highest, but significant anticonvulsant effects were found 24 h after administration, when the drug was almost completely eliminated. During chronic treatment with primidone, marked anticonvulsant efficacy was determined after 3-15 days of three times daily treatment with 50 mg/kg i.p., indicating that this effect was due to the accumulation of metabolites, especially phenobarbital. Maximum anticonvulsant activity attained during chronic primidone medication was almost equal to that found during chronic treatment of kindled rats with phenobarbital, 30 mg/kg once daily. However, drug plasma level determinations during both treatments showed that on days when both treatments were about equieffective, levels of metabolically derived phenobarbital in the primidone group were significantly lower than levels in rats treated with phenobarbital alone, thus indicating that primidone potentiated the anticonvulsant effect of metabolically derived phenobarbital. Additional evidence for potentiation of the anticonvulsant effect of phenobarbital by primidone was found in single dose experiments with combined injection of both drugs, whereas side-effects, such as ataxia and muscle relaxation, induced by phenobarbital were not increased by combined treatment with primidone. Accordingly, side-effects occurring during chronic primidone treatment were less pronounced than side-effects found during chronic phenobarbital medication. In both treatment groups, tolerance to the anticonvulsant effect developed during the 2nd week of administration, while attenuation of side-effects took place already in the first week. Following cessation of treatment, signs of physical dependence, such as withdrawal hyperexcitability and weight loss, were observed. The data indicate that, at least in kindled rats, the anticonvulsant activity of primidone during chronic treatment is due to the combined and possibly synergistic actions of primidone and metabolically derived phenobarbital.
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PMID:Comparison of the anticonvulsant efficacy of primidone and phenobarbital during chronic treatment of amygdala-kindled rats. 272 68

Clinically, patients with Delirium Tremens (DT) and acute alcohol hallucinosis (impending DT) appear excited with vivid false perception. Cerebral blood flow and eeg correspondingly point to hyperexcitability in the CNS during these conditions. Clinical trials with barbital treatment in alcohol withdrawal shows that the amount of drug and the drug plasma concentration is the same no matter whether the physical signs of withdrawal are accompanied by hallucinations and clouding of consciousness. The psychotic signs in DT and acute alcoholic hallucinosis develops after many years of alcoholism as does seizures. We hypothesize that physical withdrawal is determined by the degree of physical dependence developed during the most recent drinking period whereas the psychotic signs and seizures are due to a cumulated CNS hyperactivity developed over many years of repeated alcohol intoxication and withdrawal. Changes of electrolyte concentrations in plasma or CSF do not play an important role in the pathogenesis of DT and related clinical states except that changes in calcium and inorganic phosphate metabolism indirectly point to changes in membrane excitability. A new model for a study of rapidly repeated intoxication and withdrawal episodes in rats has shown that repetition of episodes augments the convulsive component of withdrawal whereas the non-convulsive signs are dependent on the most recent episode only. The augmentation of the convulsive component correlates with regional differences in brain glucose consumption. Furthermore, synaptic proteins and acidic phospholipids may be involved in the development of CNS hyperexcitability during alcohol withdrawal. In conclusion both clinical and experimental studies indicate that severe alcohol withdrawal reactions may consist of two components: 1) Physical withdrawal signs determined by recent physical dependence. 2) A long term cumulated CNS hyperexcitability relating to seizures and psychotic signs during withdrawal. This state is elicited by alcohol withdrawal but it represents a cumulated and permanent or long lasting CNS dysfunction in alcoholics. The precise biochemical/pathophysiological mechanisms for the development of the two-component dysfunction still remain to be clarified in detail.
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PMID:Delirium tremens and related clinical states: psychopathology, cerebral pathophysiology and psychochemistry: a two-component hypothesis concerning etiology and pathogenesis. 306 44

Previous reports using rats have failed to demonstrate convulsions upon withdrawal from chronic benzodiazepine (BZ) treatment. We have shown earlier that rats develop tolerance to benzodiazepines following continuous exposure to low levels of diazepam (DZ) obtained by treatment with s.c. diazepam-filled silastic capsules. This report shows that intravenous infusion of the benzodiazepine antagonist Ro 15-1788 can induce seizures in rats treated for prolonged periods (4 weeks) with such diazepam-filled capsules. Precipitated seizures are also seen in rats 24 h after the cessation of chronic diazepam exposure. This procedure may provide a useful paradigm with which to study in rats the neural changes which are related to the physical dependence and withdrawal associated with prolonged exposure to the benzodiazepines.
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PMID:Ro 15-1788-induced seizures in rats continually exposed to diazepam for prolonged periods. 314 57

The technique of chronic schedule-induced drug solution intake was used to determine the possible addiction liability of the short-acting benzodiazepine midazolam. Schedule-induction produces polydipsia over a wide range of fluids as a function of the imposed schedule of food availability. The inducing schedule used presented food pellets automatically once per minute, fixed time (FT) 1-min, for 3 h daily. Two groups of rats, drinking either water or 0.05 mg/ml midazolam solution, were exposed to schedule-induction sessions for approx. 2 months. Then, other FT-values (0, 0.5, 3 and 5 min) were instituted on occasion for single sessions. Each of these 'probe' session determinations was done twice. Although midazolam concentration had been adjusted so that the mean group intakes were equal at FT 1-min, probe values greater than 1 min revealed a greater acceptance of midazolam compared to water. This technique produced session midazolam intakes as great as 25 mg/kg. In the next phase, the entire experiment was repeated except both groups were offered a choice between water and midazolam solution during sessions. Only at FT 0 and FT 5-min was there an indication that midazolam was preferred over water. Two additional groups of animals were exposed to the same schedule-induced polydipsia regimen, drinking water and midazolam solution, respectively. Pre-session administration of doses of Ro 15-1788, CGS 8216 (benzodiazepine antagonists) or midazolam had no effects on either water or midazolam intakes, although the higher dose of midazolam (2 mg/kg, s.c) had a moderately suppressive effect on the non-tolerant water-polydipsic group. All groups were tested on occasion for physical dependence on midazolam with an auditory stimulus as the precipitator and midazolam polydipsic groups were found to have a mild to moderate dependence (clonic seizures, running fits).
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PMID:Midazolam oral self-administration. 316 May 67

Selective breeding was used to produce lines of mice which differ markedly from one another in ethanol physical dependence development as indexed by handling-induced convulsions (HIC) induced by withdrawal from ethanol. These are known as the Withdrawal Seizure Prone (WSP) and Withdrawal Seizure Resistant (WSR) selected lines. Mice selectively-bred for severe HIC (Withdrawal Seizure Prone lines) exhibited 3-fold greater HIC scores than did mice selectively-bred for mild HIC (Withdrawal Seizure Resistant lines) after five generations of selective-breeding. When phenobarbital was used as the dependence-producing drug rather than ethanol, the WSP vs. WSR differences in HIC were similar to those seen with ethanol. This implies that a high degree of commonality exists between ethanol and phenobarbital in the determinants of this commonly used index of physical dependence. Both WSP and WSR mice showed equivalent brain phenobarbital concentrations and equal functional tolerance development as indexed by several measures of impairment.
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PMID:Ethanol and barbiturate withdrawal convulsions are extensively codetermined in mice. 339 63

Groups of rats drank either a solution of the ultrashort-acting benzodiazepine midazolam or water under schedule-induced polydipsia conditions in chronic, daily, 3-hr sessions. In Experiment 1, the physical dependence status of animals was tested after 9 months by the precipitated withdrawal method using the benzodiazepine-blocking agent Ro 15-1788 and by exposure to a brief audio stimulus at 1.5, 12 and 24 hr following drug withdrawal. Ro 15-1788 failed to produce withdrawal signs, while the audio stimulus plus withdrawal did. In Experiment 2, similar groups were periodically tested for susceptibility to audiogenically-induced seizures at 3, 6, 12, 15, 18, 21, 24 and 26 weeks 90 minutes after their drug or vehicle intake sessions. In the midazolam-drinking group, physical dependence developed at about 12 weeks and increased in severity over the course of the study. Serum measures confirmed that continuous elevation of drug and active metabolite levels are not necessary for the development of physical dependence. A chronic, daily, single elevation of a few hr was sufficient.
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PMID:Development of physical dependence on midazolam by oral self-administration. 360 36

Twenty generations of selective breeding were used to produce lines (strains) of mice which differ markedly from one another in ethanol physical dependence development as indexed by handling-induced convulsions (HIC) induced by withdrawal from ethanol. These withdrawal seizure prone (WSP) and withdrawal seizure resistant (WSR) selection lines now differ by over 10-fold in HIC scores after equivalent exposure to intoxicating levels of ethanol via inhalation. Since handling-induced convulsions can be readily elicited following withdrawal from nitrous oxide, we sought to determine if the very large differences in ethanol withdrawal-induced HIC bred into these selection lines would generalize to nitrous oxide. Following a 60 min exposure to 75% nitrous oxide (in O2), a greater than 10-fold difference in HIC scores, and a 2-fold difference in tremor incidence was seen upon withdrawal in WSP vs. WSR mice. These findings closely parallel those seen with ethanol, and demonstrate that a large degree of commonality exists in the genes and the mechanisms determining these withdrawal signs. HIC elicited by nitrous oxide withdrawal were readily suppressed by ethanol, and HIC elicited by ethanol withdrawal were promptly suppressed by 75% nitrous oxide in WSP mice. Nitrous oxide also suppressed HIC and tremor associated with nitrous oxide withdrawal.
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PMID:Ethanol and nitrous oxide produce withdrawal-induced convulsions by similar mechanisms in mice. 366 9


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