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

Abecarnil, a beta-carboline acting at benzodiazepine receptors, has been shown to have anxiolytic and anticonvulsant properties in a number of models. It has reduced muscle relaxant and incoordinating effects in comparison to diazepam. Given the wide clinical application of diazepam to prevent alcohol withdrawal seizures, a genetic animal model was employed to compare abecarnil with diazepam for its anti-withdrawal effects. Withdrawal Seizure Prone (WSP) mice, genetically selected to develop severe handling-induced convulsions after withdrawal from chronic ethanol treatment, were exposed to ethanol vapor for 24 h. WSP mice given doses of abecarnil or diazepam at the peak of withdrawal had significantly reduced handling-induced convulsion scores. While abecarnil was slightly more potent than diazepam, its effects were shorter-lasting. Similar results were seen in an experiment where withdrawal handling-induced convulsions were assessed after a single high-dose ethanol injection. Abecarnil and diazepam also reduced the smaller handling-induced convulsion scores seen in naive WSP mice. Single doses of abecarnil or diazepam did not lead to a rebound elevation of handling-induced convulsion scores suggestive of a withdrawal reaction.
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PMID:Antagonism of ethanol withdrawal convulsions in Withdrawal Seizure Prone mice by diazepam and abecarnil. 136 Sep 3

In this paper, we present examples of some of the several behaviors which have been taken to indicate the reinforcing efficacy of drugs, including ethanol. Efforts to identify the genetic determinants of these behaviors have employed diverse pharmacogenetic methods. For example, we have used selective breeding to develop mice selected for severe or attenuated ethanol withdrawal and have found that Withdrawal Seizure Prone mice show a greater conditioned preference for ethanol-associated locations than the selected Withdrawal Seizure Resistant line. Similarly, HOT mice, selected for insensitivity to ethanol-induced hypothermia, had greater conditioned place preference after ethanol training than COLD mice, selected for ethanol hypothermic sensitivity. We have also developed selected mouse lines responsive or unresponsive to ethanol-stimulated locomotor activity. These FAST and SLOW lines develop sensitization rather than tolerance to ethanol-induced activity. Using inbred strains of mice, others had shown that strains differed in preference for drinking ethanol solutions. We found that these strains also differed in acceptance of ethanol. Single-gene techniques have been used to show that preference drinking is significantly altered in mutant rodent strains lacking hypothalamic vasopressin, or with nephrogenic diabetes insipidus. In a specific panel of Recombinant Inbred mouse strains, we found that a single gene appeared to control a significant portion of the variance in preference drinking. These examples show that traits putatively related to drug reinforcement show substantial genetic control. Specifically, single-gene methods show promise of identification and mapping of genes related to drug reinforcement.
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PMID:Genetic determinants of ethanol reinforcement. 163 89

Seizure predisposition in Genetically Epilepsy-Prone Rats (GEPRs) is characterized by abnormal sensitivity to a number of seizure provoking stimuli. The GEPR model is composed of two independently derived colonies with each exhibiting a characteristic convulsive pattern. In response to a standardized sound stimulus, GEPR-3s exhibit moderate or clonic convulsions while GEPR-9s exhibit more severe tonic extensor convulsions. In order to further characterize the neurochemical abnormalities that underlie seizure predisposition in GEPRs, the current study examined serotonin concentrations in 14 discrete brain areas of controls, GEPR-3s and GEPR-9s. In all areas examined, serotonin concentrations were lower in either one or both GEPR types than in seizure resistant controls. In 6 of the 14 areas both GEPR-3s and GEPR-9s had levels significantly lower than controls. In an additional 7 areas GEPRs had serotonin concentrations of similar magnitude which were significantly lower than control when the GEPR values were combined. In cerebellum, GEPR-3s had significantly lower serotonin concentration than either controls of GEPR-9s while in the striatum, GEPR-9s had significantly lower serotonin levels than either GEPR-3s or controls. In summary, GEPRs have widespread deficits in serotonin concentration and that these abnormalities appear to contribute to the seizure predisposition that characterizes these animals.
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PMID:Serotonergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats. 173 2

A powerful technique for determining the role of a particular neurotransmitter in mediating a response to ethanol (EtOH) is the analysis of selectively bred lines of animals. Lines selected for sensitivity and resistance to an EtOH effect differ principally in gene frequencies for genes affecting the selected response. Hence, other differences between the lines are likely due to pleiotropic actions of those genes. We discuss behavioral pharmacological experiments in two sets of selected lines. Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mouse lines were selected for severe and minimal handling-induced convulsions (HIC), respectively, after withdrawal from chronic EtOH inhalation. The HIC is also elevated after acute administration of low doses of convulsant drugs. WSP mice were found to be more sensitive than WSR mice to many such drugs. There was no apparent specificity of such effects to any particular neurotransmitter system. Thus, genetic determination of a behavioral response to EtOH in this case cannot be traced to the influence of a single neurotransmitter system. COLD and HOT mice were selectively bred to show severe and mild hypothermia, respectively, after acute EtOH administration. COLD mice are also more sensitive to a number of other alcohols, barbiturates, and other general central nervous system depressants. When tested for sensitivity to a number of drugs with specific effects on neurotransmitter systems, COLD and HOT mice did not differ in sensitivity to drugs affecting dopaminergic, alpha-adrenergic, or nicotinic acetylcholinergic systems. COLD mice were more sensitive, however, to opioid and serotonergic drugs. Thus, analysis of these selected lines was successful in identifying particular neurotransmitters which may be important in EtOH-induced hypothermia.
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PMID:Genetic components of ethanol responses. 218 36

Using the techniques of selective breeding, mouse lines have been developed that express severe (Withdrawal Seizure Prone: WSP) or mild (Withdrawal Seizure Resistant: WSR) handling induced convulsions after cessation of chronic ethanol exposure. These lines differ at least ten-fold in severity of withdrawal after identical ethanol treatment. One feature of the genetic model is that other traits which distinguish these lines are presumably influenced by those genes determining ethanol withdrawal severity. WSP and WSR mice do not differ markedly in the metabolism of ethanol. In addition to handling induced convulsions, they also differ in other withdrawal signs: for example, WSP mice show more pronounced tremor. WSP and WSR mice do not differ in sensitivity to ethanol's hypothermic, anesthetic, or locomotor stimulant effects, nor in the magnitude of tolerance development to these responses. This suggests that sensitivity, tolerance and dependence are distinct genetic entities. WSP mice also display more severe withdrawal from diazepam, phenobarbital, and nitrous oxide than WSR mice, suggesting that some genes generally predispose mice to withdrawal from depressants. WSP mice display withdrawal handling induced convulsions after a single dose of ethanol, pentobarbital, or diazepam. The effective dose for producing drug seizures is not markedly different between WSP and WSR mice for a number of compounds with varied mechanisms of action. However, WSP mice are more sensitive than WSR mice to the effects of acute doses of convulsants to elevate handling induced convulsions. WSP mice have more binding sites in hippocampus for the N-methyl-D-aspartate antagonist MK 801. Binding of this ligand is increased during ethanol dependence in both mouse lines.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alcohol dependence and withdrawal: a genetic animal model. 224 62

In order to develop a rational clinical treatment for any pathological state, the molecular bases for that state must be understood. As simple and logical as that statement appears, it remains the major obstacle to effective treatment of the family of neurological disorders collectively called the epilepsies. Under the term, the epilepsies are grouped as several types of seizure processes that undoubtedly have multiple pathophysiological causes. Thus, the search to elucidate the molecular bases for the epilepsies has as one of its fundamental components the careful selection of an appropriate model system. The search for an "ideal" seizure model has essentially followed two paths. In the first, animals are rendered "epileptic" by artificial methods and then the pathophysiological, electrophysiological, and pharmacological changes are evaluated. In the second, animals are developed with a genetic predisposition to seizures and used to evaluate the molecular bases for the seizure-prone state. Work using both types of models have provided valuable information about the epileptic state. This review describes an epilepsy model developed using the second approach, namely, the Genetically Epilepsy-Prone Rat (GEPR). These animals represent a valuable model for the study of the inborn neurological defect that predisposes these animals to seizures. A brief description of the work done in several laboratories characterizing the model is presented. Finally, the value of the GEPR as a model for studying the pathophysiology of the epilepsies will be described.
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PMID:The genetically epilepsy-prone rat. A valuable model for the study of the epilepsies. 257 May 85

Seizure predisposition in the Genetically Epilepsy-Prone Rat (GEPR) is at least partially dependent on central nervous system noradrenergic deficits. We have previously shown that moderate seizure GEPRs (GEPR-3) experience an increase in seizure severity after receiving Ro 4-1284, a monoamine vesicle inactivating drug. We are now reporting the effect of this drug on severe seizure GEPRs (GEPR-9). Motives for this study were: (a) to determine the effects of further depletion of innately deficient monoaminergic stores on seizure latencies and (b) to investigate whether a previously documented seizure severity difference between the sexes is related to the defective monoaminergic system in these subjects. GEPR-9s with known seizure history were tested for latency to onset of running phase and convulsion 45 minutes after Ro 4-1284 or saline administration. Brain norepinephrine levels were also determined. Ro 4-1284 caused severe depletion of monoamines in all brain areas assayed in both sexes of GEPR-9s and also caused a reduction in the latencies for onset of running and convulsion. The drug-induced norepinephrine depletion across the brain areas surveyed was significantly greater in females than in their male littermates. These observations prompt us to postulate that noradrenergic neurons in female GEPR-9s are functionally different from those in males and that this difference is detected in the differential effectiveness of Ro 4-1284 between the two sexes. Also, the influence of gonadal hormones on seizure predisposition and on the neurochemical actions of Ro 4-1284 may be different in GEPR-9 males and females.
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PMID:Brain norepinephrine and convulsions in the genetically epilepsy-prone rat: sex-dependent responses to Ro 4-1284 treatment. 334 43

The genetic correlation between voluntary consumption of ethanol solutions and severity of withdrawal seizures after chronic ethanol exposure was assessed using the selectively bred Withdrawal Seizure Prone (WSP) and Resistant (WSR) mouse lines. WSP mice have at least ten-fold more severe withdrawal than WSR mice after equal chronic ethanol exposure, and withdrawal in a nonselected control line (WSC) is intermediate to withdrawal in the WSP and WSR lines. In the first experiment, mice from the WSP, WSC and WSR lines were offered a choice between 2.2, 4.6 and 10.0% ethanol solutions and water in three consecutive eight-day sessions. WSR mice consumed more ethanol than WSP mice, and WSC mice were intermediate. In a second experiment, WSP and WSR mice were offered ethanol solutions in concentrations that were adjusted up or down every two days depending upon the amount of ethanol consumed. WSP and WSR mice displayed very different patterns of drinking, with WSP mice drinking more ethanol in early stages of the experiment, and WSR mice drinking more ethanol later. Results of these experiments suggest that some genes influencing severity of withdrawal from ethanol also influence voluntary ethanol drinking.
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PMID:Voluntary consumption of ethanol in WSP, WSC and WSR selectively bred mouse lines. 336 55

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

The Genetically Epilepsy-Prone Rat (GEPR) is a widely studied model of epileptiform disorders. While there is considerable evidence that neurotransmitter abnormalities contribute to the unusual sensitivity of these animals to seizures, the possibility that seizure susceptibility may reflect developmental changes in the central nervous system has not been fully addressed. In the present study, 91 GEPR-9 pups were tested for incidence, latency and severity of an audiogenically induced seizure at 6, 9, 12, 15, 18, 21, 24, 27, 28, 29, or 30 days postpartum (1 test per pup) and retested at 60 days. Seizure incidence, latency, and severity were significantly greater on Days 27, 28, 29, and 30 than on all previous days. The first observation of running fits occurred in Day 18 pups and the first evidence of seizures occurred in Day 21 pups. When retested at Day 60, seizure incidence and severity were significantly greater than on initial tests while latency declined. The results suggest that seizure susceptibility in the GEPR-9 occurs as the result of developmental events in the CNS occurring on or shortly after Day 18 postpartum.
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PMID:Ontogeny of seizure incidence, latency, and severity in genetically epilepsy prone rats. 359 61


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