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)

Ethanol, acutely, is a potent and selective inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in primary cultures of cerebellar granule cells. The effect of ethanol can be reversed by high concentrations of glycine, and nonequilibrium ligand binding studies in brain membrane preparations suggest that ethanol may act by decreasing the frequency of ion channel opening. After chronic consumption of ethanol by animals, the number of NMDA receptors (measured by ligand binding) is increased in many brain areas. Similarly, NMDA receptor function is increased in cerebellar granule cells exposed chronically to ethanol. In the intact animal, this receptor up-regulation may be associated with ethanol withdrawal seizures, which are attenuated by uncompetitive antagonists at the NMDA receptor. In contrast to ethanol, barbiturates have a greater inhibitory effect at the kainate subtype of glutamate receptor than at the NMDA receptor. After chronic barbiturate ingestion, kainate binding is decreased in certain brain areas, while ligand binding to the NMDA receptor is increased. Overall, the pattern of brain area-specific effects of barbiturates on NMDA and kainate receptor function is quite distinct from that of ethanol.
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PMID:Ethanol, sedative hypnotics, and glutamate receptor function in brain and cultured cells. 839 Feb 39

The anxiolytic and anticonvulsant effects of benzodiazepines, barbiturates, ethanol and neuroactive steroids are mediated by selective interactions with gamma-aminobutyric acidA (GABA(A)) receptors. Chronic ethanol exposure decreases the sensitivity of GABA(A) receptors to benzodiazepines, barbiturates and ethanol. Ethanol withdrawing rats are cross-tolerant to the anticonvulsant effects of benzodiazepines as shown by a 16% decrease in the anticonvulsant efficacy of diazepam compared to controls. In contrast, ethanol withdrawing rats are sensitized to the anticonvulsant effects of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP), exhibiting a 46% increase in the anticonvulsant effect against bicuculline-induced seizures compared to control rats. This effect may involve a change in the sensitivity of GABA(A) receptors to 3 alpha,5 alpha-THP because potentiation of GABA(A) receptor mediated chloride uptake into cerebral cortical synaptoneurosomes is enhanced by 3 alpha,5 alpha-THP up to 50% in ethanol withdrawing rats compared to controls. 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC) potentiation of GABA(A) receptor-mediated chloride uptake is also enhanced during ethanol withdrawal. Moreover, the plasma levels of 3 alpha,5 alpha-THP and progesterone did not differ in ethanol withdrawing rats compared to controls. These alterations in neurosteroid sensitivity were also accompanied by selective alterations in cortical GABA(A) receptor subunit mRNA levels. Levels for the alpha 1 and alpha 4 subunit showed only slight alteration during withdrawal whereas we had previously observed a significant decrease in alpha 1 and a significant increase in alpha 4 mRNA levels in ethanol dependent (not withdrawing) animals. beta 2, beta and gamma 1 mRNA levels significantly increased during ethanol withdrawal. Taken together, these results suggest that ethanol withdrawal produces alterations in GABA(A) receptors that sensitize rats to the pharmacological effects of neuroactive steroids. Because ethanol-dependent or withdrawing rats are tolerant to the intoxicating, anxiolytic and anticonvulsant effects of ethanol and cross-tolerant to many effects of benzodiazepines and barbiturates, sensitization to the effects of neuroactive steroids could have significant therapeutic potential.
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PMID:Sensitization of gamma-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal. 876 98

Experiments were carried out in which a nutritionally balanced liquid diet previously used in this laboratory was modified as to total calorie content and high or low carbohydrate and fat concentration. Ethanol was added at 4.5% and 6.2% of diet weight and provided either 27% or 34-37% of total calories depending upon the changes in nutrient content. Measurements included 8-day food/calorie and ethanol consumption, plasma ethanol level, liver alcohol dehydrogenase (ADH) activity, and rate of audiogenic-induced withdrawal seizures. The original liquid diet with 4.5% ethanol was consumed in significantly lesser amounts than the alcohol-free diet, and essentially no body weight gain occurred, regardless if the major nonalcohol, nonprotein calorie source was fat or carbohydrate. When the calorie content of the diet was boosted through the addition of extra carbohydrate or fat (at the expense of water), appreciable weight gain was noted; in the case of the higher calorie diet boosted with more carbohydrate (maltodextrin) calories, growth was similar to that observed on the alcohol-free control diet. On this latter diet ethanol calories appeared to be utilized close to their theoretical value of 7 kcal/g. Blood alcohol levels were significantly higher on the lower calorie diets and were lowest on the high-calorie, high-carbohydrate, 4.5% ethanol diet. This diet also allowed for the lowest rate of withdrawal seizures despite an ethanol intake that was as high as on the lower calorie diets. Essentially, no differences were noted among ADH activities for the dietary treatments studied and thus, did not explain the differences observed among blood ethanol levels. When the alcohol concentration in the high-carbohydrate, high-calorie diet was raised to 6.2% from 4.5% to provide 34% of total calories, the rats responded by decreasing their food (and alcohol) intake to the same level as did the animals receiving a much lower calorie diet, but with 37% of caloric alcohol content. This suggests that at a diet alcohol concentration of 34-37%, one or more nutrient metabolites become limiting in the utilization of ethanol, resulting in food intake adjustments that maintain similar amounts of alcohol consumption.
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PMID:Diet composition, alcohol utilization, and dependence. 881 56

The inferior colliculus (IC) is the initiation site in the neuronal network for audiogenic seizure (AGS) in rats undergoing ethanol withdrawal (ETX). Considerable evidence supports a role of gamma-aminobutyric acid (GABA)-mediated inhibition in normal acoustic processing in the IC. Altered GABA-mediated inhibition in the IC is suggested to be important in the control of AGS initiation. The present study used microiontophoresis to examine the effectiveness of GABA on acoustically-evoked neuronal responses in the central nucleus of the IC (ICc). GABA effectiveness was compared in normal controls and a group of animals displaying high audiogenic seizure susceptibility (100% AGS) (HAGS), and a group exhibiting a low (mean, 33%) incidence of AGS (LAGS). Ethanol was administered for 4 days in three daily doses (9-15 g/kg/day) sufficient to maintain a moderate degree of intoxication. Tonic-clonic seizures were observed in HAGS animals, while LAGS rats exhibited less severe seizures, consisting primarily of wild running. Iontophoretic application of GABA consistently inhibited ICc neuronal firing in controls and in animals undergoing ETX. However, the mean dose (current) of GABA required to produce a 50% reduction of the ICc neuronal firing in the HAGS group was nearly twice that of the control animals. The mean dose of GABA for 50% inhibition in the LAGS group was about one-half that of the control group. Both of these differences were statistically significant. These data suggest that decreased GABA effectiveness in the IC neurons of HAGS susceptible animals is an important mechanism contributing to the propagation of severe AGS seen during ETX in these animals.
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PMID:Decreased GABA effectiveness in the inferior colliculus neurons during ethanol withdrawal in rats susceptible to audiogenic seizures. 882 69

Effects of chronic moclobemide administration on ethanol consumption, blood ethanol level, motor coordination and seizures induced by an audiogenic stimulus during ethanol withdrawal syndrome have been investigated in chronically ethanol intoxicated rats. Adult male Wistar rats (211-289 g) were used. Ethanol (7.2% v/v) was given to rats by a special liquid diet for 15 days. Moclobemide (10, 30 and 45 mg kg-1) or saline was injected to ethanol-feeding rats subcutaneously through 15 days. Daily ethanol intake and body weight gain of the rats were recorded. Blood ethanol levels were measured in rats given saline or chronic moclobemide (30 mg kg-1) just before and 6 h after ethanol withdrawal. At the sixth hour of the ethanol withdrawal, the incidence, intensity and latency of the seizures induced by an audiogenic stimulus were recorded in saline and acute (30 mg kg-1) or chronic (10, 30 and 45 mg kg-1) moclobemide-administered rats. Accelerod performances of the chronic moclobemide (45 mg kg-1) or saline injected rats were also evaluated. The mean ethanol intake of the rats ranged from 10.06 to 15.63 g kg-1 day-1 during the study. Chronic moclobemide treatment did not occur any significant effect on daily ethanol consumption, ethanol clearance and accelerod performances of the rats. No significant changes on the incidence, intensity and the latency of the audiogenic seizures were also observed. Our results suggest that there has been no adverse interaction between ethanol and moclobemide.
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PMID:Investigation of the effects of moclobemide in chronic ethanol feeding rats. 886 58

The effects of N(G)-nitro arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), nitric oxide synthase inhibitors, and L-arginine, a nitric oxide precursor, on ethanol withdrawal signs were investigated in rats. Ethanol (7.2% v/v) was given to rats by a liquid diet for 16 days. L-NAME (30 and 60 mg/kg), 7-NI (40 and 80 mg/kg), L-arginine (100 mg/kg), a combination of L-arginine (100 mg/kg) and 7-NI (40 mg/kg), and saline or vehicle were injected to rats intraperitoneally 30 min before ethanol withdrawal. A second series of injections was given at 6 hour after the first one, and subjects were then tested for audiogenic seizures. 7-NI (40 mg/kg), vehicle and saline were also administered to naive rats. 7-NI (40 mg/kg) did not produce any significant change in locomotor activity in naive rats. Both L-NAME and 7-NI significantly inhibited locomotor hyperactivity from the 2nd to the 6th hour of the withdrawal period. They also reduced the total ethanol withdrawal score from the 30th min to the 6th hour, and they significantly decreased audiogenic seizures. Neither drug increased locomotor activity nor total ethanol withdrawal score, which were increased significantly by L-arginine (100 mg/kg); however, L-arginine (100 mg/kg) prevented the inhibitory effects of 7-NI (40 mg/kg) on increased locomotor activity, total ethanol withdrawal score, and audiogenic seizure. Our results suggest that nitric oxide synthase inhibition by L-NAME and 7-NI alleviates the signs of ethanol withdrawal. The data also support the hypothesis that nitric oxide may take part in the neuroadaptation that develops during chronic ethanol ingestion in rats.
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PMID:Nitric oxide synthase inhibition attenuates signs of ethanol withdrawal in rats. 939 39

Recent evidence suggests that ethanol abuse produces its diverse effects on the brain to a substantial degree by disrupting the function of the major excitatory neurotransmitter, glutamate. Ethanol, at concentrations associated with behavioral effects in humans, inhibits the N-methyl-D-aspartate (NMDA) receptor, which mediates the post-synaptic excitatory effects of glutamate. Tolerance to ethanol results in up-regulation of the NMDA receptor so that abrupt withdrawal produces a hyperexcitable state that leads to seizures, delerium tremens, and excitotoxic neuronal death. Ethanol's inhibition of the NMDA receptor in the fetal brain likely contributes to the CNS manifestations of fetal alcohol syndrome. Therapeutic strategies aimed at correcting glutamatergic dysregulation in alcoholism need to be explored.
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PMID:The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. 950 57

A history of multiple ethanol withdrawal experiences has been shown to exacerbate the severity of future withdrawal episodes, and this sensitization of the withdrawal response has been hypothesized to represent a 'kindling' phenomenon. Since adenosine functions as an inhibitory modulator of seizure activity and may interact with ethanol to influence neuronal excitability, the present study was conducted to examine the effects of single and repeated episodes of ethanol withdrawal on adenosine A1 and A2A receptors in adult C3H/He mice. Mice were chronically exposed to ethanol vapor in inhalation chambers and tested for withdrawal seizures following multiple withdrawal (MW) experience (four cycles of 16 h ethanol intoxication interrupted by 8 h periods of abstinence), single withdrawal experience following 16 h (SW) or 64 h (CE) continuous ethanol intoxication, or no ethanol exposure (controls). Separate groups of mice from each withdrawal condition were used to generate pooled cortical and striatal tissue for ligand saturation experiments using [3H]cyclohexyladenosine to label A1 receptors and [3H]CGS 21680 to label A2A receptors. Results indicated that withdrawal seizures were significantly more severe in mice with multiple withdrawal experience in comparison to animals that experienced only a single withdrawal episode, even when total amount of ethanol exposure was equated among groups. The density of A1 receptors in cerebral cortex was significantly increased over controls 8 h following final ethanol withdrawal by approximately 35% in SW and CE groups, with the largest increase observed in the MW group (56%). Withdrawal treatment groups did not differ in cortical A1 binding sites immediately upon withdrawal from ethanol, and no significant differences in binding of [3H]CGS 21680 to striatal A2A receptors were observed following ethanol withdrawal. Ethanol exposure and withdrawal did not significantly alter ligand affinity for either adenosine receptor. These results indicate that adenosine A1 receptors are selectively upregulated during ethanol withdrawal and that the degree of upregulation may be enhanced following multiple withdrawal episodes. Further, these observations suggest that the upregulation of brain A1 receptors during ethanol withdrawal may represent a compensatory inhibitory response to increased seizure severity associated with repeated episodes of ethanol withdrawal.
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PMID:Single and repeated episodes of ethanol withdrawal increase adenosine A1, but not A2A, receptor density in mouse brain. 955 62

The present study examines alterations in the cytoplasmic immunoreactivity of brain beta-endorphin, an endogenous opioid peptide regarded as the mediator of both euphoria and antinociceptive systems, in relation to toxicities due to cocaine and combined cocaine-ethanol. Beta-endorphin-immunoreactive cells were visualized and counted in adjacent sections from male rat brains at the level of the arcuate nucleus. In this region, cytoplasmic beta-endorphin immunoreactivity is prevalent. An intraperitoneal injection of cocaine (75 or 15 mg/kg) was given 15 min after an intraperitoneal injection of 3 g/kg ethanol or vehicle. With a fatally toxic dose (75 mg/kg) of cocaine, the number of neurons exhibiting cytoplasmic beta-endorphin immunoreactivity (immunoreactive nerve cells) was significantly increased immediately after the drug administration. Ethanol further enhanced the effects of both 15 and 75 mg/kg of cocaine. When the immunoreactivity was visually estimated by computer imaging analysis, lightly stained, weakly immunoreactive cells with photographic light absorption values greater than 50% were enhanced in the cocaine-ethanol groups compared to the cocaine only groups. Fatal toxicities were only observed in the groups treated with the high cocaine doses (75 mg/kg), with or without ethanol. In these groups, the number of strongly immunoreactive cells had increased significantly compared to the other groups. In the group treated with the high cocaine dose (75 mg/kg) plus ethanol, an increased frequency of late deaths that occurred over 1 h after the drug administration was observed, together with a decreased severity of cocaine-induced seizures and an early enhancement of weakly immunoreactive cells. Unlike the strongly immunoreactive cells, the weakly immunoreactive cells appeared to be continuously enhanced, based on an experiment examining beta-endorphin immunoreactivity at 24 h after an injection of 50 mg/kg cocaine.
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PMID:Brain beta-endorphin immunoreactivity as an index of cocaine and combined cocaine-ethanol toxicities. 961 Sep 51

There is extensive evidence that ethanol interacts with a variety of neurotransmitters. Considerable research indicates that the major actions of ethanol involve enhancement of the effects of gamma-aminobutyric acid (GABA) at GABAA receptors and blockade of the NMDA subtype of excitatory amino acid (EAA) receptor. Ethanol increases GABAA receptor-mediated inhibition, but this does not occur in all brain regions, all cell types in the same region, nor at all GABAA receptor sites on the same neuron, nor across species in the same brain region. The molecular basis for the selectivity of the action of ethanol on GaBAA receptors has been proposed to involve a combination of benzodiazepine subtype, beta 2 subunit, and a splice variant of the gamma 2 subunit, but substantial controversy on this issue currently remains. Chronic ethanol administration results in tolerance, dependence, and an ethanol withdrawal (ETX) syndrome, which are mediated, in part, by desensitization and/or down-regulation of GABAA receptors. This decrease in ethanol action may involve changes in subunit expression in selected brain areas, but these data are complex and somewhat contradictory at present. The sensitivity of NMDA receptors to ethanol block is proposed to involve the NMDAR2B subunit in certain brain regions, but this subunit does not appear to be the sole determinant of this interaction. Tolerance to ethanol results in enhanced EAA neurotransmission and NMDA receptor upregulation, which appears to involve selective increases in NMDAR2B subunit levels and other molecular changes in specific brain loci. During ETX a variety of symptoms are seen, including susceptibility to seizures. In rodents these seizures are readily triggered by sound (audiogenic seizures). The neuronal network required for these seizures is contained primarily in certain brain stem structures. Specific nuclei appear to play a hierarchical role in generating each stereotypical behavioral phases of the convulsion. Thus, the inferior colliculus acts to initiate these seizures, and a decrease in effectiveness of GABA-mediated inhibition in these neurons is a major initiation mechanism. The deep layers of superior colliculus are implicated in generation of the wild running behavior. The pontine reticular formation, substantia nigra and periaqueductal gray are implicated in generation of the tonic-clonic seizure behavior. The mechanisms involved in the recruitment of neurons within each network nucleus into the seizure circuit have been proposed to require activation of a critical mass of neurons. Achievement of critical mass may involve excess EAA-mediated synaptic neurotransmission due, in part, to upregulation as well as other phenomena, including volume (non-synaptic diffusion) neurotransmission. Effects of ETX on receptors observed in vitro may undergo amplification in vivo to allow the excess EAA action to be magnified sufficiently to produce synchronization of neuronal firing, allowing participation of the nucleus in seizure generation. GABA-mediated inhibition, which normally acts to limit excitation, is diminished in effectiveness during ETX, and further intensifies this excitation.
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PMID:Ethanol and neurotransmitter interactions--from molecular to integrative effects. 967 Feb 16


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