Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gamma-aminobutyric acid (GABA) receptor-operated chloride channel complex was evaluated in mice selected for differential sensitivity to the ataxic effects of diazepam (diazepam-sensitive (DS) and diazepam-resistant (DR) lines). The ataxic effects of several drugs purported to produce some of their actions through the benzodiazepine-GABA receptor complex were examined using the rotarod test. The duration of impairment produced by diazepam, ethanol, 4,5,6,7-tetrahydroisoxazol[5,4-C]pyridine-3-ol (THIP) and phenobarbital was greater in the diazepam-sensitive than in the diazepam-resistant mice. In contrast, pentobarbital produced an equivalent duration of ataxia in the two lines. Muscimol-stimulated 36Cl- influx and the binding of [35S]t-butylbicyclophosphorothionate (TBPS) and [3H]flunitrazepam were measured using isolated brain membrane vesicles (microsacs). Depolarization-dependent 45Ca2+ uptake was measured in whole brain synaptosomes. Muscimol was a more potent stimulator of 36Cl- flux in the DS compared to the DR mice, although no difference between the lines was found in muscimol-stimulation of [3H]flunitrazepam binding. Flunitrazepam augmented the muscimol-stimulated 36Cl- uptake in the DS but not in the DR mice. However, no differences between the lines of mice were found in either density or affinity of [3H]flunitrazepam binding sites. Similarly, no differences in either the density or affinity of [35S]TBPS binding sites was found. Ethanol (10-45 mM) potentiated the muscimol-stimulation of 36Cl- in DS, with no effect in DR mice. However, ethanol inhibition of [35S]TBPS binding was equivalent in the two lines of mice. Pentobarbital produced an equal potentiation of the muscimol-stimulated 36Cl- flux in the two lines, but phenobarbital potentiated the muscimol-induced 36Cl- influx slightly more in DS mice.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Genetic selection for benzodiazepine ataxia produces functional changes in the gamma-aminobutyric acid receptor chloride channel complex. 245 24

Forty female out-patients undergoing therapeutic abortion participated in a double-blind study comparing flunitrazepam 0.05 mg . kg-1 with thiopentone 6.0 mg . kg-1 as induction agents for general anaesthesia. Induction time, as measured by the time to loss of lid reflex and voluntary speech, was not only significantly longer in patients receiving flunitrazepam, but also much more variable and imprecise than with thiopentone. The Steward recovery room scores and psychomotor drawing test results revealed that recovery was significantly slower in the flunitrazepam group. Anterograde amnesia was observed in all patients who had received flunitrazepam and in one patient who had received thiopentone. No retrograde amnesia was found in either group. Flunitrazepam produced postoperative drowsiness, sedation, ataxia and nausea while with thiopentone discomfort from surgery and discomfort at the intravenous injection site were the main complaints. Because of the slowness of induction with flunitrazepam and marked individual variation, we do not feel that this drug can be considered a suitable agent for routine induction of general anaesthesia.
 ...
PMID:Comparison of flunitrazepam and thiopentone for induction of general anaesthesia. 610 7

The effects of 5-2500 microM concentrations of neutral ammonium salts on the binding of ligands to components of the GABAA receptor complex were investigated. [3H]Flunitrazepam binding to the benzodiazepine receptor was enhanced by ammonium (10-500 microM), but not sodium tartrate with EC50 = 98 microM and Emax = 31%. Further increasing ammonium tartrate concentrations (500-2500 microM) decreased [3H]flunitrazepam binding to control levels. The ammonium tartrate-induced increase in [3H]flunitrazepam binding was manifested as a 50% decrease in Kd. Furthermore, GABA increased the potency of ammonium tartrate in enhancing [3H]flunitrazepam binding by 63%. [3H]Ro 15-1788 and [3H]Ro 15-4513 binding to the benzodiazepine receptor was not significantly enhanced by ammonium tartrate (Emax approximately 13%). Ammonium tartrate also increased, then decreased the binding of 500 nM [3H]muscimol to the GABAA receptor (EC50 = 52 microM, Emax = 30%) in a concentration-dependent manner, but had no effect on [3H]SR 95-531 binding (Emax < 16%). The ammonium tartrate-induced alterations in [3H]muscimol binding were demonstrated in saturation assays as the loss of the high affinity binding site and a 27% increase in the Bmax of the low affinity binding site. These results indicate that ammonia biphasically enhances, then returns ligand binding to both the GABA and benzodiazepine receptor components of the GABAA receptor complex to control levels in a barbiturate-like fashion. This suggests that ammonia may enhance GABAergic neurotransmission at concentrations commonly encountered in hepatic failure, an event preceding the suppression of inhibitory neuronal function observed at higher (> 1 mM) ammonia concentrations. This increase in GABAergic neurotransmission is consistent with the clinical picture of lethargy, ataxia and cognitive deficits associated with liver failure and congenital hyperammonemia.
 ...
PMID:Modulation of ligand binding to components of the GABAA receptor complex by ammonia: implications for the pathogenesis of hyperammonemic syndromes. 878 94