GABA receptors inhibited by benzodiazepines mediate fast inhibitory transmission in the central amygdala. (1/65)

The amygdala is intimately involved in emotional behavior, and its role in the generation of anxiety and conditioned fear is well known. Benzodiazepines, which are commonly used for the relief of anxiety, are thought to act by enhancing the action of the inhibitory transmitter GABA. We have examined the properties of GABA-mediated inhibition in the amygdala. Whole-cell recordings were made from neurons in the lateral division of the central amygdala. Application of GABA evoked a current that reversed at the chloride equilibrium potential. Application of the GABA antagonists bicuculline or SR95531 inhibited the GABA-evoked current in a manner consistent with two binding sites. Stimulation of afferents to neurons in the central amygdala evoked an IPSC that was mediated by the release of GABA. The GABA(A) receptor antagonists bicuculline and picrotoxin failed to completely block the IPSC. The bicuculline-resistant IPSC was chloride-selective and was unaffected by GABA(B)-receptor antagonists. Furthermore, this current was insensitive to modulation by general anesthetics or barbiturates. In contrast to their actions at GABA(A) receptors, diazepam and flurazepam inhibited the bicuculline-resistant IPSC in a concentration-dependent manner. These effects were fully antagonized by the benzodiazepine site antagonist Ro15-1788. We conclude that a new type of ionotropic GABA receptor mediates fast inhibitory transmission in the central amygdala. This receptor may be a potential target for the development of new therapeutic strategies for anxiety disorders.  (+info)

Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance. (2/65)

1 The residual effects of two benzodiazepines, nitrazepam (10 mg) and flurazepam hydrochloride (30 mg), and pentobarbitone sodium (200 mg) were studied by adaptive tracking and by reaction time. Performance was measured at 10 h, 13 h, 16 h, 19 h and 34 h after ingestion of each drug. Impaired performance on adaptive tracking was observed at 10 h, 13 h, 16 h and 19 h after nitrazepam and pentobarbitone sodium and at 10 h, 13 h and 16 h after flurazepam hydrochloride. Enhanced performance was observed at 34 h after nitrazepam and pentobarbitone sodium. 2 Increased reaction time persisted to 16 h after nitrazepam, flurazepam hydrochloride and pentobarbitone sodium and reaction time was also increased at 34 h after nitrazepam and pentobarbitone sodium. 3 During the morning immediately after ingestion, the subjects as a group were able to differentiate correctly between placebo and drugs, but they were not able to assess accurately the persistence of the residual effects of nitrazepam and pentobarbitone sodium. 4 Flurazepam hydrochloride would appear to be a more promising benzodiazepine than nitrazepam for use as a hypnotic by persons involved in skilled activity. There was a rapid recovery of performance during the afternoon and, unlike pentobarbitone sodium and nitrazepam, subjects retained the ability to recognize impaired skill.  (+info)

Effect of nitrazepam and flurazepam on the ventilatory response to carbon dioxide. (3/65)

Ventilatory response to CO2 was measured before and after two different benzodiazepine hypnotics in both chronic bronchitics and patients without chest disease. Flurazepam, but not nitrazepam, produced a significant decrease in CO2 sensitivity, although there was no significant change in FEV1 or mixed venous PCO2. This is the first unequivocal evidence of central depression of respiration by a benzodiazepine and may be the mechanism by which benzodiazepines cause deterioration in patients with respiratory failure.  (+info)

Characteristics of the association of brotizolam, a thieno-triazolo diazepine derivative, with the benzodiazepine receptor: a selective and high affinity ligand of the central type I benzodiazepine receptor. (4/65)

Characteristics of the association of brotizolam, a thieno-triazolo diazepine derivative, to central benzodiazepine receptors were examined. Brotizolam significantly displaced the [3H]flunitrazepam and [3H]beta-carboline carboxylate ethylester bindings to crude synaptic membrane from the rat brain. This agent had the highest affinity for benzodiazepine receptors in the cerebellum, and it was found to be 2.1 times that in the spinal cord. Furthermore, a low concentration of brotizolam potentiated the GABA-stimulated 36Cl- influx into membrane vesicles. In contrast, the bindings of [3H]8-hydroxy-2-(di-n-propylamino)tetralin to 5-hydroxytryptamine1A receptors and [3H]ketanserin to 5-hydroxytryptamine2 receptors were not affected by brotizolam. The present results suggest that brotizolam may be a selective and high affinity ligand for the type I central benzodiazepine receptor. The anxiolytic and hypnotic actions of brotizolam seem to be not due to the association with 5-hydroxytryptamine receptor, but due to the activation of the GABAA receptor complex. Furthermore, the present results suggest that the lower affinity of brotizolam to benzodiazepine receptors in the spinal cord than those in the cerebellum may be related to the low muscle relaxation action of this drug.  (+info)

Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats. (5/65)

The encephalographic (EEG) properties of zaleplon were investigated in comparison with those of other sedative hypnotics in conscious rats with chronically implanted electrodes. The oral administration of zaleplon (0.25-1.0 mg/kg), triazolam (0.0625-0.25 mg/kg), zopiclone (1.0-4.0 mg/kg), brotizolam (0.0625-0.25 mg/kg), and nitrazepam (0.125-0.5 mg/kg) lengthened the total sleep in a dose-dependent manner. On distribution of sleep-wakefulness stages, zaleplon, in particular, increased the slow wave deep sleep (SWDS), whereas triazolam, brotizolam, and nitrazepam increased the slow wave light sleep (SWLS) in a dose-dependent manner. Zopiclone significantly increased the SWDS at a dose of 2 mg/kg and both the SWLS and the SWDS at a dose of 4 mg/kg. All tested hypnotics caused no influence on fast wave sleep (FWS) at doses tested. The appearance of the sleep-inducing activity of zaleplon was more rapid than those of any compounds tested, and zaleplon significantly increased the relative EEG power density in the delta frequency band over that of triazolam at 20 and 30 min after the administration in the spectral analysis. Therefore, the present findings suggest that the non-benzodiazepine zaleplon can be expected to exhibit high practical potential as a hypnotic and is characterized by an increase in SWDS with rapid onset of hypnotic action.  (+info)

Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. (6/65)

OBJECTIVE: To determine the current best practice for treatment of infantile spasms in children. METHODS: Database searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme. RESULTS: Adrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis. CONCLUSIONS: ACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective.  (+info)

Detection of benzodiazepine intake in therapeutic doses by immunoanalysis of urine: two techniques evaluated and modified for improved performance. (7/65)

We evaluated the EMIT (enzyme-multiplied immuno technique) and FPIA (fluorescence polarization immunoassay) urine screening systems for detection of benzodiazepine intake. Healthy male volunteers were given single oral therapeutic doses of alprazolam (2 mg), chlordiazepoxide (25 mg), flunitrazepam (1 mg), lorazepam (3.75 mg), nitrazepam (5 mg), and triazolam (0.25 mg), after which urine was collected for the next 32 h. The EMIT method failed to detect the intake of flunitrazepam, lorazepam, and nitrazepam. FPIA did not detect the intake of chlordiazepoxide, flunitrazepam, lorazepam, nitrazepam, and triazolam. Modification of the EMIT method to include enzymatic hydrolysis did not significantly alter the results obtained with this method. A modification of the FPIA method to include enzymatic hydrolysis and a lower cutoff value improved the results considerably, so that we reliably detected all studied substances but flunitrazepam. We conclude that (a) both EMIT and FPIA techniques, when used as intended by the manufacturers, are unreliable for the detection of intake of therapeutic doses of these benzodiazepines, and (b) the described modification of the FPIA should provide a much improved tool for detection of benzodiazepine intake.  (+info)

Infantile spasms. A retrospective study of 105 cases. (8/65)

This paper is a summary of our observations on 105 cases of infantile spasms. The age of onset was around six months after birth, but the patients came for treatment mainly about one year after onset. Fever of unknown cause, asphyxia, birth injury, infection of the central nervous system, tuberous sclerosis, phenylketonuria and recent immunization etc. were complained. Clinically, it is characterized by head nodding, mental retardation, myoclonic jerks and various neurologic deficits. EEG findings showed classical or modified arrythmia or other epileptiform patterns. About one third of 22 cases examined had abnormal brain stem auditory evoked potentials. Among 42 patients who underwent CT scanning before ACTH treatment, 18 were normal and 7 abnormal; during ACTH treatment 3 normal and 4 abnormal; after completion of treatment, 4 normal and 6 abnormal, suggesting no further atrophy of the brain. Examination of trace elements of the hair by particle-induced X-ray emission (PIXE) method in 23 patients revealed a significant difference in lead, calcium and zinc contents between patients and 101 controls, but no statistical difference in iron and copper contents between the two groups. Sodium valproate, prednisone and ACTH appear to be effective in the treatment of infantile spasms. Eight patients fully recovered, and they can go to school without difficulty. Many patients derived various degrees of improvement to the satisfaction of their parents. Two patients were still amented and often attacked by myoclonus. The effects, side effects of these drugs, and the possible pathogenesis were discussed.  (+info)