Psychopharmacology
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The anxiolytic profile of dexmedetomidine, a novel, highly-selective alpha 2-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1-10 micrograms/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1-10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. ⋯ This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an alpha 2-adrenergic antagonist, atipamezole, 10-50 micrograms/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the alpha 1-adrenergic antagonist, prazosin, 0.1-10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and alpha 2-agonist responses do not share any molecular component, there does appear to be "crosstalk" between these two systems. These may involve GABA or noradrenergic "downstream" effects of either dexmedetomidine or midazolam, respectively.
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Clinical Trial Controlled Clinical Trial
Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans.
The effects of depletion of the serotonin precursor, L-tryptophan, on the threshold and tolerance to cold pressor pain, and the analgesic effect of morphine (10 mg intramuscularly), were tested in a double blind trial on human volunteers. Effects on mood were also assessed using the Profile of Mood States and the Addiction Research Center Inventory (ARCI) Scales. To deplete tryptophan, subjects were fed a tryptophan-deficient amino acid mixture 4.5 h before morphine was administered. ⋯ In subjects with normal tryptophan, the analgesic effect of morphine was predicted by the level of plasma morphine-6-glucuronide, but not by the level of morphine. Morphine increased scores on the LSD scale of the ARCI, but had no effect on other measures of mood. Tryptophan depletion also failed to alter mood in these subjects, who had unusually low depression scores before tryptophan depletion.
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Randomized Controlled Trial Comparative Study Clinical Trial
Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder.
The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54-59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. ⋯ The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.
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Clinical Trial Controlled Clinical Trial
Differentiating the sedative, psychomotor and amnesic effects of benzodiazepines: a study with midazolam and the benzodiazepine antagonist, flumazenil.
Sixteen healthy volunteers were administered midazolam followed by placebo or the benzodiazepine antagonist, flumazenil, in a double-blind, cross-over study. Flumazenil reversed midazolam-induced sedation on the subjective, psychophysiological and motor indices used. In contrast, there was little evidence of any reversal of amnesic effects, which were assessed using both direct (explicit) and indirect (implicit) measures of memory. Results are discussed in terms of dissociating the sedative and amnesic effects of benzodiazepines.
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A paradigm for assessing benzodiazepine receptor sensitivity was developed using intravenous midazolam in normal volunteers. After administration of incremental doses of midazolam, alterations in saccadic eye movement parameters and psychological self ratings were assessed. Significant changes included dose-dependent slowing of peak velocity, peak acceleration, peak deceleration, reduced saccade acceleration/deceleration ratio and saccade accuracy, and increased sedation self-ratings. ⋯ No significant changes were seen in saccade latency or anxiety self-ratings. Pharmacological specificity of these changes was demonstrated by their reversal with the benzodiazepine antagonist flumazenil. This challenge paradigm appears to be a sensitive means of assessing benzodiazepine receptor function in man.