PubMed · 6552292
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1983. Panic attacks: a debilitating disorder for millions.. https://doi.org/10.3928/0279-3695-19830501-07
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We report here on the ability of IDRA 21 and aniracetam, two negative allosteric modulators of glutamate-induced DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization, to attenuate alprazolam-induced learning deficit in patas monkeys working in a complex behavioral task. In one component of a multiple schedule (repeated acquisition or "learning"), patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four discriminative stimuli (geometric forms or numerals). In the other component (performance) the four-response chain was the same each session. The response chain in each component was maintained by food presentation under a fixed-ratio schedule. When alprazolam (0.1 or 0.32 mg/kg p.o.) was administered alone, this full allosteric modulator of gamma-aminobutyric acid type A (GABAA) receptors produced large decreases in the response rate and accuracy in the learning component of the task. IDRA 21 (3 or 5.6 mg/kg p.o.) and aniracetam (30 mg/kg p.o.) administered 60 min before alprazolam, having no effect when given alone, antagonized the large disruptive effects of alprazolam on learning. From dose-response studies, it can be estimated that IDRA 21 is approximately 10-fold more potent than aniracetam in antagonizing alprazolam-induced learning deficit. We conclude that IDRA 21, a chemically unrelated pharmacological congener of aniracetam, improves learning deficit induced in patas monkeys by the increase of GABAergic tone elicited by alprazolam. Very likely IDRA 21 exerts its behavioral effects by antagonizing AMPA receptor desensitization.
Urinary glucuronide metabolites of the benzodiazepines were converted back to the parent molecules after treatment with B-glucuronidase. The benzodiazepines were extracted by a one-step liquid/liquid extraction from urine or by a liquid/solid phase extraction. For the limit of detection (LOD), a standard solution of diazepam and oxazepam was serially diluted and analyzed to the point at which a reproducible analytical result was no longer obtained. Using a temperature program and a splitless mode of injection, excellent quantitation was achieved within an 8-min run time. Based upon specimens obtained from patients under a physician's care, we have determined that urinary concentrations of the benzodiazepines > 200 ng/ml are most likely due to abuse rather than to a prescribed ingestion under strict medical surveillance. Therefore, the calibration standard and cutoff concentration for a positive result was set at 200 ng/ml.
The two-electrode voltage-clamp technique was used to evaluate Zn block of current activated by gamma-aminobutyric acid (GABA) in Xenopus oocytes injected with cRNA coding for alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, or alpha 3 beta 3 gamma 2 subunits of the GABAA receptor (GABAAR). cDNA coded for the human form of alpha 1, alpha 2, beta 3 and gamma 2L subunits. alpha 3 subunit cDNA was obtained from an African green monkey library. Zn significantly inhibited the current evoked by application of GABA. Maximal inhibition was greater in alpha 2- and alpha 3- containing GABAARs than in alpha 1-containing GABAARs (51 +/- 1% and 53 +/- 2% vs 19 +/- 2%, respectively). The IC50 for Zn was smaller in alpha 1 than in alpha 2 or alpha 3 GABAARs (1.2 +/- 0.3 microM vs 7 +/- 1 and 9 +/- 1 microM, respectively). Zn shifted the concentration-response curve of GABA to the right in a parallel manner. These data suggest that Zn reduces the amplitude of current evoked at gamma 2 subunit containing GABAARs through an allosteric mechanism.