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 evaluated the modulatory effect of the GABA-active neurosteroid alphaxalone on the staircase test behavior of mice. Results were compared with the benzodiazepine alprazolam, the GABA(A) agonist muscimol and the peripheral steroids corticosterone and progesterone. Alphaxalone and alprazolam reduced rearing activity in a dose-dependent manner, at doses that did not suppress climbing. The rearing-suppression effect of alprazolam, but not of alphaxalone, was blocked by the benzodiazepine antagonist flumazenil. No such dissociation between the effect on rearing and climbing was obtained with muscimol, and both activities were suppressed, in a flumazenil-insensitive pattern, at high doses. Corticosterone and progesterone did not affect the behavior of the mice. The lack of sensitivity of both phenobarbital and alphaxalone to flumazenil indicates that neither agents act via the benzodiazepine recognition site at the GABA(A) receptor complex.
Abrupt termination of the treatment of humans with benzodiazepines (BDZs) leads to a rapid onset of discontinuation syndrome characterized by anxiety, muscle spasms, and occasionally convulsions. For this reason, it is recommended in clinical practice to reduce the dose of the BDZs gradually at the end of treatment. Nevertheless, many clinicians report signs of dependence even during gradual reduction of doses (tapering) of the BDZs in a large proportion of patients. Thus, there is considerable interest in discovering means of weaning patients away from BDZs without the risk of discontinuation syndrome. In the present study, mice withdrawn from chronic treatment with alprazolam showed anxiety, muscle rigidity, and seizures between days 1 and 28 after termination of the treatment. Replacement of alprazolam with the beta-carboline abecarnil for 7 days prevented the occurrence of the signs of dependence. In contrast, substitution of the beta-carboline antagonist ethyl-5-isopropoxy-4-methyl-beta-carboline-3-carboxylate (ZK93426) for alprazolam worsened the discontinuation syndrome. Replacement therapy with abecarnil after long-term treatment with the BDZs offers a novel method for rapid tapering.
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