Reversal of triazolam- and zolpidem-induced memory impairment by flumazenil

Department of Behavioral Biology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Psychopharmacology (Impact Factor: 3.88). 10/1995; 121(2):242-9. DOI: 10.1007/BF02245635
Source: PubMed


The effects of flumazenil, a benzodiazepine receptor antagonist, on triazolam- and zolpidem-induced memory impairment were investigated. Sixty subjects received oral triazolam 0.5 mg, zolpidem 20.0 mg, or placebo at 10 a.m. (n = 20 per drug). Ninety minutes later, half of the subjects (n = 10) in each oral drug group were administered flumazenil 1.0 mg, while the remaining half received placebo (normal saline), through indwelling venous catheters. Learning/memory tests (including Simulated Escape, Restricted Reminding, Paired-Associates, and Repeated Acquisition) were administered at that time, and at 1.5-h intervals over the next 6 h. Triazolam/placebo and zolpidem/placebo drug combinations impaired memory on all tests (all Ps < 0.05). However, the triazolam/flumazenil and zolpidem/flumazenil groups showed no evidence of impairment during any test session. These results demonstrate that flumazenil 1.0 mg rapidly and lastingly reverses memory impairment caused by agonists of the benzodiazepine receptor. Furthermore, nonsignificant trends suggested that performance of the placebo/flumazenil group was consistently better than that of the placebo/placebo group, denoting a possible role of endogenous benzodiazepine agonists in natural sleep/wake processes.

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    • "Number of subjects per group (12) was selected based on power calculations conducted on data from previous studies of stimulants [13] and sleep-inducing compounds in healthy adults [14]. A calculated estimate of power as a function of sample size indicated that a total N of 84 subjects (12 per group) would yield a power above 0.95 [input = 7 groups, a = 0.05, number of measurements = 10, correlation among repeated measures = 0.5, estimated effect size = 0.4]. "
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    ABSTRACT: Introduction The primary purpose of this study was to determine the extent to which low-dose huperzine A, galantamine, or donepezil selectively inhibited acetylcholinesterase (AChE) versus butyrylcholinesterase (BChE) activity in healthy adults and whether such inhibition impacted neurobehavioral performance. Methods In addition to hourly red blood cell cholinesterase sampling, neurobehavioral function was assessed before and after a single oral dose of huperzine A (100 or 200 μg), galantamine (4 or 8 mg), donepezil (2.5 or 5 mg), or placebo (n = 12 subjects per drug/dose). Results Compared to placebo, both dosages of huperzine A and galantamine inhibited circulating AChE but not BChE. With the exception of huperzine A (200 μg), which maintained declarative recall performance across sessions, compounds did not improve neurobehavioral performance. Some aspects of neurobehavioral performance correlated with AChE activity, although associations may have reflected time of day effects. Discussion Although huperzine A and galantamine significantly inhibited AChE (and likely increased central acetylcholine levels), neither compound improved neurobehavioral performance. The latter was likely due to ceiling effects in this young, healthy test population. Under conditions of reduced cholinergic activity (e.g., Alzheimer's disease), AChE inhibition (and corresponding maintenance of cholinergic tone) could potentially maintain/augment some aspects of neurobehavioral function.
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