Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/alpha1-preferring antagonist beta-CCt in squirrel monkeys. Zolpidem and triazolam interact differentially with a delay interval on a digit-enter-and-recall task. GABA(A) receptor heterogeneity in histaminergic neurons. Ambien online references

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A gentle long-lasting handling produces persistent neurochemical and behavioural changes and attenuates the impairment in the behavioural reactivity to novelty induced by the prenatal exposure to diazepam (DZ) in adult male rat progeny. This study investigated the consequences of a late prenatal treatment with three GABA/BDZ R agonists (DZ) alprazolam (ALP) and zolpidem (ZOLP)), on different stress-related behavioural patterns, in non-handled (NH), short-lasting handled (SLH) and long-lasting handled (LLH) adult male rats exposed to forced swim test (FST), acoustic startle reflex (ASR) and Vogel test (VT). The effects on motor activity were evaluated in the open field and in the Skinner box. The seizure sensitivity to picrotoxin (PTX) was investigated as an index of the functional state of GABA/BDZ Rs. A single daily s.c. injection of DZ (1.25-2.50 mg/kg) and ALP (0.125-0.250 mg/kg) over gestational days 14-20 induced a decrease in immobility time in the FST in NH rats, no change in SLH rats and an increase in LLH rats; DZ induced an increase in the peak amplitude of the ASR in NH rats, no change in SLH rats and a reduction in LLH rats; ALP was ineffective in all groups. DZ and ALP reduced the number of punished licks in the VT in NH, SLH and LLH rats while the unpunished licks were not modified. DZ decreased locomotion and the lever pressing responses while ALP increased them. DZ and ALP increased the seizure sensitivity to PTX (2.5-4.0 mg/kg i.p.). These findings indicate a convergence on anxiety-related behaviours in the effects of prenatal exposure to DZ and ALP and a differentiation on motor activity. Long-lasting handling was able to overcompensate the increased behavioural stress reactivity induced by the prenatal exposure to DZ and ALP.

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Psychopharmacology (Berl). 2002 Nov;164(2):151-9. Epub 2002 Sep 04.
Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/alpha1-preferring antagonist beta-CCt in squirrel monkeys.

Platt DM, Rowlett JK, Spealman RD, Cook J, Ma C.

Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102, USA. donna_platt

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hms.harvard.edu

RATIONALE: Delineation of the receptor mechanisms underlying the behavioral effects of benzodiazepines should allow for the development of drugs with improved clinical utility and reduced side effects. OBJECTIVES. The purpose of the present study was to investigate the role of GABAA/alpha1 receptors in the sedative and motor-impairing effects of benzodiazepines. METHODS: Squirrel monkeys were tested with the GABAA/alpha1-preferring agonist zolpidem and the nonselective benzodiazepine agonist triazolam alone and in combination with the GABAA/alpha1-preferring antagonist beta-CCt and the nonselective benzodiazepine antagonist flumazenil. During 30-min experimental sessions, all occurrences of normal behaviors like locomotion, environment- and self-directed behaviors, as well as side effects such as ataxia, rest and procumbent postures were scored. RESULTS: Zolpidem and triazolam produced dose-dependent reductions in locomotion and environment-directed behavior and increased ataxia and procumbent posture. Triazolam, but not zolpidem, also engendered species-typical rest posture at some doses. Flumazenil antagonized all of the behavioral effects of zolpidem and triazolam, whereas beta-CCt antagonized only zolpidem- and triazolam-induced ataxia. CONCLUSIONS: GABAA/alpha1 receptor mechanisms appear to play a key role in the ataxic effects of benzodiazepine agonists in squirrel monkeys, similar to recent results with transgenic mice. In contrast to the findings of these recent studies, GABAA mechanisms other than or in addition to those mediated at the alpha1 subunit may play a more important role in the sedative/hypnotic effects of benzodiazepines in squirrel monkeys.

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Hum Psychopharmacol. 2001 Mar;16(2):147-157.
Zolpidem and triazolam interact differentially with a delay interval on a digit-enter-and-recall task.

Rush CR, Baker RW.

Department of Behavioral Science, and Department of Psychiatry, College of Medicine, University of Kentucky, Lexington, KY 40536-0086, USA.

Zolpidem (AMBIEN((R))), an imidazopyridine, is now the most commonly prescribed hypnotic in the United States. Zolpidem is neuropharmacologically distinct from benzodiazepine hypnotics in that it binds with low affinity to alpha(5)-containing GABA(A)-receptor subtypes. Despite its unique benzodiazepine-receptor binding profile, the results of most of the published studies conducted with humans suggest that the absolute magnitude of impairment produced by zolpidem is comparable to that observed with benzodiazepine hypnotics like triazolam. The present study compared the acute effects of zolpidem (0, 7.5, 15 and 22.5 mg) and triazolam (0, 0.1875, 0.375 and 0.5625 mg) in 10 non-drug-abusing humans using a Digit-Enter-and-Recall task with varying delay intervals (0, 10 and 20 s). To more fully characterize the behavioral effects of zolpidem and triazolam, several other performance tasks and subject-rated drug-effect questionnaires were included. Zolpidem and triazolam impaired performance on the Digit-Enter-and-Recall task as a function of dose under all delay intervals. However, the dose-related effects of the drugs interacted differentially with the delay interval such that zolpidem produced significantly less impairment than triazolam following the longest delay (i.e., 20 s). Zolpidem and triazolam produced comparable dose-related impairment on the digit symbol substitution test (DSST), circular lights task, and picture recall/recognition task. Zolpidem and triazolam generally produced qualitatively and quantitatively similar subject-rated drug effects, although some between-drug differences were observed. Consistent with the pharmacokinetics of these drugs, the effects of zolpidem peaked sooner and were shorter in duration than those observed with triazolam. The results of this experiment suggest that zolpidem may have less potential than triazolam to impair recall, which may be due to differences between these compounds in terms of their benzodiazepine-receptor binding profile. The results of the present study are also concordant with previous studies that found that drugs that act at the GABA(A)-receptor complex can be differentiated based on their interaction with the delay interval on a Digit-Enter-and-Recall task. Copyright 2001 John Wiley & Sons, Ltd.

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Eur J Neurosci. 2002 Oct;16(8):1472-82.
GABA(A) receptor heterogeneity in histaminergic neurons.

Sergeeva OA, Eriksson KS, Sharonova IN, Vorobjev VS, Haas HL.

Department of Neurophysiology, Heinrich-Heine-Universitat, D-40001 Dusseldorf, Germany. olga.sergeeva

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