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Factors triggering abolishment of benzodiazepines effects in the Four-Plate Test--retest in mice
B Petit-Demoulière1, M Hascoët, M Bourin
1EA 3256 Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, BP 53508, 1 Rue Gaston Veil, F44035 Nantes Cedex 01 France.
Abstract:
Abolishment of anxiolytic-like effects of diazepam occurs during re-exposure to some animal tests of anxiety. We investigated the loss of anxiolytic-like effects of diazepam during Trial 2 on previously undrugged mice, namely one-trial tolerance (OTT). Swiss mice were subjected to 1) Four-Plate Test (FPT) without punishments in Trial 1 or 2) FPT without punishments in both Trials or 3) FPT with spatial modifications in Trial 1 or 4) Elevated Plus Maze (EPM), then 24 h later to FPT, with saline, diazepam (1 mg/kg) or DOI (1 mg/kg). Removing punishments in Trial 1 does not counteract the effect reduction of diazepam in Trial 2, but spatial modifications of the aversive environment. Previous exposure to EPM does not trigger a loss of efficacy of diazepam in FPT. Electric punishments do not trigger OTT to benzodiazepines; whilst knowledge of the environment seems to be responsible for this phenomenon. FPT may be useful to study OTT because punishments potentate OTT in this model of anxiety.
Insights
One-trial tolerance (OTT) to diazepam
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Anxiolytic effects of diazepam can be lost upon re-exposure to anxiety tests.
- One-trial tolerance (OTT) describes this rapid loss of drug efficacy.
- Understanding OTT is crucial for interpreting animal models of anxiety and drug effects.
Purpose of the Study:
- To investigate the mechanisms underlying the loss of diazepam's anxiolytic-like effects in a second trial.
- To determine if environmental factors, such as spatial modifications or prior exposure to different tests, contribute to OTT.
- To evaluate the role of punishments in the development of OTT to diazepam.
Main Methods:
- Swiss mice were used in a repeated-measure design involving the Four-Plate Test (FPT) and the Elevated Plus Maze (EPM).
- Experimental conditions included variations in punishment (electric shock) and spatial modifications in the FPT during Trial 1.
- Mice were re-tested 24 hours later in the FPT under saline, diazepam, or DOI administration.
Main Results:
- Removing punishments in Trial 1 did not prevent the reduction of diazepam's effects in Trial 2.
- Spatial modifications of the aversive environment in Trial 1 counteracted the reduction in diazepam's efficacy.
- Prior exposure to the Elevated Plus Maze (EPM) did not induce OTT to diazepam in the FPT.
- Electric punishments did not induce OTT to benzodiazepines; environmental familiarity appeared to be the key factor.
- Punishments potentiated OTT in the FPT model.
Conclusions:
- Environmental familiarity, not punishments, appears to be the primary driver of one-trial tolerance to diazepam.
- The Four-Plate Test (FPT) is a valuable tool for studying OTT due to the potentiation of tolerance by punishments.
- Findings suggest that careful consideration of environmental context is necessary when interpreting drug effects in animal models of anxiety.
