Original article
The object recognition task in rats and mice: A simple and rapid model in safety pharmacology to detect amnesic properties of a new chemical entity

https://doi.org/10.1016/j.vascn.2006.04.001Get rights and content

Abstract

Introduction

The aim of the present study was to evaluate the potential usefulness of the object recognition learning paradigm to detect the potential amnesic properties of a new drug for use in the characterisation of its safety pharmacology profile.

Methods and Results

In the first experiment, the time-dependent decay of object recognition memory was characterised in Sprague–Dawley rats and C57Bl/6J mice. Under our experimental conditions, it takes between 3 and 4 post-training hours for the rats and between 1 and 2 post-training hours for the mice to forget the respective value of the objects. In the second experiment, the effects of scopolamine (0.03–1 mg/kg) were investigated in both rats and mice when administered 30 min prior to training in the object recognition task. Memory retention was tested 2 h after training in rats and 1 h after training in mice. Scopolamine impairs the object recognition memory at doses of 0.1, 0.3, and 1 mg/kg in rats and at doses of 0.3 and 1 mg/kg in mice. In the last experiment, effects of two benzodiazepines (alprazolam and diazepam) were assessed in the mouse model of object recognition task. Diazepam and alprazolam were intraperitoneally administered 30 min prior to training and memory retention was tested 10 min and 1 h after training. At 0.2 mg/kg, both benzodiazepines impair object recognition memory when testing is performed 1 h after training. However, when testing is performed 10 min after training, both benzodiazepines at 0.2 mg/kg failed to disrupt memory processes.

Discussion

Taken together, these results show that the object recognition task can easily be performed in rats and mice for safety pharmacology studies related to CNS function. Because of the ageing population and the increasing number of drugs prescribed to elderly patients, it becomes important to evaluate the potential side effects of a new chemical entity on memory function during evaluation of its safety profile. The object recognition task, which is simple, rapid, and reliable, should be of great use in safety pharmacology to detect amnesic properties of new compounds.

Introduction

According to the ICH S7A Guideline for Safety Pharmacology Studies, safety pharmacology can be defined as the investigation of “the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.” To study potential adverse pharmacodynamic effects of a new chemical entity on the central nervous system, the ICH guideline strongly recommends to first perform a core battery of appropriate tests and, if necessary, to perform follow-up studies to provide a better understanding of the effects detected in the core battery studies or in clinical and/or toxicology studies. Among the different CNS functions investigated in the different follow-up studies cited in the guideline, an important function of the central nervous system is learning and memory. More specifically, from a safety pharmacology point of view, identification of amnesic properties of a new substance may be of major importance.

As a consequence of the continuous increase in life expectancy, the global patient population is aging, and as such, there are previsions for an increasing incidence of neurodegenerative disorders such as Alzheimer's disease (AD); there is a growing interest in developing new compounds providing symptomatic relief and improving quality of life of patients, especially geriatrics. There is a general agreement on the existence of a normal cognitive decline in memory performance from early to late adulthood and that disorders such as AD are associated with a global impairment of higher functions and cognitive faculties, among them, a symptomatic loss of memory. Because elderly people are the main users of drugs, it seems important to evaluate during preclinical development the potential impact of a new chemical entity on memory function. In safety pharmacology, the assessment of memory function will have to answer the following question: will this new substance impair memory and induce amnesia?

The goal of the present experiments was to investigate whether the object recognition task performed in rodents could be a simple, rapid, and useful way to detect amnesic properties of a new chemical entity in the setting of safety pharmacology studies. This learning and memory paradigm, initially described by Ennaceur and Delacour (1988), is based on natural, exploratory abilities of rodents exposed to a new environment. In this learning paradigm, the difference in exploration between a previously seen object and a novel object is taken as an index of memory performance. The object recognition task is considered as a model of short-term episodic memory. Experiments presented in this study were first designed to characterise the experimental conditions for rats and mice and then to validate the model with different compounds known for their amnesic properties. In a first series of experiments, we assessed the memory span of Sprague–Dawley rats and of C57Bl/6J mice under our experimental conditions. The second series of experiments was designed to evaluate the sensitivity of both species to scopolamine, a muscarinic receptor antagonist that disrupt memory storage (Drachman & Leavitt, 1974). Finally, the last experiment was performed to assess in mice the amnesic properties of alprazolam and diazepam, two benzodiazepines.

Section snippets

Animals

All experiments were conducted in compliance with French regulations, with the European Directive 1986/609/CEE and with OCDE GLP principles (ENV/MC/CHEM(98)).

The experiments were performed using male C57Bl/6J mice (Centre d'Elevage Janvier, France) weighing 25–30 g (10–12 weeks old) at arrival (10–12 weeks old) and male Sprague–Dawley rats (Centre d'Elevage Janvier, France), weighing 220–300 g (6–7 weeks old). The animals were used for experimentation after adaptation to the laboratory

Results

The present publication gathers all the data from different experiments performed at Biotrial in the scope of the set-up of the model.

Discussion

In the present study, we investigated whether the object recognition learning paradigm performed in rodents could easily be used in safety pharmacology studies to evaluate amnesic properties of new compounds.

In a first approach, recognition memory of rats and mice was assessed in order to define the onset of forgetting under our experimental conditions. Sprague–Dawley rats recognised a familiar object from 10 min up to 3 h after the end of the acquisition trial. Between 3 and 4 h post-training,

Acknowledgements

We thank Emilie Gérente, Céline Proth, and Marie Bureau for their technical assistance and Stéphanie Le Goaller for statistical analyses.

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