Bettina Bert⁽¹⁾, Andre Rex⁽²⁾, Heidrun Fink^(3)
(1)Institute of Pharmacology and Toxicology. Humboldt-University Berlin, Charite - Berlin. Germany
⁽²⁾Institute of Pharmacology and Toxicology. VB Vterinary medicine, Free University - Berlin. Germany
⁽³⁾Institute of Pharmacology and Toxicology. School of Veterinary Medicine, Free University Berlin - Berlin. Germany

	[Neuroscience]	[Pharmacology]

INTRODUCTION

Studies about anxiety-related behaviour have shown different and sometimes contradictory results even when identical animal models of anxiety were used ⁽¹⁾.

Rat strains kept under identical environmental conditions show distinct baseline levels of anxiety related behaviour ⁽²⁾.

It is reported in literature that strain differences might contribute to different effects to ‘anxiolytic’ or ‘anxiogenic’ drugs ⁽³⁾.

In this study Fischer 344 and Wistar rats were examined after intraperitoneally application of diazepam in an animal model of anxiety.

Additionally, the plasma concentrations of diazepam and three of its metabolites were measured.

It is an aim in future investigations to determine the changes of the behaviour of genetically manipulated animals.Therefore, the knowledge of the behaviour of different rat strains and stocks is indispensable.

MATERIAL & METHODS

Animals: Male Wistar rats (Harlan-Winkelmann and Federal Institute for Healthprotection of consumers and Veterinary medicine, FRG ) and Fischer 344 rats (Harlan-Winkelmann, FRG) 220 ± 30 g, were group housed under a 12 hr light-dark-schedule with food and water freely available. N = 8-10 per group.

Methods: A. Behavioural test

For the investigation of the anxiety-related behaviour the elevated plus maze test was used. The duration of the test was 5 min. The following parameters were measured: Time spent in the open arms, percentage of entries into the open arms, number of head dips and locomotor activity. 30 min before the start of the test the animals received an i.p. injection of saline or diazepam at a dosage of 0.5-4.0 mg/kg.

B. Plasma concentration

The plasma concentrations of diazepam, nordiazepam, temazepam and oxazepam were measured. The animals received an i.p. injection of 2.0 mg/kg diazepam and after 30 min intracardially blood samples were taken. The concentrations were measured by HPLC.

Statistics: All data are shown as means ± SEM. Statistical analysis was performed with one way ANOVA on Ranks followed by Dunn’s Test. Differences of p<0.05 were considered statistically significant.

RESULTS

Elevated plus maze test

A. Saline treated animals

fig. 1

The Harlan-Wistar rats showed a less anxious behaviour in the elevated plus maze test than the Harlan-Fischer and the FIHV-Wistar rats. The Harlan-Wistar rats spent significantly more time in the open arms and showed a higher number of head dips than the two other groups. They also entered the open arms more frequently.

B. Effect of diazepam

fig. 2

This parameter shows representatively that diazepam achieved an axiolytic effect already at a dose of 0.5 mg/kg in the more anxious Harlan-Fischer rats. Whereas, in the less anxious Harlan-Wistar rats diazepam had no anxiolytic effect at a dose of 4.0 mg/kg. In the FIHV-Wistar rats there was a tendency for an anxiolytic effect.

Plasma concentration

fig. 3

The concentrations of diazepam and the three metabolites are significantly increased in the more anxious Harlan-Fischer rats in comparison to both stocks of Wistar rats. Whereas, there is no difference between the two stocks of Wistar rats. Additionally, the Harlan-Fischer rats seem to metabolize diazepam to nordiazepam and temazepam to the same extent.

CONCLUSIONS

In the elevated plus maze test Harlan-Winkelman rats showed a less anxious behaviour than the Harlan-Fischer and the FIHV-Wistar rats.

Additionally, diazepam achieved a more pronounced anxiolytic effect in the more anxious Harlan-Fischer rats compared to the less anxious Harlan-Wistar rats (ceiling effect?).

There is also a big difference in the kinetics of diazepam between the Harlan-Fischer rats and the two stocks of Wistar rats (different liver enzymes?).

These results indicate that there are distinct strain and stock differences in the anxiety related behaviour, in the response to, and, in the kinetics of diazepam.

These differences should be taken into consideration for the interpretation of the test results.

ACKNOWLEDGEMENTS

This work is supported by the BMBF 01 ZZ 9511

REFERENCES

Hogg S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety, Pharmacol. Biochem. Behav. 54 (1996) 21-30.
Rex A, Sondern U, Voigt JP, Franck S and Fink H. Strain differences in fear-motivated behavior of rats, Pharmacol. Biochem. Behav. 54 (1996) 107-111.
Griebel G. 5-hydroxytryptamine interacting drugs in animal models of anxiety disorders: More than 30 years of research, Pharmacol. Ther. 65 (1995) 319-395.

Discussion Board

Any Comment to this presentation?

[ABSTRACT] [INTRODUCTION] [MATERIAL & METHODS] [RESULTS] [IMAGES] [CONCLUSIONS] [ACKNOWLEDGEMENTS] [REFERENCES] [Discussion Board]

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	[Neuroscience]	[Pharmacology]

Bettina Bert, Andre Rex, Heidrun Fink
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Last update: 6/01/00