Novel oral drug administration in an animal model of neuroleptic therapy

https://doi.org/10.1016/j.jneumeth.2005.02.004Get rights and content

Abstract

A novel method of oral drug administration was used in a neuroleptic animal study. Seventy male Sprague-Dawley rats were randomly subdivided into four groups, which were treated with clozapine, haloperidol, diazepam or a vehicle solution (5% sucrose solution). Oral drug treatment was achieved by training the rats to drink the drug of choice mixed with five percent sucrose or vehicle solution from a syringe.

Within 3–4 weeks the haloperidol group developed vacuous chewing movement, which did not disappear with discontinuation of the drug. Significant weight gain was observed for all drug groups in relation to the control group, whereas only the diazepam group showed a significant increase in response latency on the disengage test of sensorimotor function, which disappeared with drug withdrawal.

A novel means of testing the motivational status showed that all drug-treated groups engaged in eating chocolate before grooming (t = 11.69, p < 0.001), whereas the control group showed no specific tendency towards either task. Furthermore, there was a significant delay in grooming for the haloperidol group compared to the other drug groups and controls.

In conclusion, a novel method of oral drug administration with minimum stress was introduced that was sufficient to cause the described changes in behavioural parameters. Additionally, the combination of tests used provided an efficient discrimination between the behavioural effects of clozapine, haloperidol and diazepam in rodents.

Introduction

Previous studies have successfully used oral drug administration in neuroleptic models, where the drug of choice was either administered by gavage or added to the drinking water, after a deprivation period to ensure compliance (Gao et al., 1997, Ossowska et al., 2002, Schmitt et al., 1999, See and Chapman, 1994, Sun and Lau, 2000). The following study introduces a novel alternative to the previously used method, where a mixture of 5% sucrose solution and neuroleptic drug (clozapine, haloperidol or diazepam) was given to the test animals using a syringe for oral administration. This new method permits accurate drug administration with minimum stress to the animals.

Typical and atypical neuroleptic drug administration in rodents is a commonly used animal model to mimic some of the clinical features seen with neuroleptic drug administration. Previous rodent studies have shown that treatment with typical (e.g. haloperidol), but not with atypical neuroleptics (e.g. clozapine), will induce extrapyramidal behavioural effects such as vacuous chewing movements (Casey, 2000, Gao et al., 1997, Turrone et al., 2002). This phenomenon is considered to be an analogue to clinical tardive dyskinesia, which can occur with long term treatment of typical antipsychotics (Casey, 2000, Turrone et al., 2002).

Previous rodent studies have shown that clozapine has a similar anxiolytic effect to benzodiazepines in rodents, despite its clinical use as a neuroleptic (Sun and Lau, 2000; Weiner et al., 2003). Furthermore, it generally does not cause extrapyramidal side effects, which are not uncommonly seen after typical neuroleptics (Turrone et al., 2002). Whilst clozapine has a similar anxiolytic action to benzodiazepines it potentiates latent inhibition (Weiner et al., 2003), unlike benzodiazepines. Latent inhibition is defined as a retarded conditioning to a stimulus as a consequence of its inconsequential pre-exposure (Russig et al., 2003, Weiner et al., 2003, Zuckerman et al., 2003). While the use of benzodiazepines is not a standard clinical procedure, clinical trials have shown that benzodiazepines may be beneficial alone for the acute treatment of positive symptoms or in combination with neuroleptics in the treatment of schizophrenia (Wassef et al., 1999, Wassef et al., 2000, Wolkowitz and Pickar, 1991). This study therefore compared the behavioural patterns of atypical (e.g. clozapine) and typical neuroleptics (e.g. haloperidol) and benzodiazepines (e.g. diazepam).

Previous studies have concentrated on behavioural parameters, such as latent inhibition, forced swimming and weight gain, which have been used to dissociate between drug-specific side effects (Russig et al., 2003, Schmitt et al., 1999, Weiner et al., 2003, Zuckerman et al., 2003), but the motivational status in rats administered these drugs has not been tested previously. A novel assessment of motivational status was created to assess the effect of drug treatment on exploratory as well as motivational behaviour.

The purpose of this study was to use a novel means of oral drug administration in rodents to investigate behavioural effects (including possible extrapyramidal features) associated with clozapine, haloperidol and diazepam. A time period of 7 weeks was chosen to ensure the effectiveness of the drug therapy and to test for the reversibility of behavioural effects by withdrawing drug treatment. The effectiveness and specificity of drug treatment was tested by comparing several behavioural parameters (including weight, response latency and motivational status) between drug- and control-treated groups.

Section snippets

Animals

Seventy male Sprague-Dawley rats (LAB-animal services, Perth, Australia), weighing approximately 350 g on arrival were used in these experiments. Rats were housed in groups of five in an animal house under constant room temperature and humidity on a 12 h light–dark cycle (light on 06:00–18:00), and had access to food and water ad libitum. All rats were given a habituation time of 2 weeks before being tested.

Drugs

Clorazil 25 tablets (clozapine 25 mg, Novatis Pharmaceuticals Australia) were totally

Overall behaviour

After habituation, all rats cooperated with the daily drug administration without any difficulties. This became obvious when the tests animals lined up at the rim of the cage as soon as the cage was opened to receive their daily solution. The total time to administer 2 ml of solution to 70 rats was decreased from 3 h initially to 45 min by week three due to the above-mentioned habituation to this procedure.

Overall, all participating animals displayed minimal levels of stress, which was reflected

Drug administration

The behavioural results indicate that the route of drug administration was effective, with the amount of drug delivered being high enough to induce drug-related side effects in the test animals. The daily contact with the rats influenced the behavioural testing in a positive manner, since the animals were used to being handled on a daily basis without being harmed in any way. This was reflected by the voluntary participation in both drug administration and behavioural testing.

This study aimed

Acknowledgements

This work was supported by National Institute of Schizophrenia and Allied Disorders, utilising infrastructure funding from New South Wales Health, Australia. The authors wish to thank Mr Haydn Allbutt for his technical assistance.

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