Comparison of the effects of antipsychotic drugs in two antipsychotic screening assays: swim-induced grooming and apomorphin climbing test in mice
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1
Behavioural Pharmacology, Gedeon Richter Ltd, Hungary
Introduction The antagonism of apomorphine-induced climbing behaviour and sniffing and the swim-induced grooming test are widely used models for screening antipsychotic drugs. It is hypothesized that blockade of climbing behaviour evoked by apomorphine is related to the dopamine receptor blockade in the nucleus accumbens and antagonism of stereotyped sniffing produced by apomorphine is related to the blockade of dopamine D2 receptors in the striatum. The dopamine receptor antagonist antipsychotics inhibit both apomorphine-induced behaviours, although compounds with strong 5-HT2A inhibitory effect show higher potency in blocking the climbing vs. the sniffing response. The grooming behaviour induced by immersion in water involves mainly dopamine D1 receptors. This behaviour is inhibited in a dose dependent manner by dopamine receptor antagonists. The aim of our study was to compare these two screen assays in terms of their sensitivity to the actions of various antipsychotic compounds. We investigated the effect of a conventional neuroleptic (haloperidol), atypical antipsychotics (clozapine, olanzapine, risperidone, ziprasidone, amisulpride) and new generation, partial D2 agonist antipsychotics (arpiprazole, bifeprunox) in these screening methods.
Methods Climbing and sniffing: Male CD-1 mice were injected orally with the test compound or vehicle. Fifty minutes later the animals were placed into cylindrical cages. After 10 minutes habituation the mice were treated with apomorphine (1.5 mg/kg sc.). Ten minutes after APO treatment each animal was observed for 15 minutes. Every minute the climbing behaviour was scored. Animals were also rated for repetitive sniffing as a measure of stereotypy. Scores for both behaviours were summed for each individual and group means were calculated. Drug effect was expressed and plotted as percentage inhibition of the apomorphine-induced behaviour. Swim incuced grooming: Male NMRI mice were used. Sixty minutes after drug treatment, mice were placed individually in swimming cylinders filled with water for 3 min. They were then removed and dried with towel for 30 sec. and placed immediately into single perspex boxes. The number and the total duration of grooming episodes in seconds were recorded for 15 min. Dose-response curve was plotted for each compound and ED50 values were determined by linear regression.
Results Apomorphine-induced climbing and sniffing were potently and dose-dependently blocked by the compounds. The order of potency of antipsychotics on climbing inhibition was bifeprunox = risperidone ~ haloperidol > aripiprazole ~ olanzapine > ziprasidone ~ clozapine >> amisulpride. The order of potency of antipsychotics in blocking sniffing was bifeprunox > haloperidol ~ risperidone > aripiprazole > olanzapine = ziprasidone >> amisulpride > clozapine. Post-swimming grooming time was inhibited dose-dependently by risperidone = bifeprunox > haloperidol > olanzapine > clozapine > aripiprazole = ziprasidone. Interestingly, amisulpride elevated rather than decreased the grooming time at doses of 30 and 60 mg/kg ip while it had no effect after 120 mg/kg ip.
Conclusion Compounds which showed potent apomorphine-induced climbing inhibition relative to sniffing inhibition (risperidone, olamzapine, clozapine) have high 5-HT2A receptor antagonist effect. Olanzapine and clozapine, which have considerable dopamine D1 receptor antagonist effect, showed potent blockade of swim-induced grooming relative to their climbing inhibition. As the two widely used screening methods showed different sensitivity to the various antipsychotics their parallel use in antipsychotic screening systems is therefore warranted.
Conference:
12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009.
Presentation Type:
Poster Presentation
Topic:
Behavioural neuroscience
Citation:
Kedves
R,
Saghy
K and
Gyertyan
I
(2009). Comparison of the effects of antipsychotic drugs in two antipsychotic screening assays: swim-induced grooming and apomorphin climbing test in mice.
Front. Syst. Neurosci.
Conference Abstract:
12th Meeting of the Hungarian Neuroscience Society.
doi: 10.3389/conf.neuro.01.2009.04.093
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Received:
03 Mar 2009;
Published Online:
03 Mar 2009.
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Correspondence:
Rita Kedves, Behavioural Pharmacology, Gedeon Richter Ltd, Budapest, Hungary, r.kedves@richter.hu