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Novel object recognition test as a simple screening procedure to evaluation antipsychotic properties of compounds with cognition-enhancing component Aims: Phencyclidine (PCP) as well as ketamine (KET) when given acutely to healthy humans or laboratory animals seem to induce the full spectrum of psychopathology associated with schizophrenia, including positive, negative symptoms and cognitive impairment [1, 2]. For these reasons both compounds are used as a pharmacological model of a schizophrenia-like state. Particularly, PCP/KET models show high predictive value in identifying antipsychotic properties of compounds with cognition-enhancing component. One of the domains of cognition impaired in schizophrenia patients is visual learning and recognition memory, which could be modeled in rodents in a novel object recognition (NOR) test. NOR is simple, non-rewarded paradigm based on spontaneous exploratory activity of rodents and it is considered to be a valid model of human declarative memory. Vast majority of researchers used a regimen of sub-chronic treatment with PCP followed by a wash-out period. However, even single PCP administration produces robust cognitive deficit in NOR test. Thus, the first aim of the present study was to a established simple and reliable screening test based on acute PCP regimen. Atypical antipsychotics, in contrast to typical, seemed to produce more favorable improvement of cognitive impairments. It is postulated that antagonism at 5-HT6 receptor might be is responsible for these effects. Thus, the second aim was to study the effects of various typical and atypical antipsychotics as well as 5-HT6 antagonists in the NOR test to evaluate the usefulness of acute PCP regimen in screening for novel antipsychotic compounds with potential pro-cognitive effects. Methods: Procedure started with 5 min habituation of male Spraque-Dawley rats to the object-free arena, 24 hours before the test. The test session comprised of two trials separated by an inter trial intervals (ITI) of 1 min, 1 or 3 h. During the first trial (familiarization, T1) two identical objects (A1 and A2) were presented in opposite corners of the open field. In the second trial (recognition, T2) one of the objects was replaced by a novel one (A=familiar and B=novel). Both trials lasted 3 min and rats were returned to their home cage after T1. PCP or KET was administrated (IP) 45 min before T1. Sertindole (PO) was given 2 h before T1. Other compounds: haloperidol (SC), clozapine (SC), olanzapine (IP), quetiapine (IP), SB271046 (IP) and SB399885 (IP) were given 1.15 h before T1. N=6-10 rat per treatment. For statistical analysis Student’s paired t-test and one-way ANOVA were performed. Results: Single administration of either PCP or KET showed dose-dependent memory deficits which lasted in case of PCP even up to 3 hours. The 1 hour ITI was chosen for further experiments. As expected, haloperidol not only did not reverse PCP-induced cognitive deficits, but also decreased the time of object exploration during familiarization phase. Interestingly, all atypical antipsychotics and both 5-HT6 antagonists reversed the PCP-induced cognitive impairment without affecting familiarization phase. Conclusions: Our study confirms that even single PCP or KET administration produce a robust cognitive deficit in the NOR test that lasted even up to 3 hours. Reversion of PCP-induced cognitive impairment by various atypical antipsychotics and also 5-HT6 antagonists, underlined high predictive value of the acute procedure for simple and fast screening of novel compounds. This study was supported by statutory funds from the Institute of Pharmacology, Polish Academy of Sciences (Kraków, Poland) and the project WND- POIG.01.01.02-12-004/09 (DeMeTer) co-financed by European Union from the European Fund of Regional Development (EFRD). [1] Javitt DC and Zukin SR (1991) Am J Psychiatry 148(10):1301-8. [2] Krystal JH et al., (1994) Arch Gen Psychiatry 51(3):199-214.
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