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Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors

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Abstract

Rationale

Cognitive deficits, including memory impairment, are regarded as a core feature of schizophrenia. Aripiprazole, an atypical antipsychotic drug, has been shown to improve disruption of prepulse inhibition and social interaction in an animal model of schizophrenia induced by phencyclidine (PCP); however, the effects of aripiprazole on recognition memory remain to be investigated.

Objectives

In this study, we examined the effect of aripiprazole on cognitive impairment in mice treated with PCP repeatedly.

Materials and methods

Mice were repeatedly administered PCP at a dose of 10mg/kg for 14days, and their cognitive function was assessed using a novel-object recognition task. We investigated the therapeutic effects of aripiprazole (0.01–1.0mg/kg) and haloperidol (0.3 and 1.0mg/kg) on cognitive impairment in mice treated with PCP repeatedly.

Results

Single (1.0mg/kg) and repeated (0.03 and 0.1mg/kg, for 7days) treatment with aripiprazole ameliorated PCP-induced impairment of recognition memory, although single treatment significantly decreased the total exploration time during the training session. In contrast, both single and repeated treatment with haloperidol (0.3 and 1.0mg/kg) failed to attenuate PCP-induced cognitive impairment. The ameliorating effect of aripiprazole on recognition memory in PCP-treated mice was blocked by co-treatment with a dopamine D1 receptor antagonist, SCH23390, and a serotonin 5-HT1A receptor antagonist, WAY100635; however, co-treatment with a D2 receptor antagonist raclopride had no effect on the ameliorating effect of aripiprazole.

Conclusions

These results suggest that the ameliorative effect of aripiprazole on PCP-induced memory impairment is associated with dopamine D1 and serotonin 5-HT1A receptors.

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Acknowledgements

This work was supported, in part, as Research on Regulatory Science of Pharmaceuticals and Medical Devices, and Research on Risk of Chemical Substances, Health and Labour Sciences Research Grants from the Ministry of Health, Labor and Welfare, Japan, Academic Frontier Project for Private Universities (2007–2011) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and from Uehara Memorial Foundation, International Research Project supported by The Meijo Asian Research Center (MARC). We are grateful to Otsuka Pharmaceutical Co. for providing the aripiprazole.

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Authors and Affiliations

  1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Taku Nagai & Toshitaka Nabeshima

  2. Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya, 468-8503, Japan

    Rina Murai & Toshitaka Nabeshima

  3. Department of Health-Care Pharmacy, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan

    Kanae Matsui & Hiroyuki Kamei

  4. Division of Clinical Science in Clinical Pharmacy Practice, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan

    Yukihiro Noda

  5. Department of Medical Chemistry, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan

    Hiroshi Furukawa

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  1. Taku Nagai
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Correspondence to Toshitaka Nabeshima.

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ESM Supplemental Fig. 1

Effect of single administrations of aripiprazole on PCP-induced cognitive impairment in novel object recognition. Eight days after withdrawal from repeated PCP (10 mg/kg, s.c., for 14 days) treatment, mice were subjected to the novel-object recognition test. Objects A and B were used in the training. Object B was replaced by object C in the retention session. Aripiprazole (0.01–1.0 mg/kg, p.o.) or vehicle (0.1% CMC) was administered 1 h before the training session. A paired comparisons test for each group comparing the time spent on objects in the training session (a) and retention session (b). Values indicate the mean ± S.E. (n = 8–16). **p < 0.01 compared with object A. (DOC 54.0 KB)

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Nagai, T., Murai, R., Matsui, K. et al. Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors. Psychopharmacology 202, 315–328 (2009). https://doi.org/10.1007/s00213-008-1240-6

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