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Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice

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Abstract

Rationale

Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients.

Objectives

In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD.

Results

Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density.

Conclusions

These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.

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Acknowledgments

This study was supported in part by JSPS KAKENHI [JP13J05359 (YH), JP25460099 (YA), JP26293020 (HH), JP26670122 (HH), JP15H01288 (HH), and JP16K15126 (KT)], the Neuropsychiatry Drug Discovery Consortium established by Dainippon Sumitomo Pharma Co., Ltd. (Japan) with Osaka University (TM, HH), Dainippon Sumitomo Pharma Joint Research Fund (KT), Uehara Memorial Foundation (Japan) (KT), the JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2603; HH), and the SRPBS and Brain/MINDS from AMED (HH).

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Authors and Affiliations

  1. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yuta Hara, Yukio Ago, Atsuki Taruta, Haruki Kawase, Wataru Tanabe, Shinji Tsukada, Takanobu Nakazawa & Hitoshi Hashimoto

  2. Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Shigeru Hasebe, Takanobu Nakazawa & Kazuhiro Takuma

  3. United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Hitoshi Hashimoto & Kazuhiro Takuma

  4. Division of Bioscience, Institute for Datability Science, Osaka University, 1-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Hitoshi Hashimoto

  5. Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Toshio Matsuda

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  1. Yuta Hara
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Supplementary Fig. S1

Effects of acute and chronic administration of antipsychotic drugs on extracellular noradrenaline (NA) levels in the prefrontal cortex of mice prenatally exposed to VPA. Male offspring, born to mothers treated with saline (a, c) or VPA (500 mg/kg, i.p.) (b, d) on gestation day 12.5, were subjected to the experiments at 8 weeks of age. Risperidone (0.2 mg/kg), aripiprazole (3 mg/kg), haloperidol (0.1 mg/kg) or vehicle was administered intraperitoneally at 0 min (arrow). Extracellular NA levels in the prefrontal cortex of male offspring were measured by microdialysis. (a, b) Changes after first administration. (c, d) Changes at the final day of 2 week-chronic administration. Values indicate the means ± SEM (n = 6). † P < 0.05, †† P < 0.01, ††† P < 0.001, compared to the vehicle-treated mice. (PDF 477 kb)

Supplementary Fig. S2

Effects of acute and chronic administration of antipsychotic drugs on extracellular serotonin (5-HT) levels in the prefrontal cortex of mice prenatally exposed to VPA. Male offspring, born to mothers treated with saline (a, c) or VPA (500 mg/kg, i.p.) (b, d) on gestation day 12.5, were subjected to the experiments at 8 weeks of age. Risperidone (0.2 mg/kg), aripiprazole (3 mg/kg), haloperidol (0.1 mg/kg) or vehicle was administered intraperitoneally at 0 min (arrow). Extracellular 5-HT levels in the prefrontal cortex of male offspring were measured by microdialysis. (a, b) Changes after first administration. (c, d) Changes at the final day of 2 week-chronic administration. Values indicate the means ± SEM (n = 6). † P < 0.05, compared to the vehicle-treated mice. (PDF 424 kb)

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Hara, Y., Ago, Y., Taruta, A. et al. Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice. Psychopharmacology 234, 3217–3228 (2017). https://doi.org/10.1007/s00213-017-4703-9

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