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Effects of central activation of serotonin 5-HT2A/2C or dopamine D2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test

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Abstract

Rationale

Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect.

Objective

The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats.

Methods

2,5-dimethoxy-4-iodo-amphetamine (DOI, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance disruptive effect of clozapine were tested.

Results

Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance.

Conclusions

Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC.

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Acknowledgments

We would like to thank Ms. Shinn-Yi Chou and Ms. Natashia Swalve for their thoughtful comments on an earlier version of this manuscript. Research reported in this paper was supported by the National Institute of Mental Health of the National Institutes of Health under award number R01MH085635 to Professor Ming Li.

Conflicts of interest

The authors declare no conflict financial interests.

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Authors and Affiliations

  1. Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China

    Min Feng & Nan Sui

  2. Department of Psychology, University of Nebraska-Lincoln, 238 Burnett Hall, Lincoln, NE, 68588-0308, USA

    Min Feng, Jun Gao & Ming Li

  3. Graduate School of Chinese Academy of Sciences, Beijing, China

    Min Feng

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  1. Min Feng
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  2. Jun Gao
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Correspondence to Ming Li.

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Min Feng and Jun Gao contributed equally to this work.

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Feng, M., Gao, J., Sui, N. et al. Effects of central activation of serotonin 5-HT2A/2C or dopamine D2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test. Psychopharmacology 232, 1219–1230 (2015). https://doi.org/10.1007/s00213-014-3756-2

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