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Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance conditioning

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Abstract

Rationale

Acute antipsychotic treatment disrupts conditioned avoidance responding, and repeated treatment induces a sensitization- or tolerance-like effect. However, the neurochemical mechanisms underlying both acute and repeated antipsychotic effects remain to be determined.

Objective

The present study examined the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine effect in a rat two-way conditioned avoidance model.

Methods

Well-trained Sprague–Dawley rats were administered with haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with either saline, quinpirole (a selective dopamine D2/3 agonist, 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI; a selective 5-HT2A/2C agonist, 2.5 mg/kg, sc), and their conditioned avoidance responses were tested over 3 days. After 2 days of drug-free retraining, the repeated treatment effect was assessed in a challenge test.

Results

Pretreatment of quinpirole, but not DOI, attenuated the acute haloperidol-induced disruption of avoidance responding and to a lesser extent, olanzapine-induced disruption. In contrast, pretreatment of DOI, but not quinpirole, attenuated the acute effect of clozapine. On the repeated effect, pretreatment of DOI, but not quinpirole, attenuated the potentiated disruption of haloperidol, whereas pretreatment of quinpirole attenuated the potentiated disruption of olanzapine but enhanced the tolerance-like effect of clozapine.

Conclusions

These findings suggest that acute haloperidol and olanzapine disrupt avoidance responding primarily by blocking dopamine D2 receptors, whereas acute clozapine exerts its disruptive effect primarily by blocking the 5-HT2A receptors. The repeated haloperidol effect may be mediated by 5-HT2A/2C blockade-initiated neural processes, whereas the repeated clozapine and olanzapine effect may be mediated by D2/3 blockade-initiated neural processes.

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Acknowledgments

This study was supported in part by the NARSAD Young Investigator Award (2007–2009), and the NIMH (R21MH079894) grant to Professor Ming Li. We thank Mr. Wei He and Ms. Natashia Swalve for their technical and editorial help. We also thank two anonymous reviewers for their extensive and constructive comments on earlier drafts of this manuscript.

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Authors and Affiliations

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

    Ming Li, Tao Sun & Chen Zhang

  2. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China

    Tao Sun & Gang Hu

  3. Shanghai Mental Health Center, Shanghai Jiaotong University, 600 South Wanping, Xuhui District, Shanghai, People’s Republic of China

    Chen Zhang

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  1. Ming Li
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  2. Tao Sun
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Correspondence to Ming Li.

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Li, M., Sun, T., Zhang, C. et al. Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance conditioning. Psychopharmacology 212, 45–57 (2010). https://doi.org/10.1007/s00213-010-1925-5

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