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Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats

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Abstract

Introduction

Prepulse inhibition (PPI) of the startle reflex has been extensively studied because it is disrupted in several psychiatric diseases, most notably schizophrenia. In rats, and to a lesser extent, in humans, PPI can be diminished by dopamine (DA) D2/D3 and serotonin 5-HT1A receptor agonists. A novel class of potential antipsychotics (SSR181507, bifeprunox, and SLV313) possess partial agonist/antagonist properties at D2 receptors and various levels of 5-HT1A activation.

Materials and methods

It thus appeared warranted to assess, in Sprague-Dawley rats, the effects of these antipsychotics on basal PPI.

Results

SSR181507, sarizotan, and bifeprunox decreased PPI, with a near-complete abolition at 2.5–10 mg/kg; SLV313 had a significant effect at 0.16 mg/kg only. Co-treatment with the 5-HT1A receptor antagonist WAY100,635 (0.63 mg/kg) showed that the 5-HT1A agonist activity of SSR181507 was responsible for its effect. By contrast, antipsychotics with low affinity and/or efficacy at 5-HT1A receptors, such as aripiprazole (another DA D2/D3 and 5-HT1A ligand), and established typical and atypical antipsychotics (haloperidol, clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) had no effect on basal PPI (0.01–2.5 to 2.5–40 mg/kg).

Discussion

The present data demonstrate that some putative antipsychotics with pronounced 5-HT1A agonist activity, coupled with partial agonist activity at DA D2 receptors, markedly diminish PPI of the startle reflex in rats.

Conclusions

These data raise the issue of the influence of such compounds on sensorimotor gating in humans.

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Acknowledgments

The authors thank Solvay Pharmaceuticals for supplying SLV313. All authors of this manuscript are employees of the Pierre Fabre Research Center.

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  1. Division of Neurobiology 2, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106, Castres, France

    Agnès L. Auclair, Alexandra Galinier, Joël Besnard, Adrian Newman-Tancredi & Ronan Depoortère

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  1. Agnès L. Auclair
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  2. Alexandra Galinier
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  3. Joël Besnard
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Correspondence to Agnès L. Auclair.

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Auclair, A.L., Galinier, A., Besnard, J. et al. Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats. Psychopharmacology 193, 45–54 (2007). https://doi.org/10.1007/s00213-007-0762-7

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