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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.

Auclair AL, Galinier A, Besnard J, Newman-Tancredi A, Depoortère R.
Psychopharmacology (Berl). 2007 Jul;193(1):45-54. Epub 2007 Mar 29.

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.