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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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.
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).
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.
These data raise the issue of the influence of such compounds on sensorimotor gating in humans.
Keywords5-HT1A agonist Antipsychotics Dopamine D2 antagonist Prepulse inhibition Sensorimotor gating Startle reflex
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