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 (Berl). 2007 Jul;193(1):45-54. doi: 10.1007/s00213-007-0762-7. Epub 2007 Mar 29.

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) D(2)/D(3) and serotonin 5-HT(1A) receptor agonists. A novel class of potential antipsychotics (SSR181507, bifeprunox, and SLV313) possess partial agonist/antagonist properties at D(2) receptors and various levels of 5-HT(1A) 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-HT(1A) receptor antagonist WAY100,635 (0.63 mg/kg) showed that the 5-HT(1A) agonist activity of SSR181507 was responsible for its effect. By contrast, antipsychotics with low affinity and/or efficacy at 5-HT(1A) receptors, such as aripiprazole (another DA D(2)/D(3) and 5-HT(1A) 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-HT(1A) agonist activity, coupled with partial agonist activity at DA D(2) 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.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Dopamine D2 Receptor Antagonists
  • Dose-Response Relationship, Drug
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists*
  • Reflex, Startle / drug effects*
  • Serotonin 5-HT1 Receptor Agonists*

Substances

  • Antipsychotic Agents
  • Dopamine D2 Receptor Antagonists
  • Receptors, Dopamine D2
  • Serotonin 5-HT1 Receptor Agonists