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.
BACKGROUND
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.


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).


CONCLUSIONS
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.
Auclair
Agnès L
AL
Division of Neurobiology 2, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106, Castres, France. agnes.auclair@pierre-fabre.com
Galinier
Alexandra
A
Besnard
Joël
J
Newman-Tancredi
Adrian
A
Depoortère
Ronan
R
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013216:Reflex, Startle / Q000187:drug effects*; D058825:Serotonin 5-HT1 Receptor Agonists
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists