Some, but not all, antipsychotic drugs potentiate a low level of prepulse inhibition shown by rats of the Wistar strain.
In a previous study using Sprague-Dawley rats, we showed that in a prepulse inhibition (PPI) procedure with levels of PPI ranging from approximately 10 to 40% (for prepulse intensities 2, 9 and 15 dB above background noise), the antipsychotics clozapine and haloperidol, but also the alpha 1 adrenoceptor antagonist prazosin, robustly and dose-dependently potentiated PPI. In contrast, the antipsychotics risperidone, amisulpride, raclopride and remoxipride did not potentiate PPI. The false positive (prazosin) and the four false negatives led us to conclude that this PPI-enhancing procedure had poor predictive validity as a screening tool for potential antipsychotics. In the present study, we used Wistar rats, which under the same protocol as that used for Sprague-Dawley rats show a very low level of PPI. We examined the ability of six antipsychotics, given intraperitoneally (i.p.), to reverse this PPI deficit. It was found that clozapine (5-20 mg/kg), olanzapine (5-20 mg/kg) and sertindole (1-10 mg/kg) reversed this deficiency of PPI (i.e. potentiated the low level of PPI). In contrast, risperidone (0.1-1 mg/kg), remoxipride (1-10 mg/kg) and haloperidol (0.1-1 mg/kg) were inactive. The negative results with three clinically active antipsychotics (risperidone, remoxipride and haloperidol) indicate that reversal of this PPI deficit in Wistar rats has poor predictive validity to screen for potential antipsychotic activity. In an attempt to investigate the mechanism that might underlie the reversing effect of clozapine, olanzapine and sertindole, we tested the ability of the alpha 1 adrenoceptor antagonist prazosin (3-20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.01-0.1 mg/kg) and the 5-HT2 antagonist ritanserin (0.3-3 mg/kg) to reverse the PPI deficit. Negative results with these three drugs did not allow us to characterize the receptor(s) that might be implicated in the reversal of this type of PPI deficit.
Depoortere
R
R
Synthelabo Recherche, Bagneux, France.
Perrault
G
G
Sanger
D J
DJ
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology; D001569:Benzodiazepines; D003024:Clozapine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects; D017330:Remoxipride / Q000494:pharmacology; D018967:Risperidone / Q000494:pharmacology; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D001552:Benzazepines; D007093:Imidazoles; D007211:Indoles; D012702:Serotonin Antagonists; D017330:Remoxipride; D001569:Benzodiazepines; D016713:Ritanserin; D010890:Pirenzepine; C066304:sertindole; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine; D011224:Prazosin