Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats.
Sensorimotor gating of the startle reflex measured by prepulse inhibition (PPI) is impaired in schizophrenia patients and in rats treated with either dopamine (DA) agonists or with N-methyl-D-aspartate (NMDA) antagonists. While both typical and atypical antipsychotics restore PPI in DA agonist-treated rats, studies thus far have demonstrated that only atypical antipsychotics restore PPI in rats treated with NMDA antagonists. This model for predicting atypical antipsychotic properties has been studied extensively in rats, and there is interest in moving these studies into humans, where the NMDA antagonist ketamine is also reported to significantly reduce PPI. In anticipation of such studies, and to facilitate the use of this model in humans, we examined the effects of high and low potency typical antipsychotics (haloperidol and chlorpromazine), the atypical antipsychotic clozapine, and the putative atypical antipsychotic, Seroquel, on ketamine-disrupted PPI in rats, across a range of ketamine that produced submaximal, as well as maximal disruptions of PPI. Ketamine dose-dependently reduced PPI, and this effect was significantly opposed by Seroquel, clozapine and chlorpromazine, but not haloperidol. The effects of chlorpromazine on ketamine-disrupted PPI demonstrate that the ability of antipsychotics to restore PPI in NMDA antagonist-treated rats is not specific to clinically atypical antipsychotics. Receptor properties shared by Seroquel, clozapine and chlorpromazine, but not haloperidol, may implicate critical substrates in the NMDA antagonist-induced disruption of PPI.
Swerdlow
N R
NR
Department of Psychiatry and Neuroscience Program, School of Medicine, University of California, San Diego, La Jolla 92093-0804, USA.
Bakshi
V
V
Waikar
M
M
Taaid
N
N
Geyer
M A
MA
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002746:Chlorpromazine / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D000069348:Quetiapine Fumarate; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013216:Reflex, Startle / Q000187:drug effects*
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D016194:Receptors, N-Methyl-D-Aspartate; D000069348:Quetiapine Fumarate; D007649:Ketamine; D003024:Clozapine; D006220:Haloperidol; D002746:Chlorpromazine