Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys.
BACKGROUND
Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating, which occurs across species and is deficient in severe neuropsychiatric disorders such as schizophrenia. In monkeys, as in rodents, phencyclidine (PCP) induces schizophrenia-like deficits in PPI. In rodents, in general, typical antipsychotics (e.g. haloperidol) reverse PPI deficits induced by dopamine (DA) agonists (e.g. apomorphine), but not those induced by N-methyl- d-aspartate (NMDA) receptor antagonists [e.g. phencyclidine (PCP)], whereas atypical antipsychotics (e.g. clozapine) reverse PPI deficits induced by DA agonists and NMDA antagonists. However, some discrepancies exist with some compounds and strains of rodents.


OBJECTIVE
This study investigated whether a typical (haloperidol, 0.035 mg/kg) and an atypical (clozapine, 2.5 mg/kg) antipsychotic could be distinguished in their ability to reverse PCP-induced deficits in PPI in eight monkeys ( Cebus apella).


METHODS
First, haloperidol dose was determined by its ability to attenuate apomorphine-induced deficits in PPI. Then, haloperidol and clozapine were tested in eight monkeys with PCP-induced deficits of PPI. Experimental parameters were similar to standard human PPI procedures, with 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse 16 dB above the 70 dB background noise.


RESULTS
Clozapine reversed PCP-induced PPI deficits. In contrast, haloperidol did not significantly attenuate PCP-induced PPI deficits even at doses that significantly attenuated apomorphine effects.


CONCLUSIONS
In this primate model, clozapine was distinguishable from haloperidol by its ability to attenuate PCP-induced deficits in PPI. The results provide further evidence that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.
Linn
Gary S
GS
The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Linn@nki.rfmh.org
Negi
Shobhit S
SS
Gerum
Scott V
SV
Javitt
Daniel C
DC
D000161:Acoustic Stimulation; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal; D002428:Cebus; D003024:Clozapine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020820:Dyskinesias / Q000188:drug therapy; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology*; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol