Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys
- First Online:
- 175 Downloads
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.
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).
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.
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.
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.
KeywordsApomorphine Clozapine Haloperidol NMDA receptor Non-human primate model Phencyclidine (PCP) Prepulse inhibition (PPI) Schizophrenia Neuroleptic sensitization Sensorimotor gating
- Casey DE (1988) Persisting changes in dystonia and sedation after brief neuroleptic treatment in cebus monkeys. Program of the 43rd Annual Meeting of the Society of Biological Psychiatry:371Google Scholar
- Casey DE (1993) Serotonergic and dopaminergic aspects of neuroleptic-induced extrapyramidal syndromes in nonhuman primates. Psychopharmacology 112:S55–S59Google Scholar
- Karper LP, Grillon C, Charney DS, Krystal JH (1994) The effect of ketamine on pre-pulse inhibition and attention. Proc Am Coll Neuropsychopharmacol 124Google Scholar
- Lifshitz K, O'Keeffe RT, Lee KL, Linn GS, Mase D, Avery J, Lo ES, Cooper TB (1991) Effect of extended depot fluphenazine treatment and withdrawal on social and other behaviors of Cebus apella monkeys. Psychopharmacology 105:492–500Google Scholar
- Mansbach RS, Geyer MA (1991) Parametric determinants in prestimulus modification of acoustic startle: interaction with ketamine. Psychopharmacology 105:162–168Google Scholar
- Martinez ZA, Oostwegel J, Geyer MA, Ellison GD, Swerdlow NR (2000) "Early" and "late" effects of sustained haloperidol on apomorphine- and phencyclidine-induced sensorimotor gating deficits. Neuropsychopharmacology. 23:517–527Google Scholar
- Swerdlow NR, Varty GB, Geyer MA (1997) Discrepant findings of clozapine effects on prepulse inhibition of startle: is it the route or the rat? Neuropsychopharmacology 18:50–56Google Scholar