Differential effects of the strychnine-insensitive glycine site antagonist (+)-HA-966 on the hyperactivity and the disruption of prepulse inhibition induced by phencyclidine in rats

The amplitude of the acoustic startle response is reduced by a preceding weak stimulation which by itself does not elicit the startle response. This phenomenon is named prepulse inhibition (PPI) and is thought to reflect the operation of the sensorimotor gating system, which is deficient in schizophrenic patients. It has been reported that an antagonist at the strychnine-insensitive glycine site has atypical neuroleptic properties in experimental animals. To evaluate the effect of an antagonist at the site on disrupted PPI, we examined whether (+)-HA-966 antagonizes phencyclidine-induced (3 mg/kg s.c.) and apomorphine-induced (1 mg/kg s.c.) disruption of PPI in rats. In addition, its effect on phencyclidine-induced hyperactivity was tested. The effects of (+)-HA-966 were compared with those of haloperidol, a typical neuroleptic. (+)-HA-966 antagonized phencyclidine-induced hyperactivity, but not phencyclidine-induced disruption of PPI, which is thought to be a model of refractory symptoms in schizophrenia. Furthermore, (+)-HA-966 did not improve the deficit in PPI induced by apomorphine. On the other hand, haloperidol antagonized phencyclidine-induced hyperactivity and the disruption of PPI by apomorphine, but not by phencyclidine. The results of this study might mean that (+)-HA-966 antagonizes the behavioral change induced by excessive dopamine release (the increment of locomotor activity due to phencyclidine), but not the effect induced by a direct dopamine agonist or the dopamine-independent effect of phencyclidine (the disruption of PPI). Thus, as regards antagonism of phencyclidine-induced disruption of PPI, (+)-HA-966 does not appear to have an atypical neuroleptic-like effect.