CLOZAPINE ANTAGONIZES, PHENCYCLIDINE-INDUCED DEFICITS IN SENSORIMOTORGATING OF THE STARTLE RESPONSE

Intense auditory stimuli elicit an involuntary startle response that i s attenuated when the startling stimulus (the pulse) is preceded immed iately by a low intensity stimulus (the prepulse). This phenomenon of prepulse inhibition (PPI) is utilized as a measure of sensorimotor gat ing and is significantly reduced in schizophrenic patients. Noncompeti tive N-methyl-D-aspartate antagonists such as phencyclidine (PCP) and {(+)5-methyl-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5,1O-imine} (di zocilpine or MK-801) have been found previously to disrupt PPI in anim als. The present investigation assessed the ability of several antipsy chotic drugs to reverse PCP-induced deficits in PPI in rats. Animals w ere pretreated with either the atypical antipsychotic clozapine (0, 1. 25, 2.5, 5.0 or 10.0 mg/ kg), the D2 dopamine antagonist raclopride (0 , 0.1 or 0.5 mg/ kg), the D1 dopamine antagonist SCH23390 (0, 0.01 or 0.05 mg/kg) or the 5-hydroxytryptamine(2) antagonists ritanserin (0 or 2.0 mg/kg) or ketanserin (0 or 1.0 mg/kg) and then were given PCP (1. 0 mg/kg). After drug administration, animals were tested in startle ch ambers. PCP repeatedly and robustly decreased PPI without affecting ba se-line startle reactivity. Clozapine (5.0 mg/kg) antagonized this eff ect of PCP without altering PPI by itself. Raclopride, SCH23390, ritan serin and ketanserin were ineffective at reversing the PCP-induced def icit in PPI. As with PCP, 0.1 mg/kg of MK-801 disrupted PPI; this disr uption also was antagonized by 5.0 mg/kg of clozapine. Thus, it appear s that the ability of clozapine to reverse deficits in PPI produced by noncompetitive N-methyl-D-aspartate antagonists cannot be attributed to a sole antagonism of either D1 dopamine, D2 dopamine or 5-hydroxytr yptamine(2) receptors. Rather, simultaneous antagonistic properties at multiple receptors and neurotransmitter systems may underlie the effi cacy of clozapine. The PCP-induced disruption of PPI may serve as a us eful model with which to study possible novel treatments for sensorimo tor gating abnormalities in schizophrenia.