Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response.
Intense auditory stimuli elicit an involuntary startle response that is attenuated when the startling stimulus (the pulse) is preceded immediately by a low intensity stimulus (the prepulse). This phenomenon of prepulse inhibition (PPI) is utilized as a measure of sensorimotor gating and is significantly reduced in schizophrenic patients. Noncompetitive N-methyl-D-aspartate antagonists such as phencyclidine (PCP) and ((+)-D-aspartate 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (dizocilpine, or MK-801) have been found previously to disrupt PPI in animals. The present investigation assessed the ability of several antipsychotic drugs to reverse PCP-induced deficits in PPI in rats. Animals were 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-hydroxytryptamine2 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 chambers. PCP repeatedly and robustly decreased PPI without affecting base-line startle reactivity. Clozapine (5.0 mg/kg) antagonized this effect of PCP without altering PPI by itself. Raclopride, SCH23390, ritanserin and ketanserin were ineffective at reversing the PCP-induced deficit in PPI. As with PCP, 0.1 mg/kg of MK-801 disrupted PPI; this disruption also was antagonized by 5.0 mg/kg of clozapine. Thus, it appears 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-hydroxytryptamine2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Psychiatry, University of California at San Diego School of Medicine.
V P
VP
Bakshi
N R
NR
Swerdlow
M A
MA
Geyer
D000161:Acoustic Stimulation; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010622:Phencyclidine / Q000037:antagonists & inhibitors*; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D016713:Ritanserin / Q000494:pharmacology; D012457:Salicylamides / Q000494:pharmacology
D001552:Benzazepines; D012457:Salicylamides; D016713:Ritanserin; D020891:Raclopride; D016291:Dizocilpine Maleate; D007650:Ketanserin; D010622:Phencyclidine; D003024:Clozapine