Disruption of Prepulse Inhibition and Increases in Locomotor Activity by Competitive N-Methyl-D-aspartate Receptor Antagonists in Rats 1 VAISHALI P. BAKSHI, MARK TRICKLEBANK, HANS C. NEIJT, VIRGINIA LEHMANN-MASTEN and MARK A. GEYER Program in Neurosciences (V.P.B., M.A.G.) and Department of Psychiatry (V.L.-M., M.A.G.), University of California at San Diego, La Jolla, California; and Nervous System Research, Novartis Pharma AG, Basel, Switzerland (M.T., H.C.N.) Accepted for publication September 1, 1998 This paper is available online at http://www.jpet.org ABSTRACT Noncompetitive N-methyl-D-aspartate (NMDA) receptor antag- onists such as phencyclidine are psychotomimetics and disrupt prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia. Systemically administered com- petitive NMDA receptor antagonists do not disrupt PPI in rats, leading to speculation that these compounds might have use as neuroprotective agents without the risk of psychotomimetic side effects. The effects on sensorimotor gating and locomotor activity of competitive NMDA receptor antagonists that either penetrate (SDZ 220-581 and SDZ EAB-515) or poorly penetrate [SDZ EAA-494 (D-CPPene)] the blood-brain barrier were com- pared. Rats were treated with either SDZ 220-581 (0, 2.5, or 5.0 mg/kg) or SDZ EAB-515 (0, 3.0, 10.0, or 30.0 mg/kg) and tested for PPI and locomotor activity. Different rats were tested for PPI after either systemic (0, 0.5, 1.0, or 5.0 mg/kg) or intra-amyg- dala (0 or 1.0 g/l) administration of D-CPPene. Finally, rats were pretreated with clozapine (0 or 5.0 mg/kg) or haloperidol (0 or 0.1 mg/kg), together with SDZ 220-581 (0 or 2.5 mg/kg), and tested. SDZ 220-581 and SDZ EAB-515 decreased PPI without affecting startle magnitude. Reduced PPI was noted after cen- tral but not systemic administration of D-CPPene. The gating deficits produced by SDZ 220-581 were blocked by clozapine or haloperidol. Movement pattern analysis indicated that loco- motor activity was increased by SDZ 220-581 and SDZ EAB- 515 in a phencyclidine-like manner. These results indicate that competitive NMDA receptor antagonists, if they gain sufficient access to the brain, produce a behavioral profile that resembles that of the psychotomimetic noncompetitive antagonists. N-Methyl-D-aspartate (NMDA) receptor stimulation is con- sidered a critical event in several pathological conditions, including ischemia-induced neurotoxicity (Choi, 1990) and epilepsy (Meldrum, 1988). The development of clinically via- ble NMDA receptor antagonists (NMDA-RAs) has therefore been of great interest (Rogawski, 1993). A major factor com- promising the therapeutic use of NMDA-RAs is their psy- chotomimetic profile; noncompetitive NMDA-RAs such as phencyclidine (PCP) produce in healthy humans a psychosis that closely resembles schizophrenic symptomatology (Javitt and Zukin, 1991). Preclinical behavioral studies, however, have indicated a possible functional dissociation between the noncompetitive NMDA-RAs, which bind to a site inside the cation channel, and the competitive NMDA-RAs, which re- versibly bind to the glutamate recognition site outside the channel (Watkins, 1994). For example, noncompetitive and competitive NMDA-RAs do not substitute for each other in drug discrimination paradigms (Gold and Balster, 1993; Wiley and Balster, 1994). One paradigm with particular relevance for the sensory disturbances associated with drug-induced psychotic states and in which striking differences have been observed be- tween noncompetitive and competitive NMDA-RAs is pre- pulse inhibition (PPI). PPI refers to the normal inhibition of a startle response when a weak stimulus immediately pre- cedes a startling stimulus and is thought to provide an oper- ational measure of sensorimotor gating, one of the processes by which an organism filters information from its surround- ings (Geyer et al., 1990). Deficits in PPI are observed in schizophrenic patients (Braff et al., 1992) and in rats or healthy humans treated with noncompetitive NMDA-RAs such as PCP, dizocilpine, or ketamine (Mansbach and Geyer, 1989; Geyer et al., 1990; Karper et al., 1994). In contrast, multiple studies demonstrate that competitive NMDA-RAs Received for publication March 18, 1998. 1 This work was supported in part by Grant R37-MH42228 from the Na- tional Institute of Mental Health and Grant R02-DA02925 from the National Institute on Drug Abuse. V.P.B. was supported by Grant F31-MH11636 from the National Institute of Mental Health. M.A.G. was supported by a Research Scientist Award (K05-MH01223) from the National Institute of Mental Health and holds an equity position with San Diego Instruments. ABBREVIATIONS: NMDA, N-methyl-D-aspartate; BPM, behavior pattern monitor; PPI , prepulse inhibition; ANOVA, analysis of variance; NMDA-RA, N-methyl-D-aspartate receptor antagonist; PCP, phencyclidine; ANOVA, analysis of variance; AP-5, d-2-amino-5-phosphonopen- tanoic acid; D-CPPene, SDZ EAA-494; AP-7, d-2-amino-7-phosphonopentanoic acid; CNS, central nervous system. 0022-3565/99/2882-0643$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 288, No. 2 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 288:643–652, 1999 643 at ASPET Journals on December 26, 2016 jpet.aspetjournals.org Downloaded from