Vol. 288, Issue 2, 643-652, February 1999

Disruption of Prepulse Inhibition and Increases in Locomotor Activity by Competitive N-Methyl-D-aspartate Receptor Antagonists in Rats¹

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.)

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine are psychotomimetics and disrupt prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia. Systemically administered competitive 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 compared. 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-amygdala (0 or 1.0 µg/µl) 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 central 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 locomotor 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.