Disruption of prepulse inhibition and increases in locomotor activity by competitive N-methyl-D-aspartate receptor antagonists in rats

Noncompetitive N-methyt-D-aspartate (NMDA) receptor antagonists such as phe ncyclidine are psychotomimetics and disrupt prepulse inhibition (PPI), a me asure of sensorimotor gating that is deficient in schizophrenia. Systemical ly administered competitive NMDA receptor antagonists do not disrupt PPI in rats, leading to speculation that these compounds might have use as neurop rotective agents without the risk of psychotomimetic side effects. The effe cts on sensorimotor gating and locomotor activity of competitive NMDA recep tor antagonists that either penetrate (SDZ 220-581 and SDZ EAB-515) or poor ly 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 E AB-515 (0, 3.0, 10.0, or 30.0 mg/kg) and tested for PPI and locomotor activ ity. 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 mu g/mu l) administration of D-C PPene. Finally, rats were pretreated with clozapine (0 or 5.0 mg/kg) or hal operidol (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 administra tion of D-CPPene. The gating deficits produced by SDZ 220-581 were blocked by clozapine or haloperidol. Movement pattern analysis indicated that locom otor activity was increased by SDZ 220-581 and SDZ EAB-515 in a phencyclidi ne-like manner. These results indicate that competitive NMDA receptor antag onists, if they gain sufficient access to the brain, produce a behavioral p rofile that resembles that of the psychotomimetic noncompetitive antagonist s.