The amino acid L-lysine blocks the disruptive effect of phencyclidine on prepulse inhibition in mice.

Cognitive and attentional deficits in schizophrenia, such as impaired sensory filtering measured by prepulse inhibition (PPI), can be modeled in animals using the drug phencyclidine (PCP), which disrupts PPI. Nitric oxide (NO) may mediate some of PCP's effects, as NO synthase inhibitors block PCP-induced deficits. This study tested whether blocking L-arginine transport—a step in NO production—with L-lysine could prevent PCP-induced PPI disruption in mice. Subchronic, and to some extent acute, L-lysine pretreatment blocked the PCP-induced PPI deficit without affecting baseline PPI. The results support the idea that PCP's effects in the brain involve NO and that L-arginine transport may regulate NO production.

Study at a glance

Abstract

The cognitive and attentional deficits observed in schizophrenic patients are now considered central to the pathophysiology of the disorder. These deficits include an inability to filter sensory input as measured by, e.g., prepulse inhibition (PPI) reflex. Administration of phencyclidine (PCP), a drug that can induce a schizophrenia-like psychosis in humans, disrupts PPI in experimental animals. In rodents, this PCP-induced deficit can be blocked by pretreatment with nitric oxide (NO) synthase inhibitors. This suggests that some of the behavioral effects of PCP are mediated via NO. The substrate for in vivo NO production is L-arginine, and active transport of L-arginine via the cationic amino acid transporter may serve as a regulatory mechanism in NO production. The aim of the present study was to study the effects of L-arginine transport inhibition, using acute and repeated L-lysine treatment, on PCP-induced disruption of PPI in mice. Subchronic, and to some extent acute, pretreatment with L-lysine blocked a PCP-induced deficit in PPI without affecting basal PPI. L-lysine has been shown to block L-arginine transport in vitro, most likely via a competitive blockade and down regulation of cationic amino acid transporters. However, the importance of L-arginine transport as a regulatory mechanism in NO production in vivo is still not clear. The present results lend further support to the notion that some of the effects of PCP in the central nervous system are mediated via NO and that L-arginine transport may play a role in the regulation of NO production in the brain.