Simulation of psychosis by continuous delivery of phencyclidine from controlled-release polymer implants

To simulate psychosis in rats we have developed a method for the continuous delivery of phencyclidine (PCP) using implantable controlled-release polymers. PCP polymer implants produced deficits in latent inhibition which do not occur after repeated bolus injections. PCP implanted rats were also devoid of any anxiogenic signs, motoric hyperactivity and learning acquisition which can be seen in rats receiving daily bolus injections of a comparable PCP dose. This behavioral double-dissociation of the two modes of PCP application was accompanied by respective neurochemical changes. PCP binding sites were reduced in both striatum and hippocampus, but in the hippocampus, loss of PCP binding sites was more severe following pulsatile PCP administration. Morphological assessment revealed a significant shrinkage of the CA3 region in hippocampus in both groups. Pharmacokinetic analysis showed that the maximum PCP concentration in the brain after bolus injections was 10-fold above the PCP implants.