Repeated treatment with phencyclidine (PCP) over 14 days at 7.5 mg/kg per day significantly reduced the frequency of backpedalling, a serotonergic stereotyped behavior, indicating tolerance. This repeated treatment also decreased the equilibrium dissociation constant (Kd) of [3H]paroxetine binding to serotonin transporters in whole brain excluding the cerebellum, without changing the maximum number of binding sites (Bmax). A single PCP treatment did not alter binding parameters. The results suggest that repeated PCP treatment induces tolerance in serotonergic stereotyped behavior and increases the affinity of serotonin transporters, possibly as a compensatory response to chronic inhibition of serotonin uptake.
The binding properties and brain distribution of a radioactive form of the compound 3-OH-PCP, a derivative of phencyclidine (PCP), were examined in rat brain tissue using autoradiography. Binding occurred with fast and slow components, and the pattern of binding matched that of other PCP receptor labels, TCP and MK-801. Highest binding was in the hippocampus and outer cerebral cortex layers, while low binding was in the brain stem and cerebellum. The binding was strongly blocked by MK-801 and 3-OH-PCP, but less so by a related compound, (+)-SKF 10047, in certain brain regions. Antagonists of the NMDA receptor complex also displaced binding similarly to MK-801, indicating the binding site is essentially the same as the PCP site labeled by TCP and MK-801.