Acute and chronic phencyclidine administration: Relationships between biodispositional factors and behavioral effects

Acute administration of phencyclidine hydrochloride (PCP) to mice in a dose of 8 mg/kg (s.c.) impairs motor performance for 3.5 hours (50% recovery time). One to 4 hours after administration of ³H-PCP plasma and brain radioactivity declined in a roughly linear and parallel fashion, while the disappearance of ³H-PCP and metabolites from liver was considerably delayed. Radioactivity was distributed approximately evenly throughout the major anatomical areas of the brain, with only the hypothalamus showing an elevated concentration. On a subcellular level, most of the radioactivity was associated with the soluble fraction while most of the remainder was found in the crude synaptosomal fraction. Very little radioactivity was found in either the nuclear or mitochondrial fractions. Pretreatment with PCP for six days decreased the recovery time of the mice in the motor performance task to 2.5 hours. The plasma half-life of ³H-PCP and metabolites was not significantly decreased by chronic PCP pretreatment. However, the amount of radioactivity found in various subcellular fractions (particularly the synaptosomal fraction) was less in the brains of mice pretreated with PCP as compared to those pretreated with saline. In addition, chronic administration of PCP altered the regional distribution of ³H-PCP and metabolites, in that the concentration of radioactivity in the cortex ws 7.31% less than that of whole brain, while other, smaller areas (particularly the hypothalamus) had a greater concentration relative to whole brain. These data suggest that biodispositional factors may influence the duration of action of PCP in previously exposed animals.