Effect of p-chlorophenylalanine on cerebral serotonin binding, serotonin concentration and motor activity in the rat

The effect of p-chlorophenylalanine (PCPA) on the specific binding of 3H-serotonin (5-HT) was investigated in crude membrane preparations of the rat forebrain. The level of cerebral 5-HT and 5-hydroxyindoleacetic acid were concomitantly determined. A single dose of PCPA (300 mg/kg i.p.) increased specific binding at a low concentration of 3H-5-HT within 24 h by more than 100%. The time course of the elevation of specific binding was mirrored by the reduction in the 5-HT level. However, 8--10 days after drug administration, specific binding was close to the control level, while 5-HT was still significantly reduced. A Scatchard analysis revealed that the apparent affinity was significantly increased (KD reduced) during the initial period after PCPA administration, whereas the number of binding sites (BMax) was little changed. In contrast, after reported injections of PCPA (3 injections of 300 mg/kg at 6--8 day intervals, or 100 mg/kg/day for up to 12 days) leading to a prolonged 5-HT depletion, BMax was significantly increased, while KD tended to be restored towards the baseline level. Daily injections of PCPA (100 mg/kg) for 12 days resulted in a transitory increase in day-time motor activity with a maximum on drug day 3, and in a persistent reduction of night-time activity. It is concluded that the initial PCPA-induced decrease in KD was due to a reduced competition for binding sites by the endogenous 5-HT, whereas the increase of BMax after a prolonged 5-HT depletion may reflect a 5-HT receptor supersensitivity.