P-CHLOROPHENYLALANINE CHANGES SEROTONIN TRANSPORTER MESSENGER-RNA LEVELS AND EXPRESSION OF THE GENE-PRODUCT

After a single intraperitoneal injection of the irreversible tryptopha n hydroxylase inhibitor p-chlorophenylalanine (PCPA; 300 mg/kg), there was a rapid down-regulation of serotonin (5-HT) transporter mRNA leve ls in cell bodies, This change was significant at 1 and 2 days after P CPA administration within the ventromedial but not the dorsomedial por tion of the dorsal raphe nucleus, Seven days after PCPA treatment, 5-H T transporter mRNA levels were significantly elevated compared with co ntrols in both regions of the dorsal raphe nucleus, PCPA administratio n produced no change in the [H-3]-citalopram binding and synaptosomal [H-3]5-HT uptake in terminal regions at 2 and 7 days after treatment b ut significantly reduced both these parameters by similar to 20% in th e hippocampus and in cerebral cortex 14 days after PCPA administration , The striatum showed a lower sensitivity to this effect. No significa nt changes were observed in the levels of [H-3]citalopram binding to 5 -HT cell bodies in the dorsal raphe nucleus, In the same animals used for 5-HT transporter mRNA level measurements, levels of tryptophan hyd roxylase mRNA in neurons of the ventromedial and dorsomedial portions of the dorsal raphe nucleus were increased 2 days after PCPA administr ation and fell to control levels 7 days after injection in the ventrom edial region but not in the dorsomedial portion of the dorsal raphe nu cleus, where they remained significantly higher than controls, Altoget her, these results show that changes in 5-HT transporter mRNA are not temporally related to changes in 5-HT transporter protein levels. In a ddition, our results suggest that the 5-HT transporter and tryptophan hydroxylase genes are regulated by different mechanisms, We also provi de further evidence that dorsal raphe 5-HT neurons are differentially regulated by drugs, depending on their location.