EFFECTS OF DEXFENFLURAMINE OR 5,7-DIHYDROXYTRYPTAMINE ON TRYPTOPHAN-HYDROXYLASE AND SEROTONIN TRANSPORTER MESSENGER-RNAS IN RAT DORSAL RAPHE

Dexfenfluramine (DF), given in high doses, can produce long-lasting de creases in brain levels of serotonin (5-HT) and 5-HT transporter (5-HT T) protein. The purpose of this study was to determine if DF-induced d ecreases in 5-HT and 5-HTT in rat forebrain are correlated with compen satory changes in the expression of the genes for tryptophan hydroxyla se (TPH) and 5-HTT in the dorsal raphe nucleus. Gene transcripts were measured by quantitative reverse transcription-polymerase chain reacti on (RT-PCR). Rats were treated with either one or eight injections of DF at either high (10 mg/kg) or low (2 mg/kg) doses. A positive contro l group for 5-HT cell loss received a single cerebroventricular inject ion of 5,7-dihydroxytryptamine (DHT). Rats were killed either 5, 15 or 30 days after their last treatment. Paroxetine binding to the 5-HTT p rotein in frontal cortex was, as expected, reduced in all of the treat ed groups relative to vehicle controls. TPH mRNA levels in the dorsal raphe of animals that received DHT were significantly higher than thos e measured in all other treatment groups 15 days following treatment. By 30 days, the amount of TPH mRNA in DHT-treated rats had fallen to w ell below control levels. None of the DF regimens significantly affect ed TPH mRNA levels. Unlike the TPH mRNA changes in DHT-treated rats, t he 5-HTT mRNA levels in the dorsal raphe declined progressively throug hout the 30 day survival period. None of the DF regimens significantly affected 5-HTT mRNA levels. The significance of these data are discus sed in terms of whether loss of forebrain markers for 5-HT reflects ei ther the loss of fine caliber 5-HT axon terminals or a decrease in the expression of these markers in the somata of these cells which are lo cated in the dorsal raphe.