POSSIBLE INVOLVEMENT OF DOPAMINE IN THE LONG-TERM SEROTONIN DEPLETIONBY P-CHLOROAMPHETAMINE AND BETA,BETA-DIFLUORO-P-CHLOROAMPHETAMINE IN RATS

The role of dopamine in the long-term depletion of serotonin in rat br ain by p-chloroamphetamine (PCA) and related compounds was investigate d by comparing effects of beta,beta-difluoro-p-chloroamphetamine (beta ,beta-difluoro-PCA) and 4-methyl-alpha-ethyl-meta-tyramine (H75/12), r eported to cause only short-term serotonin depletion, with those of PC A. A single dose of beta,beta-difluoro-PCA had no long-term effects on serotonin in whole rat brain, even after pretreatment with proadifen which decreased the rate at which beta,beta-difluoro-PCA disappeared f rom brain. The possibility that proadifen might antagonize serotonin d epletion was ruled out; proadifen did not prevent long-term serotonin depletion by PCA. Long-term depletion of brain serotonin was found aft er repeated injections of beta,beta-difluoro-PCA (five injections 4 hr apart) and was prevented by fluoxetine pretreatment. 3,3-Difluoro-PCA given after the monoamine oxidase inhibitor pargyline or after carbid opa/L-dopa also caused long-term serotonin depletion, although H75/12 did not. At early times after single doses producing the same initial depletion of serotonin, PCA caused a large increase in dopamine and a large decrease in the metabolite 3,4-dihydroxyphenylacetic acid in who le brain, thereby increasing the ratio dopamine/3,4-dihydroxyphenylace tic, and the other two drugs caused smaller effects. Extracellular dop amine was increased markedly by PCA, less by beta,beta-difluoro-PCA, a nd not at all by H75/12. These results suggest an association between dopamine release and long-term depletion of serotonin and add to evide nce that dopamine release by PCA may be essential to its neurotoxic ac tions on brain serotonin neurons.