Possible involvement of dopamine in the long-term serotonin depletion by p-chloroamphetamine and beta,beta-difluoro-p-chloroamphetamine in rats.
The role of dopamine in the long-term depletion of serotonin in rat brain by p-chloroamphetamine (PCA) and related compounds was investigated by comparing effects of beta,beta-difluoro-p-chloroamphetamine (beta,beta-difluoro-PCA) and 4-methyl-alpha-ethyl-meta-tyramine (H75/12), reported to cause only short-term serotonin depletion, with those of PCA. 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 from brain. The possibility that proadifen might antagonize serotonin depletion was ruled out; proadifen did not prevent long-term serotonin depletion by PCA. Long-term depletion of brain serotonin was found after repeated injections of beta,beta-difluoro-PCA (five injections 4 hr apart) and was prevented by fluoxetine pretreatment. beta,beta-Difluoro-PCA given after the monoamine oxidase inhibitor pargyline or after carbidopa/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 whole brain, thereby increasing the ratio dopamine/3,4-dihydroxyphenylacetic, and the other two drugs caused smaller effects. Extracellular dopamine was increased markedly by PCA, less by beta,beta-difluoro-PCA, and not at all by H75/12. These results suggest an association between dopamine release and long-term depletion of serotonin and add to evidence that dopamine release by PCA may be essential to its neurotoxic actions on brain serotonin neurons.
Henderson
M G
MG
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Perry
K W
KW
Fuller
R W
RW
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors; D010133:p-Chloroamphetamine / Q000031:analogs & derivatives / Q000494:pharmacology*
D000662:Amphetamines; C001632:4-methyl-alpha-ethyl-m-tyramine; D012701:Serotonin; D010133:p-Chloroamphetamine; D004298:Dopamine