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COMPARISON OF 4-CHLORO-, 4-BROMO- AND 4-FLUOROAMPHETAMINE IN RATS: DRUG LEVELS IN BRAIN AND EFFECTS

COMPARISON OF 4-CHLORO-, 4-BROMO- AND 4-FLUOROAMPHETAMINE IN RATS: DRUG LEVELS IN BRAIN AND EFFECTS

  1. User-126494
    R. W. FULLER, J. C. BAKER, K. W. PERRY and B. B. MOLLOY

    The Lilly Research Laboratories, Eli Lilly and Company
    Indianapolis, Indiana 46206

    Accepted 3 March 1975

    Summary-The ability of 4-chjo~oamphetamine, 4-bromoamphetamine, and 4-fluoroamphetamine to deplete brain S-hydroxyindoles and some pharmacokinetic properties of these drugs were compared in rats. Half-lives of the three compounds in rat brain were 3.7, 4.4, and 5.7 hr, respectively for the 4-fluoro, 4-chloro, and 4-bromo amphetamines. The tendency of the drugs to be associated with particulate material in brain homogenates or to prefer an organic versus an aqueous phase in uitro varied in the order 4-bromo > 4-chloro > 4-fluoro. This order of activity also applied to the inhibition of monoamine oxidase in vitro. All three 4-haloamphetamines reduced the activity of tryptophan hydroxyiase and lowered the levels of serotonin and S-hydroxyindoleacetic acid in whole brain initially. With 4-chloroamphetamine and 4-bromoamphetamine, the depletion of brain 5-hydroxyindoies lasted for at least a week. 4-Fluoroamphetamine, in contrast, lowered serotonin and 5-hydroxyindolea~tic acid levels only for short times (2-6 hr) after drug injection, and 5-hydroxyindole levels were essentially back to normal within 24 hr. Prior treatment with an uptake inhibitor prevented the serotonin depletion by all of the haloamphetamines, indicating they all required the membrane uptake pump for entry into the neurone. The effect of 4-bromoamphetamine, like that of 4-chloroamphetamine, could be reversed by subsequent injection of the uptake inhibitor after short periods but not after 24-48 hr. The failure of 4-tluoroamphetamine to produce a long-lasting depletion of brain serotonin like that produced by 4chloroamphetamine or 4-bromoamphetamine may reflect the inability of the fluoro-compound to be metabolized in the same way as the other haloamphetamines.