Long-term reduction of brain serotonin by p-chloroamphetamine: effects of inducers and inhibitors of drug metabolism.
The present experiments were designed to test the hypothesis that the long-term effects of p-chloroamphetamine (PCA) on serotonergic neurons in rats are mediated by a neurotoxic metabolite. The effects of well-known inducers and an inhibitor of hepatic microsomal drug-metabolizing enzymes on the PCA-induced decreases in brain levels of 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase activity and the half-life of PCA in brain were examined. All of these modified the half-life of PCA in a predictable manner: 3-methylcholanthrene and, to a much lesser extent, phenobarbital decreased the half-life of PCA while piperonyl butoxide markedly increased it. Fluoxetine, an inhibitor of 5-HT uptake, also increased the half-life of PCA in brain. In addition, fluoxetine blocked the long-term effects of PCA on 5-HT levels and tryptophan hydroxylase activity. Of the classical metabolic tools, only 3-methylcholanthrene provided complete protection from the long-term, neurotoxic effects of PCA. Although the mechanism of this protection is unknown, it is not mediated by a blockade of 5-HT uptake since 3-methylcholanthrene did not decrease the synaptosomal uptake of 5-HT. Piperonyl butoxide pretreatment markedly increased the half-life of PCA in brain, but it failed to modify consistently the effects of PCA. The results indicate that the long-term, neurotoxic effects of PCA are not mediated by the major, hepatic metabolites of the drug, but leave open the possibility of a minor, neurotoxic metabolite.
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000648:ultrastructure; D001923:Brain Chemistry / Q000187:drug effects*; D003864:Depression, Chemical; D006207:Half-Life; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D010133:p-Chloroamphetamine / Q000494:pharmacology*
D000662:Amphetamines; D011437:Propylamines; D012702:Serotonin Antagonists; D012701:Serotonin; D008748:Methylcholanthrene; D010133:p-Chloroamphetamine; D014365:Tryptophan Hydroxylase; D010882:Piperonyl Butoxide; D010634:Phenobarbital