Serotonin neurotoxins: recent advances in the mode of administration and molecular mechanism of action.

1. Slow infusion of 5,7-DHT into the left lateral ventricle of nomifensine pretreated, pentobarbitone anaesthetized rats produces moderate, asymmetric regional forebrain 5-HT depletions 24 h after the injection; rapid pulse injection of 5,7-DHT results in more extensive and almost symmetric 5-HT reductions. By the eighth day, both injection procedures cause a comparable pattern of 5-HT depletion throughout the CNS. RAdioactivity distribution patterns (following 14C-5,7-DHT) correlate with the characteristics of 5-HT depletions. The type of anaesthetic used (pentobarbitone; pentobarbitone plus ketamine; ether) has little, if any, influence on the long-term 5-HT reductions in the rat CNS. 2. In forebrain regions, near the ventricle, nomifensine does not totally protect catecholamine fibre systems when pentobarbitone is used as the anaesthetic. However, optimum selectivity is provided by a combination of DMI and nomifensine in animals anaesthetized with a combination of pentobarbitone and ketamine. 3. Reaction of 5,6- and 5,7-DHT with oxygen is essential for these drugs to act as neurotoxins. Both drugs interact with the electron transfer chain of mitochondria (at the site of complex III) resulting in accelerated formation of reactive quinoidal intermediates. Metabolism of 5,7-DHT by MAO contributes to the overall in vivo neurotoxicity of this m-substituted dihydroxytryptamine.