Para-halogenated phenethylamines: similar serotonergic effects in rats by different mechanisms

The serotonin (5-HT) behavioral syndrome in rats served as a model to test for possible acute serotonergic effects of para-halogenated phenethylamines. p-Chloro-, p-chloro-beta-methyl-, p-fluoro-, p-bromo-, and p-iodophenethylamine produced the same 5-HT behavioral syndrome as did p-chloroamphetamine, but unlike the latter did not deplete brain 5-HT 3 days after injection. Pretreatment of rats with the 5-HT depletor p-chlorophenylalanine (pCPA)( prevented the serotonergic effects of both chloro-derivatives, and partially prevented the effects of bromo- and iodophenethylamine. 5-hydroxytryptophan restored the behavioral responses to these compounds in pCPA-pretreated rats. pCPA treatment did not prevent the behavioral effects of p-fluorophenethylamine. Similarly, zimelidine, a 5-HT uptake inhibitor, prevented the serotonergic behavioral effects of all compounds tested except p-fluorophenethylamine. Taken as a group, para-halogenated phenethylamines are short-acting serotonergic compounds which, unlike p-chloroamphetamine, do not produce long-lasting depletion of brain 5-HT. p-Chlorophenethylamine and its beta-methyl analog apparently activate central 5-HT receptors indirectly, i.e., by 5-HT release; p-fluorophenethylamine is a direct 5-HT agonist. The p-bromo- and p-iodo-derivatives apparently possess both properties.