The role of neurotransmitter uptake in the mechanism of action of hallucinogens

Abstract

Hallucinogens have been used by man for thousands of years, but only recently have the mechanisms of action of these compounds come under scientific scrutiny. On the basis of early experiments and the similarity in chemical structure between hallucinogens and known neurotransmitters, it was proposed that hallucinogens acted in the central nervous system by disruption of the normal processes of neurotransmission. One major neurotransmission process that had not received systematic study was that of uptake of neurotransmitters into the pre-synaptic terminal. A model of this process was based upon the use of synaptosomes and by means of time, temperature, Na('+) content and kinetic analyses, was shown to be reliable and robust. Studying the effects of 13 hallucinogens on the uptake of 5HT and 1-NE into hippocampal synaptosomes and of 5HT and DA into caudate synaptosomes, it was found that all compounds, with the notable exceptions of d-LSD and 2-Br-LSD, inhibited the uptake of 5HT, DA and 1-NE. In general, it was found that indolealkylamines were more potent than phenylethylamines. These results suggest the possibilities that either d-LSD operates by a separate mechanism or the entire process of hallucinogenesis is a complex one and uptake plays only a secondary role in determining the potency of a hallucinogen. The relationship of these results in the overall process of hallucinogenesis is discussed and a holistic approach for future research is proposed.