Role of Serotoninergic Neurons and 5-HT Receptors in the Action of Hallucinogens

Introduction

Nichols frames the topic by noting renewed scientific interest in serotonin receptors and serotoninergic pathways as targets for psychoactive drugs, contrasted with the relative neglect of so-called hallucinogens. He emphasises that hallucinogens remain poorly understood pharmacologically, are subject to strict legal controls that have impeded clinical research, and that even nomenclature for the class is unsettled; terms such as "hallucinogen", "psychotomimetic", "psychedelic" and "entheogen" each carry different implications and none has universal acceptance. The introduction also highlights the long cultural and ritual history of hallucinogenic substances, and the considerable variability of their psychological effects, which depend strongly on dose, individual ‘‘set’’ (expectation and personality) and ‘‘setting’’ (environment). This chapter sets out to review experimental evidence bearing on the mechanism(s) of action of hallucinogens, with a particular focus on interactions with serotonin (5-HT) receptor subtypes and on how different chemical classes of hallucinogens (notably tryptamines, ergolines and phenethylamines) may act through overlapping but not identical serotonergic and monoaminergic mechanisms. Nichols frames the review around key experimental approaches (biochemistry, receptor pharmacology, electrophysiology, and behavioural paradigms) and highlights the central unresolved questions: which 5-HT receptor subtypes mediate the characteristic effects of hallucinogens, how tolerance develops, and how findings in laboratory animals map onto human experience.