Neuropharmacology of 5-hydroxytryptamine

Abstract

This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists. The existence of a vasoconstrictive substance in the blood has been known for over 135 years. The substance was named serotonin and finally identified as 5-HT in 1949. The presence of 5-HT in the brain was reported by Gaddum in 1954 and it was Gaddum who also demonstrated that the action of 5-HT (in the gut) was antagonised by the potent hallucinogen lysergic acid diethylamide. This provoked the notion that 5-HT played a pivotal role in the control of mood and subsequent investigations have generally confirmed this hypothesis. Over the last 50 years a good understanding has been gained of the mechanisms involved in control of the storage, synthesis and degradation of 5-HT in the brain. Knowledge has also been gained on control of the functional activity of this monoamine, often by the use of behavioural models. A considerable literature also now exists on the mechanisms by which many of the drugs used to treat psychiatric illness alter the functional activity of 5-HT, particularly the drugs used to treat depression. Over the last 20 years the number of identified 5-HT receptor subtypes has increased from 2 to 14, or possibly more. A major challenge now is to utilise this knowledge to develop receptor-specific drugs and use the information gained to better treat central nervous system disorders.

Figure 1

Maurice Rapport presenting to the Serotonin Club satellite conference to the 4th EPHAR meeting, Porto, Portugal, 18th July 2004.

Figure 2

The structure of 5-HT and lysergic acid diethylamide (LSD).

Figure 3

Some members of the plenary ‘Workshop on 5-HT Receptor Classification' chaired by Pat Humphrey and Brian Richardson following dinner at the first Serotonin Club satellite meeting to the 1987 IUPHAR Congress. The satellite meeting was held on Heron Island, Queensland, Australia. Pictured (left to right) are: Günter Engel (Sandoz, Basle), Toshiro Shibano (Daiichi Pharmaceutical, Tokyo), Brain Richardson (Sandoz, Basle), Ewan Mylecharane (University of Sydney), Stephen Peroutka (Stanford University, Ralph Purdey (University of California, Irvine), John Fozard (Sandoz, Basle) and Pat Humphrey (Glaxo, Ware). Missing is Pramod Saxena. Members are indicating the number of 5-HT receptor subtypes they believed existed (Purdey is suggesting an action at the α-adrenoceptor). Company names are given as they then existed. The elected ‘Nomenclature Committee' was Patrick Humphrey (Chairman), Jack Peter Green (Vice-Chairman), George Aghajanian, Philip Bradley, Marlene Cohen, John Fozard, Josée Leysen, Ewan Mylecharane, Stephen Peroutka, Brian Richardson and Pramod Saxena. I thank Ewan Mylecharane for providing this photograph.

Figure 4

Current 5-HT receptor subtype classification scheme. Lower case designates that receptors that have not been demonstrated to definitively function in native systems. cAMP, 3′–5′ cycle adenosine monophosphate; PLC; phospholipase C; −ve, negative; +ve, positive. Reprinted from Hoyer et al. (2002) with permission of Elsevier Ltd.