Serotonin receptors--where are they going?

Thirty-three years ago, Gaddum and Picarelli classified the serotonin (5-HT) receptors in the guinea-pig ileum into D and M types based on the activity of dibenzyline (D) and morphine (M) to block contractions of intestinal smooth muscles caused by 5-HT. The subsequent location of specific ligand binding sites for 5-HT in the brain has led to the identification of 10 5-HT receptor subtypes in rat brain. While there is some controversy over the functional importance of many of these receptor subtypes, there is evidence that they fall into two major groups according to the nature of their coupling to secondary messengers or ion channels. Thus the 5-HT1 and 5-HT2 receptors appear to occupy the G protein receptor subfamily which may be coupled either to adenylate cyclase (most 5-HT1 subtypes) or phosphatidyl inositol (5-HT2 subtypes). The central "M" receptors (now termed 5-HT3) appear to occupy a ligand-gated ion channel superfamily. The cloning of these receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. A problem now arises with regard to the linking of the changes in the cellular activity of the various receptor subtypes with the plethora of behavioural changes that arise as a consequence of the actions of 5-HT in the brain. The present review summarizes the evidence implicating the role of specific 5-HT receptor subtypes in thermoregulation, modulation of cardiovascular function, eating disorders, sleep, sexual activity, anxiety states, aggression, schizophrenia and depression. A summary of the relationship between these receptor subtypes and their possible involvement in the aetiology of these diseases is also given.