It is over 25 years since it was first suggested that presynaptic autoreceptors modulate 5-HT release. These autoreceptors have since been subdivided into two categories: those that reside on serotonergic cell bodies and those on the fibre terminals. The subsequent development of selective ligands led to the discovery that 5-HT autoreceptors belonged to the 5-HT1 subfamily, which is composed of 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F receptor subtypes which negatively couple to adenylyl cyclase via a number of inhibitory G proteins. With the advent of molecular biology techniques these 5-HT autoreceptors have been cloned, sequenced and more fully characterised. The interrelationship between 5-HT and depression was first alluded to in 1957, since then the role of 5-HT in the aetiology of psychiatric disorders, such as depression and anxiety has received substantial interest. This has led to the development of a variety of selective ligands targeted at 5-HT autoreceptors as potential drug moieties for the treatment of these conditions. Here we will review the development of these pharmacological tools and their potential therapeutic utility in the treatment of psychiatric disease.
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