5-HT1 Receptors

Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT1 class is comprised of five receptor types, with the 5-HT1A, 5-HT1B and 5-HT1D characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT1E and 5-HT1F characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand. The genes encoding 5-HT1 receptors have been cloned in both human and rodents, allowing the demonstration that they all belong to the G-protein-coupled receptor superfamily with the characteristic 7 hydrophobic (transmembrane) domain-containing amino acid sequence. All the 5-HT1 receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels. Probes derived from the knowledge of amino acid sequence of the receptor proteins and of nucleotide sequence of their encoding mRNAs allowed the mapping of all the 5-HT1 receptor types in the central nervous system and other tissues. For the last twenty years, both pharmacological investigations with selective agonists and antagonists and phenotypical characterization of knock-out mice have been especially informative regarding the physiological implications of 5-HT1 receptor types. This research ends notably with the development of triptans, whose agonist activity at 5-HT1B, 5-HT1D and 5-HT1F receptors underlies their remarkable efficacy as antimigraine drugs. Clear-cut evidence of the implication of 5-HT1 receptors in anxiety- and depression-like behaviours and cognitive performances in rodents should hopefully promote research toward development of novel drugs with therapeutic potential in psychopathological and dementia-related diseases.