5-HT2B Receptors and Antidepressants

Abstract

Serotonin (5-Hydroxytryptamine, 5-HT) is a neurotransmitter involved in many psychiatric diseases including depression. The serotonergic neurons that innervate forebrain originate predominantly from the rostral cell group of neurons in the dorsal raphe nucleus (DRN). These neurons express the serotonergic markers tryptophan hydroxylase (TPH2), and serotonin transporter (SERT), and also the negative autoreceptors, 5-HT1A and 5-HT1B, whose expression is restricted to somatodendritic compartments of serotonergic neurons, and to axonal terminals, respectively. The 5-HT1A autoreceptor activation elicits an outward current carried through G protein-coupled inwardly-rectifying potassium channels (GIRK) of the Kir3 family leading to membrane hyperpolarization and inhibition of serotonergic neuron fring [4]. The presence of synaptic vesicles in dendrites of serotonergic neurons led to the suggestion that autoinhibition is mediated via dendritic release of 5-HT, for review see. However, activity of serotonin DRN neurons can also be positively modulated by 5-HT2A/2B/2C receptors triggering directly or indirectly inward currents [6–10]. Upon electrical stimulation of leech serotonergic neurons, transmembrane Ca2+ entry through L-type channels frst evokes an early dendritic exocytosis; subsequently, the released serotonin activates dendritic 5-HT2 autoreceptors coupled to Gq and phospholipase C, resulting in a positive feedforward loop that maintains sustained exocytosis. It has thus been proposed that DRN neurons can display responses ranging from inhibition to excitation depending on a balance of functional 5-HT1A and 5-HT2 receptors.