Physiological and therapeutic relevance of constitutive activity of 5-HT 2A and 5-HT 2C receptors for the treatment of depression

Prog Brain Res. 2008:172:287-305. doi: 10.1016/S0079-6123(08)00914-X.

Abstract

Serotonin(2A) (5-HT(2A)) and 5-HT(2C) receptors are highly homologous members of the serotonin(2) family of 7-transmembrane-spanning (7-TMS) receptors. Both of these receptor subtypes have been implicated in the aetiology and/or treatment of affective disorders such as anxiety and depression. Regulation of dopaminergic neurotransmission by 5-HT(2A) and 5-HT(2C) receptor systems has been well established. In general, agonist activation of 5-HT(2A) receptors can facilitate stimulated dopamine (DA) release, whereas 5-HT(2C) agonists inhibit dopaminergic neural activity and DA release under both basal and activated conditions. However, recent experimental evidence suggests that 5-HT(2A) and 5-HT(2C) receptors can be constitutively active (agonist-independent activity) in vivo. Alterations in the constitutive activity of 5-HT(2A) and 5-HT(2C) receptor systems could be involved in the mechanisms underlying anxiety and depression or exploited for therapeutic benefit. Consequently, drugs with inverse agonist properties may have more activity in vivo to regulate DA neurotransmission than that afforded by simple competitive antagonism.

Publication types

  • Review

MeSH terms

  • Animals
  • Anxiety / drug therapy
  • Anxiety / metabolism
  • Anxiety / physiopathology
  • Corpus Striatum / metabolism
  • Depression / drug therapy*
  • Depression / metabolism*
  • Depression / physiopathology
  • Humans
  • Nucleus Accumbens / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Editing
  • Receptor, Serotonin, 5-HT2A / genetics
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptor, Serotonin, 5-HT2C / genetics
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / therapeutic use*
  • Serotonin Receptor Agonists / metabolism
  • Serotonin Receptor Agonists / therapeutic use*
  • Synaptic Transmission / physiology

Substances

  • Protein Isoforms
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Serotonin Antagonists
  • Serotonin Receptor Agonists