Physiological and therapeutic relevance of constitutive activity of 5-HT_2A and 5-HT_2C receptors for the treatment of depression

Serotonin_2A (5-HT_2A) and 5-HT_2C receptors are highly homologous members of the serotonin₂ 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.