Serotonin 5-HT1A Receptors as Targets for Agents to Treat Psychiatric Disorders: Rationale and Current Status of Research

• Published in: CNS drugs 2013-09, Vol.27 (9), p.703-716
• Main Authors: Celada, Pau, Bortolozzi, Analía, Artigas, Francesc
• Format: Article
• Language: English
• Subjects: Animals; Humans; Leading Article; Medicine; Medicine & Public Health; Mental Disorders - drug therapy; Mental Disorders - metabolism; Molecular Targeted Therapy; Neurology; Neurosciences; Pharmacotherapy; Psychiatry; Psychopharmacology; Receptors, Serotonin, 5-HT1 - metabolism; Serotonin 5-HT1 Receptor Agonists - pharmacology; Serotonin 5-HT1 Receptor Agonists - therapeutic use
• ISSN: 1172-7047; 1179-1934
• DOI: 10.1007/s40263-013-0071-0

Psychiatric disorders represent a large economic burden in modern societies. However, pharmacological treatments are still far from optimal. Drugs used in the treatment of major depressive disorder (MDD) and anxiety disorders (selective serotonin [5-HT] reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) are pharmacological refinements of first-generation tricyclic drugs, discovered by serendipity, and show low efficacy and slowness of onset. Moreover, antipsychotic drugs are partly effective in positive symptoms of schizophrenia, yet they poorly treat negative symptoms and cognitive deficits. The present article reviews the neurobiological basis of 5-HT 1A receptor (5-HT 1A -R) function and the role of pre- and postsynaptic 5-HT 1A -Rs in the treatment of MDD, anxiety and psychotic disorders. The activation of postsynaptic 5-HT 1A -Rs in corticolimbic areas appears beneficial for the therapeutic action of antidepressant drugs. However, presynaptic 5-HT 1A -Rs play a detrimental role in MDD, since individuals with high density or function of presynaptic 5-HT 1A -Rs are more susceptible to mood disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the indirect activation of presynaptic 5-HT 1A -Rs by SSRIs/SNRIs reduces 5-HT neuron activity and terminal 5-HT release, thus opposing the elevation of extracellular 5-HT produced by blockade of the serotonin transporter (SERT) in the forebrain. Chronic antidepressant treatment desensitizes presynaptic 5-HT 1A -Rs, thus reducing the effectiveness of the 5-HT 1A autoreceptor-mediated negative feedback. The prevention of this process by the non-selective partial agonist pindolol accelerates clinical antidepressant effects. Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT 1A -R agonist properties with SERT blockade. Several studies with transgenic mice have also established the respective role of pre- and postsynaptic 5-HT 1A -Rs in MDD and anxiety. In agreement with pharmacological studies, presynaptic and postsynaptic 5-HT 1A -R activation appears necessary for anxiolytic and antidepressant effects, respectively, yet, neurodevelopmental roles for 5-HT 1A -Rs are also involved. Likewise, the use of small interference RNA has enabled the showing of robust antidepressant-like effects in mice after selective knock-down of 5-HT 1A autoreceptors. Postsynaptic 5-HT 1A -Rs in the prefrontal cort