Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

Abstract

The serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatric disorders. Although this receptor is important in the pharmacological mechanisms of action of new-generation antipsychotics, its characterization remains incomplete. Studies based on in vitro molecular imaging on brain tissue by autoradiography, and more recently in vivo PET imaging, have not yielded clear results, in particular due to the limitations of current 5-HT1A radiotracers, which lack specificity and/or bind to all 5-HT1A receptors, regardless of their functional status. The new concept of PET neuroimaging of functionally active G-protein-coupled receptors makes it possible to revisit PET brain exploration by enabling new research paradigms. For the 5-HT1A receptor it is now possible to use [18F]-F13640, a 5-HT1A receptor radioligand with high efficacy agonist properties, to specifically visualize and quantify functionally active receptors, and to relate this information to subjects’ pathophysiological or pharmacological state. We therefore propose imaging protocols to follow changes in the pattern of functional 5-HT1A receptors in relation to mood deficits or cognitive processes. This could allow improved discrimination of different schizophrenia phenotypes and greater understanding of the basis of therapeutic responses to antipsychotic drugs. Finally, as well as targeting functionally active receptors to gain insights into the role of 5-HT1A receptors, the concept can also be extended to the study of other receptors involved in the pathophysiology or therapy of psychiatric disorders.

Metabolomic Connections between Schizophrenia, Antipsychotic Drugs and Metabolic Syndrome: A Variety of Players

“…Future drugs with dual antipsychotic and antidepressant therapeutic potential may also target trace amine-associated receptor 1 (TAAR1), as well as histamine 3 (H3) and adenosine 2A (A2A) receptors (84). Moreover, antipsychotics such as aripiprazole, cariprazine and brexpiprazole are considered the 'third generation' exhibit prominent direct-acting agonist properties at 5-HT1A receptors (85). Indeed, 5-HT1A receptors are now an important therapeutic target for selection of novel antipsychotics based on a range of observations (85).…”

“…Moreover, antipsychotics such as aripiprazole, cariprazine and brexpiprazole are considered the 'third generation' exhibit prominent direct-acting agonist properties at 5-HT1A receptors (85). Indeed, 5-HT1A receptors are now an important therapeutic target for selection of novel antipsychotics based on a range of observations (85).…”

Case Report: A rare case of symptomatic bradycardia secondary to aripiprazole in a patient with bipolar disorder type I

“…4,8 The mechanism of action for which atypical antipsychotics could cause bradycardia has been related to the effects on 5-HT1A (5-beta hydroxytryptamine receptor 1) activation with upregulation of α2-adrenoreceptors in the brainstem. 8,15,17,18 The complex signaling and the role played by the sympathetic and parasympathetic nervous systems, as well as serotonin pathways in the heart, is complex and is the reason behind this type of medication can have an effect on the heart. [18][19][20] Aripiprazole is a partial dopamine agonist with substantial binding affinity for the serotonin 5HT2A (short for 5-hydroxy-tryptamine subtype 2 A) receptor; it has a broad spectrum receptors interaction as mentioned by Shapiro et al 6 with high affinity for h5-HT(2B) (5-hydroxytryptamine receptors), hD(2L)-, and hD(3)-dopamine receptors.…”

MiR-4763-3p targeting RASD2as a Potential Biomarker and Therapeutic Target for Schizophrenia

“…Consistent with this report, drugs approved to treat schizophrenia block D2 receptor signaling [ 14 ]. In addition to the dopamine receptors, serotonin (5-hydroxytryptamine, 5-HT) receptors have attracted widespread attention as potential therapeutic targets for cognitive disorders including schizophrenia [ 15 ].…”

“…Moreover, inhibition of miR-4763-3p resulted in significant improvement of schizophrenia symptoms as well as enhance learning memory and recovery from anxiety in a mouse model of schizophrenia (SCZ mice). Therefore, we explored the role of RASD2 and its regulation by miR-4763-3p in dopamine-associated signaling pathways[ 15 ].…”