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Tricyclic psychiatric medications as alpha2A adrenergic receptor ligands modulating receptor function
Author(s) -
Cottingham Christopher,
Chen Yunjia,
Percival Stefanie,
Jiao Kai,
Wang Qin
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1045.11
Subject(s) - tricyclic , desipramine , heterotrimeric g protein , receptor , pharmacology , neuroscience , chemistry , antidepressant , medicine , g protein , psychology , hippocampus
Neurobiological mechanisms of action underlying psychiatric medications largely remain poorly understood. In this study, we have investigated potential effects of tricyclic drugs on the brain noradrenergic system by characterizing their interactions with and effects on α 2A adrenergic receptors (ARs), beginning with the primarily noradrenergic antidepressant desipramine (DMI). DMI was found to be an orthosteric arrestin‐biased ligand at the α 2A AR, selectively inducing recruitment of arrestin (observed by FRET) but not activation of heterotrimeric G proteins. Arrestin recruitment results in DMI‐driven downregulation of receptor expression with chronic exposure, a process which occurs for cortical α 2A ARs in vivo in an arrestin‐dependent fashion and likely underlies mechanistically unexplained neuroadaptive alterations in α 2A AR expression associated with DMI. As well, we screened a number of tricyclic antidepressants and antipsychotics as receptor ligands, and found that all tested thus far bind the α 2A AR orthosteric site with varying affinities and differing abilities to drive receptor trafficking responses. Our findings provide novel insight into tricyclic pharmacology at α 2A ARs which could be used to develop novel therapeutic targeting of the noradrenergic system in depressive disorders and schizophrenia. Supported by NIMH grant MH081917 (QW) and NIH T32 training grant NS061788‐03 (CC).