Antidepressant Effects of Novel Positive Allosteric Modulators of Trk-receptor Mediated Signaling - a Potential Therapeutic Concept?

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2023 Jul 2

PMID 37394539

Authors

Nather Madjid

Veronica Lidell

Gunnar Nordvall

Maria Lindskog

Sven-Ove Ogren

Pontus Forsell

Johan Sandin

Affiliations

Soon will be listed here.

Abstract

Background: Major depressive disorder (MDD) is defined as a complex mental disorder which is characterized by a pervasive low mood and aversion to activity. Several types of neurotransmitter systems e.g. serotonergic, glutamatergic and noradrenergic systems have been suggested to play an important role in the origination of depression, but neurotrophins such as brain derived neurotrophic factor (BDNF) have also been implicated in the disease process.

Objectives: The purpose of this study was to examine the effects of a newly developed class of molecules, characterized as positive allosteric modulators of neurotrophin/Trk receptor mediated signaling (Trk-PAM), on neurotransmitter release and depression-like behavior in vivo.

Methods: The effect of and possible interaction of neurotrophin/Trk signaling pathways with serotonergic and glutamatergic systems in the modulation of depression-related responses was studied using newly developed Trk-PAM compounds (ACD855, ACD856 and AC26845), as well as ketamine and fluoxetine in the forced swim test (FST) in rodents. Moreover, in vivo microdialysis in freely moving rats was used to assess changes in neurotransmitter levels in the rat.

Results: The results from the study show that several different compounds, which all potentiate Trk-receptor mediated signaling, display antidepressant-like activity in the FST. Moreover, the data also indicate that the effects of both fluoxetine and ketamine in the FST, both used in clinical practice, are mediated via BDNF/TrkB signaling, which could have implications for novel therapies in MDD.

Conclusions: Trk-PAMs could provide an interesting avenue for the development of novel therapeutics in this area.

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