Abstract
Major depressive disorder (MDD) is associated with significant morbidity and mortality. Most antidepressant medications target the serotonin and norepinephrine transporters, but a significant minority of patients do not respond to treatment and novel therapeutic targets are needed. We previously identified a protein complex composed of the α7 nicotinic acetylcholine receptor (nAChR) and NMDA glutamate receptors (NMDARs), through which α7nAChR upregulates NMDAR function. Disruption of the α7nAChR–NMDAR complex with an interfering peptide blocked α7nAChR-mediated upregulation of NMDAR function and cue-induced reinstatement of nicotine seeking in rat models of relapse. Here we report that disrupting the α7nAChR–NMDAR complex with the interfering peptide also has antidepressant-like effects in the forced swim test (FST), a common rat behaviour screening test for antidepressant effects. Furthermore, the interfering peptide significantly increases extracellular signal-regulated kinase (ERK) activity in the animals subjected to the FST. Our results provide a novel potential therapeutic target for the development of new antidepressant medications.
Highlights
Major depressive disorder (MDD) is a leading cause of morbidity and mortality, affecting approximately 216 million people worldwide (3% of the global population), which is an increase of 17.8% from 2005 to 2015 [1]
The TAT‐α7‐peptide has antidepressant‐like effects in the forced swim test To test potential antidepressant-like effects of the α7 Nicotinic acetylcholine receptor (α7nAChR)–NR2A interfering peptide, we delivered three doses at 4 nmol
Disruption of α7nAChR–NR2A interaction by TAT‐α7‐peptide increases extracellular signal-regulated kinase 1 (ERK1) phosphorylation in rat hippocampus We previously demonstrated that activation of α7nAChR facilitates NMDA receptor function via the α7nAChR–NR2A interaction, and that the TAT-α7peptide can block this enhanced NMDA receptormediated current [41]
Summary
Major depressive disorder (MDD) is a leading cause of morbidity and mortality, affecting approximately 216 million people worldwide (3% of the global population), which is an increase of 17.8% from 2005 to 2015 [1]. Current pharmacotherapy for MDD includes antidepressant medications in several major categories: selective serotonin reuptake inhibitors (SSRIs) [2, 3], tricyclic antidepressants (TCA) [4, 5], and monoamine oxidase inhibitors (MAOIs) [6,7,8]. Less common but highly effective brain stimulation treatments are Antidepressant medications are more effective than placebo but overall effects are modest [13]. 67% of patients improve with antidepressant treatment, the significant minority of non-responders in a very common disorder results in a great unmet need for treatment in a large number of patients [14]. Other neurotransmitter systems have been implicated in mood regulation and antidepressant treatment, and a brief review of salient findings follows
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