Disrupting dopamine-glutamate receptor complexes to alleviate stress-related mental disorders – DropStress

Stress is a key factor that predisposes to many mental disorders, such as major depression, anxiety or substance use disorders (SUD), and hinders remission. There is a strong co-morbidity between SUD and people diagnosed for mental disorders, notably anxiety and depression. Current therapies primarily target symptoms rather than their causes due to our poor knowledge of the mechanisms underlying stress-related mental disorders. Partner 1 showed that behavioral sequelae of stress and abused drugs partly result from common enduring changes within midbrain dopamine (DA) neurons. Released DA shapes glutamate (Glu) inputs converging onto striatal neurons, which thus senses rewarding and stressful states. Hence, reported dysfunctions of DA and Glu transmissions in both stress-related disorders and SUD could sustain the co-occurrence of mental disorders. So far, treatments that mostly target cognate neurotransmitter receptors show loss of therapeutic efficacy over time and serious side effects. Based on our strong preliminary generated by the consortium, we will test whether targeting DAR/NMDAR complexes, rather the receptor themselves, provides beneficial outcomes for depression and comorbid SUD.
The physical interaction between receptors (i.e receptor complexes) is as a key mechanism by which receptors can modify their functions. Receptor complexes emerge as molecular targets with growing therapeutic potentials since they display functional properties that are distinct from individual component receptors, making them attractive for the development of more selective pharmacological treatments. Partner 2 showed that the interaction between DA D1 receptor (D1R) and the GluN1 subunit of Glu NMDA receptors (NMDAR) is the molecular bridge linking increase of DA to the facilitation of NMDAR-dependent signaling, long-term striatal plasticity and cocaine-induced locomotor sensitization, while others showed that the binding of D2R to GluN2B subunits drives the inhibition of NMDAR functions by DA.
We validated the methodologies to achieve a comprehensive mapping of the modulation of endogenous D1R/GluN1 & D2R/GluN2B complexes in brain regions sensing aversive and rewarding stimuli. Our results already show that chronic stress and cocaine trigger net increases in D1R/GluN1 complexes in the ventral striatum. To test for the translational relevance of our hypothesis, changes in DAR/NMDAR complexes will be measured in human brain striatal slices from controls and patients having suffered from depression.
Next, using a viral-based interfering peptide strategy set-up by P2, we will test whether disrupting DAR/NMDAR complexes, while sparing individual DA and NMDA receptor function, can prevent and/or rescue stress outcomes. This will be done owing to a time- and region-dependent inhibition of DAR/NMDAR complexes. We will carry multi-level analyses including molecular, electrophysiological, anatomical and behavioral measures.
Last, we will explore the role of DAR/NMDAR complexes in the synergistic interplay between stress and cocaine by studying how stress pre-exposure conditions subsequent cocaine responses and reciprocally. Analyses of DAR/NMDAR complexes from post-mortem brains of depressed subjects with a history of psychostimulant dependence will be of great added value.
This project clearly falls within the aims of the health and well-being societal challenge and especially with the axis 6 Exploration of the nervous system in its normal & pathological functions, an axis with clear focus on mental disorders. Most tools and paradigms have been set-up, and preliminary data supporting each task ensure the feasibility of DROPSTRESS with low risks. DROPSTRESS has a huge potential to identify new molecular events underlying stress-induced brain allostasis and associated comorbidity, which may provide new routes for medical treatments. It will also benefit to neuropsychiatric disorders associated with an imbalance of DA/Glu transmission.