Identification of new inhibitors of dopamine-glutamate receptor heteromerization to alleviate addictive- and depressive-like symptoms

The high prevalence of comorbidities between substance use disorder (SUD) and other psychiatric diseases, including depression, suggests that brain dysfunctions underlying these disorders may share partly overlapping pathophysiological mechanisms. Identification of such common dysfunctions is therefore a key asset to design therapeutic strategies to treat both SUD and comorbid psychiatric conditions, rather than treating each disease separately, which holds poor efficacy. From mice to humans, we showed that an increase in dopamine (DAR) and glutamate NMDA (NMDAR) receptor heteromerization (i.e physical interaction) in the ventral striatum constitutes a common molecular switch for SUD and depression. Using genetically-encoded DAR-NMDAR interaction blockers delivered into the ventral striatum, it was found that disrupting DAR-NMDAR heteromers blocks cellular, molecular and behavioral adaptations in preclinical models of SUD and depression, while preserving natural reward processing. The objective of my thesis is to reinforce the translational value of these findings by identifying peripherally administered clinically-relevant small molecules targeting DAR-NMDAR heteromers. We performed an in-silico 3D-molecular modeling of D1R-NMDAR interaction interfaces, combined to a virtual High Throughput Screenin (vHTS) to identify 100 candidate inhibitors of D1R-NMDAR. We tested our two first identified molecules and proved their efficacy to disrupt receptor heteromerization in cultured neurons, therefore validating our strategy. Based on the results obtained in in vitro tests, we will select the most effective compound and evaluate its ability to alter D1R-NMDAR heteromerization in vivo in key brain regions of the reward circuit and to alleviate neurobiological and behavioral adaptations in preclinical models of addiction and depression.