Stress responses involve corticotropin releasing factor (CRF), the two cognate receptors (CRFi and CRF 2 ) and the CRF-binding protein (CRFBP). Utilizing a novel cell-based assay, a C-terminal CRFBP fragment [CRFBP(IOkD)] was found to potentiates CRF-intracellular Ca 2+ release, demonstrating that CRFBP possesses excitatory roles in addition to the inhibitory role established by the N-terminal fragment of CRFBP [CRFBP(27kD)]. This interaction was CRFa-specific, as CRF1 responses were not potentiated by CRFBP(IOkD). As there were currently no small molecule ligands available that selectively interact with either CRFBP or CRF2, a cell-based assay was miniaturized, wherein CRFBP(IOkD) was fused as a chimera with CRF 2a, that allowed us to a perform a high-throughput screen (HTS) of approximately 350,000 small molecules. This resulted in the identification of negative allosteric modulators (NAMs) of the CRFBP(10kD)-CRF2 complex that blunt CRF-induced potentiation of /V-Methyl-D-aspartic acid receptor (NMDAR)-mediated synaptic transmission in dopamine neurons in the ventral tegmental area (VTA). These results provide the first evidence of specific roles for GRF 2 and CRFBP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for the treatment of stress and substance abuse disorders such as alcohol use disorder.Les réponses au stress impliquent le facteur de libération de la corticotropine (CRF), les deux récepteurs cognates (CRFi et CRF2) et la protéine de liaison au CRF (CRFBP). Par l'utilisation d'un nouveau test à base de cellules, un fragment de CRFBP C-terminal [CRFBP(IOkD)] s'est révélé potentialiser la libération de CRF-Ca2+ intracellulaire, démontrant que CRFBP exerce des rôles excitateurs en plus du rôle inhibiteur établi par le fragment N-terminal de CRFBP [CRFBP (27 kD)]. Cette interaction était spécifique de CRFa, car les réponses en CRF1 n'ont pas été potentialisées par CRFBP(IOkD). Comme il n'y a actuellement pas de lig
