Abstract: A method of desensitizing 5-HT2R signaling in the mammal is provided. The method comprises one or more of: 1) inhibiting CRFR1 activation of 5-HT2AR signaling by preventing trafficking of intracellular vesicles or blocking recycling of 5-HT2AR to the cell surface; 2) blocking PDZ binding motifs in the carboxyl-terminal tail domains of at least one of CRFR1, 5-HT2AR or 5-HT2CR; or 3) blocking the interaction of a 5-HT2R or a CRFR1 with a PDZ-domain-containing protein selected from the group consisting of MAGI-1 PDZ1, MAGI-2 PDZ1, MAGI-3 PDZ1, PSD95 PDZ 1&2, PSD95 PDZ3, CAL PDZ, SAP97 PDZ 1&2, PTPN13 PDZ 4&5, PDZK2 PDZ1, MPP3 PDZ, ERBIN PDZ and MUPP1 PDZ 12.