Major depressive disorder is a mental illness afflicting approximately 16% of the world population. Currently available interventions including monoamine-based pharmacotherapies require several weeks to months for beneficial effects to occur. In addition, these treatments are often accompanied by undesirable side effects. Therefore, there is an urgent need for better antidepressant medications, with a faster onset of action, which will also be effective in patients who do not respond to classical antidepressants. Recent clinical findings suggest that psilocybin – a hallucinogenic serotonin 5-HT2A receptor (5-HT2AR) agonist, exerts fast-acting and long-lasting antidepressant actions in patients suffering from major depression. Despite these striking effects, a number of alterations in various mental domains, including sensory perception and thought processes, precludes the routine use of psilocybin and other hallucinogens in daily clinical practice. G protein-coupled receptors (GPCRs) are critical mediators of cell signaling. Although recognized as capable of activating G proteins in a monomeric form, numerous studies reveal their possible association into hetero-oligomers, enabling allosteric crosstalk between receptor protomers. We previously reported that 5-HT2AR and metabotropic glutamate receptor 2 (mGluR2) are able to interact physically to form a GPCR complex. Results from earlier versions of this R01 grant showed that at least part of the cellular signaling and psychosis-like behaviors induced by hallucinogenic 5- HT2AR agonists require expression of the 5-HT2AR-mGluR2 heteromer in the mouse frontal cortex. However, the ability of cortical 5-HT2AR-mGluR2 to affect behavioral states associated with depression upon hallucinogen administration remains to be elucidated. Similarly, as the functional importance of GPCR oligomerization remains controversial, additional studies related to basic structural and signaling properties of the 5-HT2AR-mGluR2 complex are needed. Our published data and the preliminary data presented here support our working hypothesis that inter-family GPCR heteromerization affects structure, sub-cellular localization and function of both 5-HT2AR and mGluR2 in living mammalian cells. Our data are also consonant with the hypothesis that a single dose of hallucinogenic 5-HT2AR agonists induces fast-acting and long-lasting effects on remission of behavioral states associated with depression, and that these therapeutic-related phenotypes require expression of 5-HT2AR and mGluR2 as a GPCR heteromer in the frontal cortex of mice. These data set the stage for a uniquely comprehensive analysis of the molecular mechanism underlying the antidepressant effects of hallucinogens, with the ultimate goal of developing safer, more effective, and non-hallucinogenic depression treatment strategies.