Project Summary G protein-coupled receptors (GPCRs) are key membrane proteins involved in transduction of external signal across the cellular membrane into the cytoplasm of target cells. Related to their quaternary structure, although this concept still remains a matter of intense speculation and debate, it is particularly intriguing the plausible ability of class A GPCRs to assemble as heterodimers or heteromers that exhibit distinct pharmacological, trafficking and functional properties as compared to their parent monomeric or homodimeric/homomeric forms. As such, GPCR complexes may represent novel drug targets with extensive therapeutic potential. However, many questions still remain open about the role of receptor complex formation in the dynamics and behavior of GPCRs. Classical psychedelics, including psilocybin, mescaline and LSD, profoundly affect processes related to perception, cognition and sensory processing. Over the past decade, psychedelic compounds have emerged as potentially transformative therapeutics for a variety of otherwise intractable neuropsychiatric conditions. Despite these striking effects, their acute symptoms and uncontrolled recreational use potential preclude the routine use of psychedelics in daily clinical practice. Additionally, although these results have interesting implications for psychiatry research and therapeutics, many questions regarding the molecular target and neural circuit mechanism of action, safety, and efficacy of psychedelics as fast-acting therapeutics still remain open. It is therefore imperative to understand the biology and pharmacology behind their therapeutic mechanisms as well as expose potential pitfalls in their widespread use as treatment. Over the past 15 years of this grant, we have accumulated several lines of evidence indicating that class A Gq/11-coupled 5-HT2A receptor (5-HT2AR) and class C Gi/o-coupled metabotropic glutamate receptor 2 (mGluR2) are able to physically interact with one another and by so doing alter G protein coupling, sub-cellular localization and function. We showed that at least part of the cellular signaling and synaptic structural plasticity effects induced by psychedelic 5-HT2AR agonists require expression of mGluR2. The final goal of this competitive renewal is to expand our prior basic work dissecting functional crosstalk mechanisms between 5-HT2AR and mGluR2 as a GPCR heteromeric complex, to understand its role in psychedelic-induced circuit-specific synaptic and behavioral plasticity. Our central hypotheses are that i) mRNA transcripts encoding 5-HT2AR and mGluR2 are associated in vitro and ex vivo in mammalian cells, that ii) co-expression of 5-HT2AR leads to agonist-induced mGluR2-Ga protein complexes located intracellularly via GPCR heteromerization, and that iii) selective deletion of mGluR2 in frontal cortex pyramidal neurons projecting to specific subcortical target regions abolishes the effects of a single dose of psychedelic 5-HT2AR agonists on synaptic structural plasticity and acceleration of contextual fear extinction. Completion of this work may provide the rationale for the development and testing of plasticity-promoting 5-HT2AR-mGluR2 ligands as safe, effective and fast-acting treatments for several psychiatric disorders.

Project Narrative Recently, psychedelics have emerged as promising candidate treatments for numerous neuropsychiatric disorders. While their potential in the clinic has yet to be fully elucidated, understanding their molecular and cellular mechanisms is imperative as these compounds are becoming widely used both in clinical settings and recreational contexts. The proposed studies aim at characterizing the structure and function of a neurotransmitter receptor complex involved in the neurobiological effects of psychedelics, and will potentially open new avenues for improving our therapeutic strategies.