A scoping review on the cross-signaling of 5HT2AR and mGluR2 through the formation of a GPCR heteromer and its implication for serotonergic psychedelics

Abstract

The growing demand of psychiatric treatment in combination with the declining development of psychiatric drugs over the last decade results in the need for new treatment modalities. Considering the current ongoing clinical studies, it seems that this needed innovative player might be psychedelic-assisted psychotherapy. Study results in the last decades indicate a renaissance for psychedelic research with especially promising results for the treatment of mental disorders, like the therapeutic usage of psilocybin for severe depression. Yet the molecular mechanism underlying the observed phenotypic changes induced by psychedelics remain mostly unresolved. So far it was discovered that these “mind manifesting” substances are mostly partial agonists of brain serotonin receptors, inducing their psychedelic effects through the 5-hydroxytryptamine 2A receptors (2AR). Although crucial for their effect, substantial evidence over the last decade indicates that the 2AR alone cannot fully explain the psychedelic response and thus further physiological interactions must be taken into account. One of the most promising targets is the metabotropic glutamate receptor 2 (mGluR2) that has been shown to be necessary to induce the pharmacological and behavioural effects of psychedelics. Interestingly, a putative 2AR-mGluR2 complex with an differential downstream signalling pathway has been identified. This complex might play an important role in regulating the molecular signature of the psychedelic response due to distinct signalling properties and allosteric cross-regulation between the two receptors. Understanding the biological mechanisms is of high importance not only regarding the development of effective treatments but also to ensure safety of the treated patients.

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