Figure 3.

Cross-signaling of 2AR and mGlu2 through (A) physiological interaction and (B) the formation of a 2AR-mGlu2 heteromer. Activation of 2AR by serotonergic psychedelics induces EPSPs/EPSCs as well as psychedelic-related behaviors such as the HTR in rodents through the activation of G_q/11 and additional signaling pathways (as described in Box 2). Stimulation of mGlu2 (by agonists or PAMs) or the presence of an mGlu2 antagonist was demonstrated to regulate these outcomes either (A) indirectly through its canonical G_i/o signaling or (B) directly through the formation of a heteromer with 2AR. The heteromer is assumed to integrate both serotonergic and glutamatergic input (such as serotonergic psychedelics and mGlu2 agonists, and PAMs or antagonists) and shift the balance of G_q/11 + (and additional signaling pathways) to G_i/o signaling, accordingly. EPSC: Excitatory postsynaptic current, EPSP: Excitatory postsynaptic potential and PAM: Positive Allosteric Modulator.