Presynaptic 5-HT(2A)-mGlu2/3 Receptor–Receptor Crosstalk in the Prefrontal Cortex: Metamodulation of Glutamate Exocytosis

The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT(2A) heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [(3)H]D-aspartate ([(3)H]D-asp) release (which mimics glutamate exocytosis). The concomitant activation of the two receptors nulls their inhibitory activities, whereas blockade of the 5-HT(2A) heteroreceptors with MDL11,939 (1 μM) strengthens the inhibitory effect elicited by the mGlu2/3 receptor agonist LY329268 (1 μM). 5-HT(2A) receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. Clozapine (0.1–10 μM) mimics the 5-HT(2A) agonist (±) DOI and inhibits the KCl-evoked [(3)H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect. mGlu2 and 5-HT(2A) proteins do not co-immunoprecipitate from synaptosomal lysates, nor does the incubation of PFc synaptosomes with MDL11,939 (1 μM) or clozapine (10 µM) modify the insertion of mGlu2 subunits in synaptosomal plasma membranes. In conclusion, 5-HT(2A) and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT(2A) metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens.