activation of metabotropic glutamate 5 mglu5 receptors induces spontaneous excitatory synaptic currents in layer v pyramidal cells of the rat prefrontal cortex serotonin and norepinephrine in addition to direct postsynaptic excitatory effects also enhances glutamate release onto layer v pyramidal cells of the prefrontal cortexneocortex via gq11coupled 5hydroxytryptamine2a 5ht2a and alpha1adrenergic receptors respectively therefore the present study was designed to test whether a metabotropic glutamate mglu receptor subtype also coupled to gq11proteins the mglu5 receptor also induces epscs when recording from layer v cortical pyramidal cells of the rat medial prefrontal cortex mpfc the mglu15 receptor agonist s35dihydroxyphenylglycine dhpg induces epscs at a similar frequency as a nearmaximally effective 5ht concentration the mglu5 receptor negative allosteric modulator 2methyl6phenylethynylpyridine mpep 300 nm potently blocked dhpginduced epscs previous work has suggested that activation of 5ht2a and ox2 receptors induces glutamate release while mglu2 mglu4 and mglu8 receptor activation suppress transmitter release from thalamocortical terminals taken together with past results these findings suggest that mglu2 mglu4 mglu5 and mglu8 may all act to modulate glutamate release from afferents impinging on layer v pyramidal cells of the mpfc these findings further suggest that monoamines neuropeptides and glutamate itself all enhance the excitability of prefrontal cortical output cells indirectly via modulation of glutamate release