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Neurosci Lett. 2008 Sep 19;442(3):239-43. doi: 10.1016/j.neulet.2008.06.083. Epub 2008 Jul 4.

Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex.

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Lilly Research Laboratories, Psychiatric Disorders Discovery Biology, Lilly Corporate Center, Mail Drop 0510, Eli Lilly and Company, Indianapolis, IN 46285, United States.


Serotonin and norepinephrine, in addition to direct postsynaptic excitatory effects, also enhances glutamate release onto layer V pyramidal cells of the prefrontal cortex/neocortex via G(q/11)-coupled 5-hydroxytryptamine(2A) (5-HT(2A)) and alpha(1)-adrenergic receptors, respectively. Therefore, the present study was designed to test whether a metabotropic glutamate (mGlu) receptor subtype also coupled to G(q/11)-proteins, the mGlu5 receptor, also induces EPSCs when recording from layer V cortical pyramidal cells of the rat medial prefrontal cortex (mPFC). The mGlu1/5 receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induces EPSCs at a similar frequency as a near-maximally effective 5-HT concentration. The mGlu5 receptor negative allosteric modulator 2-methyl-6-(phenylethynyl)pyridine (MPEP, 300 nM) potently blocked DHPG-induced EPSCs. Previous work has suggested that activation of 5-HT(2A) 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.

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