Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex

In prefrontal cortex, 5-hydroxytryptamine(2A) (5-HT2A) receptors have been linked to the action of hallucinogens and atypical antidepressant/antipsych otic drugs. Previously, we have shown in cortical layer V pyramidal cells t hat a nonselective metabotropic glutamate (mGlu) receptor agonist suppresse s the induction of excitatory postsynaptic potentials/currents (EPSPs/EPSCs ) via activation of 5-HT2A receptors. In this study, we tested the ability of the selective mGlu2/3 agonist (1S, 2S, 5R, 6S)-2-aminobicyclo[3.1.0] hex ane-2,6-dicarboxylate monohydrate (LY354740) and the selective mGlu2/3 anta gonist 2S-2-amino-2-( 1S,2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl) propano ic acid (LY341495) to modulate serotonin(5-HT)-induced EPSPs and electrical ly evoked EPSPs by using intracellular recording from layer V pyramidal cel ls in medial prefrontal cortex. The mGlu2/3 antagonist LY341495 increased t he frequency and amplitude of 5-HT-induced EPSCs, suggesting a role for mGl u2/3 receptors in mediating the action of endogenous glutamate on autorecep tors. Conversely, the mGlu2/3 agonist LY354740 was highly effective and pot ent (EC50 = 89 nM) in suppressing glutamate release induced by 5-HT2A recep tor activation in the medial prefrontal cortex, probably via a presynaptic mechanism. The mGlu2/3 antagonist LY341495 potently blocked the suppressant effect of LY354740 on 5-HT-induced EPSCs as well as electrically evoked ea rly EPSPs. Autoradiography with the radioligands [H-3] LY354740 and [I-125] (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane shows a striking overla p of the laminar distribution of mGlu2/3 and 5-HT2A receptors in the medial prefrontal cortex that is not apparent in other cortical regions. These fi ndings suggest a close coupling between mGlu2/3 and 5-HT2A receptors in the prefrontal cortex that may be relevant for novel therapeutic approaches in the treatment of neuropsychiatric syndromes such as depression and schizop hrenia.