PT  - JOURNAL ARTICLE
AU  - Gerard J. Marek
AU  - Rebecca A. Wright
AU  - Darryle D. Schoepp
AU  - James A. Monn
AU  - George K. Aghajanian
TI  - Physiological Antagonism between 5-Hydroxytryptamine<sub>2A</sub> and Group II Metabotropic Glutamate Receptors in Prefrontal Cortex
DP  - 2000 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 76--87
VI  - 292
IP  - 1
4099  - http://jpet.aspetjournals.org/content/292/1/76.short
4100  - http://jpet.aspetjournals.org/content/292/1/76.full
SO  - J Pharmacol Exp Ther2000 Jan 01; 292
AB  - In prefrontal cortex, 5-hydroxytryptamine2A(5-HT2A) receptors have been linked to the action of hallucinogens and atypical antidepressant/antipsychotic drugs. Previously, we have shown in cortical layer V pyramidal cells that a nonselective metabotropic glutamate (mGlu) receptor agonist suppresses 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]hexane-2,6-dicarboxylate monohydrate (LY354740) and the selective mGlu2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) to modulate serotonin(5-HT)-induced EPSPs and electrically evoked EPSPs by using intracellular recording from layer V pyramidal cells in medial prefrontal cortex. The mGlu2/3 antagonist LY341495 increased the frequency and amplitude of 5-HT-induced EPSCs, suggesting a role for mGlu2/3 receptors in mediating the action of endogenous glutamate on autoreceptors. Conversely, the mGlu2/3 agonist LY354740 was highly effective and potent (EC50 = 89 nM) in suppressing glutamate release induced by 5-HT2Areceptor 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 early EPSPs. Autoradiography with the radioligands [3H]LY354740 and [125I](±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane showsa striking overlap 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 findings suggest a close coupling between mGlu2/3 and 5-HT2Areceptors in the prefrontal cortex that may be relevant for novel therapeutic approaches in the treatment of neuropsychiatric syndromes such as depression and schizophrenia. The American Society for Pharmacology and Experimental Therapeutics