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Vol. 292, Issue 1, 76-87, January 2000

Physiological Antagonism between 5-Hydroxytryptamine2A and Group II Metabotropic Glutamate Receptors in Prefrontal Cortex1

Gerard J. Marek, Rebecca A. Wright, Darryle D. Schoepp, James A. Monn and George K. Aghajanian

Departments of Psychiatry and Pharmacology, Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, Connecticut (G.J.M., G.K.A.); Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (R.A.W., D.D.S., J.A.M.).

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-HT2A receptor 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-HT2A receptors in the prefrontal cortex that may be relevant for novel therapeutic approaches in the treatment of neuropsychiatric syndromes such as depression and schizophrenia.

1 This work was supported by United States Public Health Service Grants K08 Award (National Institute of Mental Health; G.J.M.) and MH17871 (National Institute of Mental Health; G.K.A.), a National Alliance for Research on Schizophrenia and Depression (NARSAD) 1999 Fairfax Investigator Award (G.J.M.), the State of Connecticut (G.J.M., G.K.A.), and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.

0022-3565/0/2921-0076$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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