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NEUROPHARMACOLOGY

Group III Metabotropic Glutamate Receptor Agonists Selectively Suppress Excitatory Synaptic Currents in the Rat Prefrontal Cortex Induced by 5-Hydroxytryptamine_2A Receptor Activation

Department of Psychiatry, Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, Connecticut

Activation and blockade of prefrontal cortical 5-hydroxytryptamine_2A (5-HT_2A) receptors have been linked to the action of hallucinogenic and antidepressant/antipsychotic drugs; these effects may involve modulation of glutamate release from thalamocortical afferents. Although activation of metabotropic glutamate 2 (mGlu2) receptors may suppress 5-HT-induced excitatory postsynaptic currents (EPSCs), group III mGlu receptors (mGlu4/7/8) also are expressed in the thalamus and may suppress 5-HT-induced EPSCs. We have found by intracellular recordings from layer V pyramidal cells of the medial prefrontal cortex (mPFC) that group III mGlu receptor agonists (R,S)-4-phosphonophenylglycine (PPG), L-4-phosphono-2-aminobutyric acid (L-AP4), L-serine-O-phosphate (L-SOP), and (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) preferentially suppress 5-HT-induced EPSCs compared with excitatory postsynaptic potentials evoked by electrical stimulation of the white matter. A number of pharmacological features [e.g., the rank order of agonist potency; MAP4 partial agonist action; differential potency for the group III mGlu receptor antagonist (R,S)--cyclopropyl-4-phosphonophenylglycine (CPPG) in blocking the suppressant action of PPG or MAP4; and a relatively low potency of 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) in blocking the suppressant action of PPG or L-SOP] suggest that activation of both mGlu4 and mGlu8 receptors may play a role in suppressing 5-HT-induced EPSCs. Furthermore, L-SOP did not alter the synaptic currents or steady-state inward current induced by -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid. Thus, although both group III and group II mGlu receptor agonists suppress the frequency of 5-HT-induced EPSCs in the mPFC, they differ in that the group III mGlu receptor agonists appear to have relatively minimal effects on glutamate released by sources other than thalamocortical afferents.

Address correspondence to: Gerard J. Marek, Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Mail Drop 0510, Indianapolis, IN 46285. E-mail: gerard_j_marek{at}lilly.com