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ORIGINAL ARTICLE

Differential Modulation of Glutamatergic Transmission by 3,5-Dibromo-L-phenylalanine

Departments of Anesthesiology (V.Y., A.V.G., N.G., D.M.D., C.N.S., A.E.M.), Physiology and Functional Genomics (C.S.), and the McKnight Brain Institute (C.S., N.G., D.M.D., A.E.M.), University of Florida, Gainesville, Florida

Abstract

An increasing body of evidence supports the hypothesis that diminished function of N-methyl-D-aspartate (NMDA) receptors and the associated increase in glutamate release and overstimulation of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors are critical elements of the pathophysiology of schizophrenia. Here, we describe a halogenated derivative of the aromatic amino acid L-phenylalanine that 1) activates NMDA receptors, 2) depresses presynaptic glutamate release, and 3) blocks AMPA/kainate receptors. The experiments were conducted in rat cerebrocortical cultured neurons by using the patch-clamp technique. 3,5-Dibromo-L-phenylalanine (3,5-DBr-L-Phe) augmented NMDA miniature excitatory postsynaptic currents (mEPSCs) and activated the steady-state current, effects that were eliminated by NMDA receptor antagonists DL-2-amino-5-phosphonopentanoic acid and MK-801 (dizocilpine maleate; 5H-dibenzo[a,d]cyclohepten-5,10-imine). 3,5-DBr-L-Phe was a partial agonist at the glutamate-binding site of NMDA receptors with an EC₅₀ of 331.6 ± 78.6 µM and with an efficacy of 30.5 ± 4.7% compared with NMDA. 3,5-DBr-L-Phe depressed both amplitude and frequency of AMPA/kainate mEPSCs. The IC₅₀ of 3,5-DBr-L-Phe to inhibit AMPA/kainate mEPSC frequency was 29.4 ± 4.3 µM. 3,5-DBr-L-Phe significantly decreased paired pulse depression of AMPA/kainate EPSCs and attenuated current activated by AMPA with higher efficacy at lower concentration of AMPA. 3,5-DBr-L-Phe neither affected GABA miniature inhibitory postsynaptic currents nor elicited action potentials. By enhancing NMDA receptor function, reducing glutamate release and blocking AMPA/kainate receptors 3,5-DBr-L-Phe represents a new type of polyvalent modulator of glutamatergic synaptic transmission with potential therapeutic applications.

Address correspondence to: Dr. Anatoly E. Martynyuk, Department of Anesthesiology, University of Florida, P.O. Box 100254, J. Hillis Miller Health Center, 1600 SW Archer Rd., Gainesville, FL 32610-0254. E-mail: amartynyuk{at}anest.ufl.edu