Vol. 300, Issue 3, 1008-1016, March 2002

Amphetamine Inhibits the N-Methyl-D-Aspartate Receptor-Mediated Responses by Directly Interacting with The Receptor/Channel Complex

Geng-Chang Yeh, Jin-Chung Chen¹, Hsiu-Chuan Tsai, Hsueh-Hsia Wu², Chao-Yu Lin, Ping-Ching Hsu and Yu-Chen Peng

Department of Pediatrics, Taipei Medical University Hospital, Graduate Institute of Medical Science, Taipei Medical University, Taipei Taiwan

Amphetamine (AMPH) induces behavioral sensitization and neurotoxicity primarily by enhancing the dopamine-mediated neurotransmission. However, the involvement of the N-methyl-D-aspartate (NMDA) receptor in AMPH-induced neuropathology is also known. Recent investigation has found that high concentration of dopamine could inhibit NMDA receptor-mediated responses by blocking the NMDA receptor channel. By virtue of the structure similarity between dopamine and AMPH, we determined whether d-AMPH and its analogs, l-AMPH and methamphetamine (MAMH), could affect the NMDA receptor-mediated [³H]N-[1-(2-thienyl)cyclohexyl] piperidine ([³H]TCP) binding in rat cortical membrane preparations and intracellular ⁴⁵Ca²⁺ accumulation and cell death in the rat primary cortical cell cultures. AMPH concentration-dependently inhibited NMDA- and glycine-stimulated [³H]TCP binding and intracellular ⁴⁵Ca²⁺ accumulation with two distinct potencies; a minor inhibition with high potency and a major inhibition with low potency. [³H]TCP binding suggested that the high-potency inhibition was produced by decreasing agonist-induced activation of the NMDA receptor channel. On the other hand, the low-potency inhibition was produced by competing with [³H]TCP binding in the NMDA receptor channel, like the action of noncompetitive antagonist of the NMDA receptor. However, AMPH analogs were less potent in inhibiting NMDA- and glycine-induced cultured cell death. Thus, this result indicates that AMPH could antagonize the NMDA receptor-mediated responses in vitro by two different mechanisms, probably, through directly interacting with two distinct sites on this receptor/channel complex.