RT Journal Article
SR Electronic
T1 Amphetamine Inhibits the<em>N</em>-Methyl-<span class="sc">d</span>-Aspartate Receptor-Mediated Responses by Directly Interacting with The Receptor/Channel Complex
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1008
OP 1016
DO 10.1124/jpet.300.3.1008
VO 300
IS 3
A1 Yeh, Geng-Chang
A1 Chen, Jin-Chung
A1 Tsai, Hsiu-Chuan
A1 Wu, Hsueh-Hsia
A1 Lin, Chao-Yu
A1 Hsu, Ping-Ching
A1 Peng, Yu-Chen
YR 2002
UL http://jpet.aspetjournals.org/content/300/3/1008.abstract
AB Amphetamine (AMPH) induces behavioral sensitization and neurotoxicity primarily by enhancing the dopamine-mediated neurotransmission. However, the involvement of theN-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 intracellular45Ca2+ 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. The American Society for Pharmacology and Experimental Therapeutics