Amphetamine inhibits the N-methyl-D-aspartate receptor-mediated responses by directly interacting with the receptor/channel complex.
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.
Yeh
Geng-Chang
GC
Department of Pediatrics, Taipei Medical University Hospital, Graduate Institute of Medical Science, Taipei Medical University, Taipei Taiwan. cmbyeh@tmu.edu.tw
Chen
Jin-Chung
JC
Tsai
Hsiu-Chuan
HC
Wu
Hsueh-Hsia
HH
Lin
Chao-Yu
CY
Hsu
Ping-Ching
PC
Peng
Yu-Chen
YC
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000662:Amphetamines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C012058:tenocyclidine; D007770:L-Lactate Dehydrogenase; D010622:Phencyclidine; D002118:Calcium; D005998:Glycine