Abstract
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.
Footnotes
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↵1 Present address: Department of Pharmacology, Chang-Gung University.
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↵2 Present address: Department of Medical Technology, Taipei Medical University.
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This work is supported by National Science Council of Taiwan Grants 85–2331-B-038–027-M27 and 86–2314-B-038–006.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- AMPH
- amphetamine
- MAMH
- methamphetamine
- [3H]TCP
- [3H]N-[1-(2-thienyl)cyclohexyl] piperidine
- LDH
- lactose dehydrogenase
- MEM
- modified Eagle's medium
- d-APV
- 2-amino-5-phosphopentanoic acid
- 7-CKA
- 7-cholorkyneurenic acid
- PCP
- phencyclidine
- ANOVA
- analysis of variance
- MAMPH
- d-methamphetamine
- Received August 21, 2001.
- Accepted November 21, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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