Potentiation of N-methyl-D-aspartate receptor-mediated neuronal injury during methamphetamine withdrawal in vitro requires co-activation of IP3 receptors.
Recent findings suggest that methamphetamine (METH) functions acutely to inhibit N-methyl-d-aspartate (NMDA) receptor function. Protracted withdrawal from METH exposure may increase the sensitivity of NMDA receptors to agonist exposure, promoting neuronal excitability. However, the relevance of METH effects on NMDA receptor activity with regard to neuronal viability has not been fully studied. The present studies examined the effects of protracted METH exposure (6 or 7 days; 1.0-100 microM) and withdrawal (1 or 7 days) on NMDA receptor-dependent neurotoxicity, determined with use of the non-vital fluorescent marker propidium iodide, in organotypic slice cultures of male and female rats. Prolonged exposure to METH (100 microM) produced only modest toxicity in the granule cell layer of the dentate gyrus. Withdrawal from METH exposure (1 or 7 days) did not produce overt neuronal injury in any region of slice cultures. Exposure to NMDA (5 microM) produced marked neurotoxicity in the CA1 pyramidal cell layer. Neither co-exposure to METH nor 1 day of METH withdrawal in combination with NMDA exposure altered NMDA-induced neurotoxicity. In contrast, protracted withdrawal from METH exposure (7 days) was associated with a marked (approximately 400%) increase in NMDA-induced neurotoxicity in CA1 region pyramidal cells. This potentiation of neurotoxicity was prevented by co-exposure to the selective NMDA receptor antagonist 5-2-amino-5-phosphonovaleric acid (20 microM) and was markedly attenuated by co-exposure of slices to xestospongin C (1 microM), an antagonist of IP(3) receptors. The results of the present studies suggest that long-term METH withdrawal functionally sensitizes the NMDA receptor to agonist exposure and requires the co-activation of NMDA and IP(3) receptors.
Smith
Katherine J
KJ
University of Kentucky, Department of Psychology, B449 Biomedical and Biological Sciences Research Building, 741 South Limestone St., Lexington, KY 40536-0509, USA.
Butler
Tracy R
TR
Self
Rachel L
RL
Braden
Brittany B
BB
Prendergast
Mark A
MA
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000009:adverse effects; D004347:Drug Interactions / Q000502:physiology; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects* / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D009924:Organ Culture Techniques; D010080:Oxazoles / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology*
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D016194:Receptors, N-Methyl-D-Aspartate; C511704:xestospongin C; D008694:Methamphetamine