Amphetamine Inhibits theN-Methyl-d-Aspartate Receptor-Mediated Responses by Directly Interacting with The Receptor/Channel Complex

Abstract

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. 3 H]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 [ 3 H]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.Amphetamine (AMPH), a commonly abused psychostimulant, induces behavioral sensitization or neurotoxcity primarily by enhancing the activities of dopaminergic systems (Robinson and Becker, 1986;Kalivas and Stewart, 1991;Segal and Kuczenski, 1992;Robinson and Berridge, 1993). However, available evidences have indicated the involvement of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors. Administration of NMDA receptor antagonists effectively prevented or attenuated a variety of AMPH-induced responses such as behavioral sensitization, neuronal degeneration, and gene expression, indicating that activation of the NMDA receptor is required for the development and expression of AMPH-induced neuropathological responses (Karler et al., 1989;Lowy, 1990; HemrickLuecke et al., 1992;Bristow et al., 1994;Wang et al., 1994;Konradi et al., 1996). The recruitment of the NMDA receptormediated neurotransmission in AMPH-mediated response has been thought to be as a result of an increase in glutamate release Yamamoto, 1992, 1993) and an increase in the sensitivity to glutamate agonist (White et al., 1995) of the dopaminergic neurons after repeatedly being exposed to AMPH. Recent investigation had shown that dopamine at concentrations higher than 100 M was able to inhibit the NMDA receptor-mediated electrophysiological responses in a concentration-dependent manner by directly blocking the NMDA receptor channel (Castro et al., 1999). Given that AMPH shares a structural similarity with dopamine ( Fig. 1) and that the dopamine transporter could potently uptake both compounds, we proposed that AMPH might be able to regulate directly the NMDA receptor-mediated activities. To test this possibility, we determined whether AMPH analogs could affect the NMDA receptor-mediated responses in vitro, including NMDA-and glycine-stimulated [ 3 H]TCP binding in

Potentiation of N-methyl-d-aspartate receptor-mediated neuronal injury during methamphetamine withdrawal in vitro requires co-activation of IP3 receptors

“…Short-term, repeated administration of METH to rodents has been shown to increase hippocampal and striatal glutamate content (Mark et al 2007;Rocher and Gardier, 2001) while long-term METH administration was shown to deplete hippocampal glutamate content (Kaiya et al 1982). Amphetamines have been shown to displace [ 3 H]N-[1-(2-thienyl)cyclohexyl] piperidine (TCP) binding to the NMDA receptor ion channel, in addition to, decreasing NMDA-induced intracellular 45 Ca accumulation in rat cortical neurons (Yeh et al, 2002). A recent report similarly demonstrated that short-term METH (≥1.0 μM) exposure antagonizes NMDAinduced neurotoxicity in organotypic hippocampal slice cultures, suggesting direct or indirect modulation of NMDA receptor activity (Smith et al, 2007).…”

“…Furthermore, some studies suggest that METH may act as an NMDA receptor antagonist (Smith et al, 2007;Yeh et al, 2002). Yeh et al (2002) reported that METH reduced NMDAinduced intracellular Ca 2+ accumulation as well as displaced [H 3 ]TCP binding.…”

“…Furthermore, some studies suggest that METH may act as an NMDA receptor antagonist (Smith et al, 2007;Yeh et al, 2002). Yeh et al (2002) reported that METH reduced NMDAinduced intracellular Ca 2+ accumulation as well as displaced [H 3 ]TCP binding. Antagonism of NMDA-induced neurotoxicity by METH was reported in organotypic hippocampal slice cultures (Smith et al, 2007), further suggesting that METH may act as a NMDA receptor antagonist.…”

“…It has become increasingly evident that N-Methyl-D-Aspartate-type glutamate receptors are targets of METH actions (Moriguchi et al, 2002;Smith et al, 2007;Yeh et al, 2002). Previous literature has suggested that METH may directly or indirectly influence the NMDA receptor in a biphasic manner (Moriguchi et al, 2002;Smith et al, 2007;Yeh et al, 2002).…”

“…Previous literature has suggested that METH may directly or indirectly influence the NMDA receptor in a biphasic manner (Moriguchi et al, 2002;Smith et al, 2007;Yeh et al, 2002). Short-term, repeated administration of METH to rodents has been shown to increase hippocampal and striatal glutamate content (Mark et al 2007;Rocher and Gardier, 2001) while long-term METH administration was shown to deplete hippocampal glutamate content (Kaiya et al 1982).…”