Acute tolerance to ethanol inhibition of NMDA-mediated EPSPs in the CA1 region of the rat hippocampus

Grover, Cathy A.; Frye, Gerald D.; Griffith, William H.

doi:10.1016/0006-8993(94)90906-7

Cited by 53 publications

(30 citation statements)

References 47 publications

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“…5, a and b, white circles and white bar) and EPSCs (37 Ϯ 7%, n ϭ 9, data not shown) in the hippocampus. In line with these previous studies (30 -32) and others, incubation with low ethanol concentration (25 mM) inhibited NMDAR-mediated EPSCs by 24 Ϯ 6% (n ϭ 18) (data not shown), and as has previously been reported (18,20,(33)(34)(35), we observed an acute desensitization to the inhibitory effects of ethanol during field-recording of channel activity (Fig. 5a).…”

Section: Versus 3)supporting

confidence: 93%

Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras

Suvarna

Borgland

Wang

et al. 2005

Journal of Biological Chemistry

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The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity and is one of the main targets for alcohol (ethanol) in the brain. Trafficking of the NMDAR is emerging as a key regulatory mechanism that underlies channel activity and synaptic plasticity. Here we show that exposure of hippocampal neurons to ethanol increases the internalization of the NR2A but not NR2B subunit of the NMDAR via the endocytic pathway. We further observed that ethanol exposure results in NR2A endocytosis through the activation of H-Ras and the inhibition of the tyrosine kinase Src. Importantly, ethanol treatment alters functional subunit composition from NR2A/NR2B-to mainly NR2B-containing NMDARs. Our results suggest that addictive drugs such as ethanol alter NMDAR trafficking and subunit composition. This may be an important mechanism by which ethanol exerts its effects on NMDARs to produce alcohol-induced aberrant plasticity. NMDARs1 are major mediators of processes such as synaptic plasticity and learning and memory (1) and of pathological states such as schizophrenia, seizures, pain, drug and alcohol addiction (2-5), and alcohol intoxication (6).NMDARs are heteromeric ligand-gated ion channels composed of an obligatory NR1 subunit and regulatory NR2A-D and NR3 subunits (2). The NMDAR subunits can undergo lateral movement between synaptic and extrasynaptic sites, as well as internalization from, or forward trafficking to, the plasma membrane (7,8). For example, prolonged inhibition of NMDAR activity results in the redistribution of the subunits from extrasynaptic to synaptic sites (9). Synaptic activity and long-term potentiation increase the forward trafficking of NMDAR subunits (10, 11), and glycine has been reported to prime the NMDAR subunits for internalization (12).NMDAR function can be regulated by changes in the phosphorylation state of the subunits via the activation of kinases or phosphatases (13). Protein phosphorylation and dephosphorylation also control the movement of NMDAR subunits to and from the plasma membrane. For example, activation of protein kinase C and cAMP-dependent protein kinase A, and the consequent phosphorylation of the NR1 subunit, increases forward trafficking of the receptor (14). Fyn kinase-mediated tyrosine phosphorylation of the NMDAR plays a role in the dopamine D1 receptor-mediated redistribution of NMDAR subunits from intracellular to postsynaptic compartments (15). Conversely, tyrosine dephosphorylation of the NR2A subunits leads to the internalization of the subunits, resulting in the rundown of channel activity (16). In addition, we recently found that H-Ras-mediated inhibition of Src kinase activity prevents the phosphorylation and membrane retention of NR2A subunits (17).We, and others, reported that the activity of the NMDAR in the presence of ethanol is modulated via changes in the phosphorylation state of the subunits (18 -20). NMDARs have been implicated in mediating ethanol-associated phenotypes such as tolerance, dependence, withdrawal, craving and relapse, ...

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Section: Versus 3)supporting

confidence: 93%

Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras

Suvarna

Borgland

Wang

et al. 2005

Journal of Biological Chemistry

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“…2). In previous studies, acute tolerance to EtOH has been demonstrated on NMDA-mediated EPSPs in hippocampal neurons (Grover et al, 1994). Therefore, we next examined whether the effects of EtOH showed any tolerance in our experimental conditions.…”

Section: Resultsmentioning

confidence: 87%

Effects of Ethanol on GABA_A Receptors in GABAergic and Glutamatergic Presynaptic Nerve Terminals

Wakita¹,

Shin²,

Iwata³

et al. 2012

J Pharmacol Exp Ther

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Ethanol (EtOH) has a number of behavioral effects, including intoxication, amnesia, and/or sedation, that are thought to relate to the activation of GABA A receptors. However, GABA A receptors at different cellular locations have different sensitivities to EtOH. The present study used the "synaptic bouton" preparation where we could stimulate nerve endings on mechanically dissociated single rat hippocampal CA1 and CA3 pyramidal neurons and investigate the effects of EtOH on presynaptic and postsynaptic GABA A receptors. Low concentrations of EtOH (10 mM) had no effect on postsynaptic GABA A and glutamate receptors or voltage-dependent Na ϩ and Ca 2ϩ channels. Higher concentrations (Ն100 mM) could significantly inhibit these current responses. EtOH at 10 mM had no direct effect on inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) evoked by focal stimulation of single boutons [evoked IPSCs (eIPSCs) and evoked EPSCs (eEPSCs)]. However, coapplication of 10 mM EtOH with muscimol decreased the amplitude of eIPSCs and eEPSCs and increased their paired-pulse ratio. The effects on eEPSCs were reversed by bicuculline. Coapplication of muscimol and EtOH significantly increased the frequency of spontaneous IPSCs and EPSCs. The EtOH effects on the postsynaptic responses and eEPSCs were similar in neurons from neonatal and mature rats. These results revealed that low concentrations of EtOH can potentiate the activation of presynaptic GABA A receptors to inhibit evoked GABA and glutamate release. These results indicate a high sensitivity of presynaptic GABA A receptor to EtOH, which needs to be accounted for when considering the cellular mechanisms of EtOH's physiological responses.

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“…Previous studies (Grover et al, 1994;Miyakawa et al, 1997) showed that electrophysiological NMDA responses became partially 3. The adaptive change of the NMDAR response to the effects of ethanol is associated with increases in the levels of STEP33 and pp38 MAPK.…”

Section: Discussionmentioning

confidence: 97%

“…Ethanol application inhibits N-methyl-D-aspartate receptor (NMDAR) activity (Lovinger et al, 1989), and subsequent studies have shown that the NMDAR in hippocampal brain slices develops resistance to the short-term effects of ethanol during a 5-to 15-min ethanol (100 mM) exposure (Grover et al, 1994;Miyakawa et al, 1997). However, precise mechanisms that regulate the development of this resistance to the inhibitory effects of short-term ethanol exposure on the NMDAR are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Functional Adaptation of the N-Methyl-d-aspartate Receptor to Inhibition by Ethanol Is Modulated by Striatal-Enriched Protein Tyrosine Phosphatase and p38 Mitogen-Activated Protein Kinase

Coultrap²,

Browning³

et al. 2011

Mol Pharmacol

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The hippocampal N-methyl-D-aspartate receptor (NMDAR) activity plays important roles in cognition and is a major substrate for ethanol-induced memory dysfunction. This receptor is a glutamate-gated ion channel, which is composed of NR1 and NR2 subunits in various brain areas. Although homomeric NR1 subunits form an active ion channel that conducts Na ϩ and Ca 2ϩ currents, the incorporation of NR2 subunits allows this channel to be modulated by the Src family of kinases, phosphatases, and by simple molecules such as ethanol. We have found that short-term ethanol application inhibits the NMDAR activity via striatal enriched protein tyrosine phosphatase (STEP)-regulated mechanisms. The genetic deletion of the active form of STEP, STEP61, leads to marked attenuation of ethanol inhibition of NMDAR currents. In addition, STEP61 negatively regulates Fyn and p38 mitogen-activated protein kinase (MAPK), and these proteins are members of the NMDAR super molecular complex. Here we demonstrate, using wholecell electrophysiological recording, Western blot analysis, and pharmacological manipulations, that neurons exposed to a 3-h, 45 mM ethanol treatment develop an adaptive attenuation of short-term ethanol inhibition of NMDAR currents in brain slices. Our results suggest that this adaptation of NMDAR responses is associated with a partial inactivation of STEP61, an activation of p38 MAPK, and a requirement for NR2B activity. Together, these data indicate that altered STEP61 and p38 MAPK signaling contribute to the modulation of ethanol inhibition of NMDARs in brain neurons.

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Acute tolerance to ethanol inhibition of NMDA-mediated EPSPs in the CA1 region of the rat hippocampus

Cited by 53 publications

References 47 publications

Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras

Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras

Effects of Ethanol on GABA_A Receptors in GABAergic and Glutamatergic Presynaptic Nerve Terminals

Functional Adaptation of the N-Methyl-d-aspartate Receptor to Inhibition by Ethanol Is Modulated by Striatal-Enriched Protein Tyrosine Phosphatase and p38 Mitogen-Activated Protein Kinase

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Acute tolerance to ethanol inhibition of NMDA-mediated EPSPs in the CA1 region of the rat hippocampus

Cited by 53 publications

References 47 publications

Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras

Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras

Effects of Ethanol on GABAA Receptors in GABAergic and Glutamatergic Presynaptic Nerve Terminals

Functional Adaptation of the N-Methyl-d-aspartate Receptor to Inhibition by Ethanol Is Modulated by Striatal-Enriched Protein Tyrosine Phosphatase and p38 Mitogen-Activated Protein Kinase

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Effects of Ethanol on GABA_A Receptors in GABAergic and Glutamatergic Presynaptic Nerve Terminals