Ethanol sensitivity and subunit composition of NMDA receptors in cultured striatal neurons

Popp, R. Lisa; Lickteig, Ronald; Browning,; Lovinger, David M.

doi:10.1016/s0028-3908(97)00186-x

Cited by 39 publications

(33 citation statements)

References 22 publications

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“…This is in agreement with previous work in cells cultured from cerebral cortex (Lovinger, 1995;Ming et al, 2001), striatum (Popp et al, 1998), HEK-293 cells (Lovinger, 1995), and neurons acutely dissociated from the medial septum (Grover et al, 1998). The concentration dependence of the effect of ethanol on NMDAgated currents was similar between brain regions with the only statistically reliable differences representing the most sensitive (lateral septum) and least sensitive (thalamus) of the brain regions.…”

Section: Discussionsupporting

confidence: 91%

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Criswell¹,

Zhang²,

Griffith³

et al. 2003

J Pharmacol Exp Ther

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In vivo, ethanol alters the effect of N-methyl-D-aspartate (NMDA) and GABA in some brain regions but is without effect in others. To determine whether these regional differences were due to differences in the effect of ethanol on postsynaptic NMDA or GABA A receptors, we examined the effect of ethanol on NMDA-and GABA-gated currents from neurons acutely dissociated from the lateral septal nucleus, substantia nigra, thalamus, hippocampus, and cerebellum. Ethanol decreased the effect of NMDA similarly in all brain areas tested and had similar effects on Chinese hamster ovary cells expressing NR2A or NR2B subunits with an NR1-1a subunit. However, ifenprodil reduced the inhibition by ethanol of NMDA-gated currents from neurons isolated from the lateral septum without affecting neurons from the substantia nigra. In contrast to the robust effect of ethanol on NMDA-gated currents, ethanol (25-300 mM) was without effect on GABA-gated currents at all brain sites tested or on Ltk Ϫ cells stably expressing the ␣1, ␤2, and ␥2L or ␥2S subunits. The neuroactive steroid alphaxalone profoundly enhanced GABA-gated currents in all brain areas and cell types tested, indicating a similar sensitivity to allosteric modulation; however, there was no interaction of alphaxalone with ethanol at any site tested. These data suggest that the regional differences in the effect of ethanol observed in vivo are not due to a differential action of ethanol at the postsynaptic NMDA or GABA A receptor subtypes.

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Section: Discussionsupporting

confidence: 91%

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Criswell¹,

Zhang²,

Griffith³

et al. 2003

J Pharmacol Exp Ther

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“…An early study demonstrated a correlation between ethanol and ifenprodil sensitivity in cultured cortical neurons (Lovinger, 1995). However, no correlation between ifenprodil sensitivity and ethanol inhibition was noted in striatal or cerebellar cultures (Popp et al, 1998(Popp et al, , 1999, suggesting region-specific selectivity of ethanol on NMDARs. This possibility is supported by findings that either NR2B, in the CeA, cortex, and the striatum (Fink and Gothert, 1996;Roberto et al, 2004), or NR2A, in the hippocampus (Suvarna et al, 2005) (also see Izumi et al, 2005), underlie the ethanol-sensitive population of NMDARs.…”

Section: Nmdar Subtype Selectivity Of Ethanol Inhibitionmentioning

confidence: 99%

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Kash

Matthews

Winder

2007

Neuropsychopharmacol

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Components of the mesolimbic dopamine system, in particular dopaminergic cells in the ventral tegmental area (VTA), have been implicated in the acute reinforcing actions of ethanol. The ventral bed nucleus of the stria terminalis (vBNST) potently regulates dopaminergic cell firing in the VTA, and has been implicated in the behavioral actions of ethanol. The N-methyl-D-asparate receptor (NMDAR) is a major molecular target of ethanol, however, current evidence suggests that ethanol regulation of NMDAR function is widely variable and likely depends on a number of factors. Thus, it is critical to investigate ethanol regulation of NMDAR function at synapses relevant to ethanol-regulated behaviors, such as in the vBNST. Here we show, using multiple techniques, that ethanol inhibits NMDAR function in vBNST neurons in a postsynaptic fashion. Further, we demonstrate the functional presence of both NR2A and NR2B-containing NMDARs in the vBNST. While genetic removal of NR2A did not alter the magnitude of ethanol inhibition, pharmacological blockade of NR2B rendered synaptically activated NMDARs insensitive to ethanol inhibition. Finally, we demonstrate that ethanol inhibits NMDARs in cells in the vBNST that project to the VTA, providing a direct means by which ethanol in the vBNST can modulate the dopaminergic system.

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“…Several studies involving recombinant receptors have demonstrated that receptors containing different types of NR2 subunits have differential sensitivity to the inhibitory effect of ethanol [170,192]. According to the earlier results, the ability of ethanol to depress NMDA evoked currents paralleled with the neuroprotective action of ifenprodil in rat cultured cortical neurons [125].…”

Section: Ethanol Is a Potent Inhibitor Of Nmda Receptorsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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Ethanol sensitivity and subunit composition of NMDA receptors in cultured striatal neurons

Cited by 39 publications

References 22 publications

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

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