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Alcohol exposure alters NMDAR function in the bed nucleus of the stria terminalis.

Kash TL, Baucum AJ, Conrad KL, Colbran RJ, Winder DG - Neuropsychopharmacology (2009)

Bottom Line: These alterations are proposed to be due in part to adaptations in the brain regions that regulate emotional behavior, including the bed nucleus of the stria terminalis (BNST), a principal output nucleus of the amygdala.Both electrophysiological and biochemical approaches suggest that this difference is not because of an alteration in glutamate release, but rather an increase in the levels of NR2B-containing NMDARs.Further, we found that ethanol modulation of NMDAR in the vBNST is altered after intermittent alcohol exposure.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.

ABSTRACT
Chronic alcohol exposure can cause dramatic behavioral alterations, including increased anxiety-like behavior and depression. These alterations are proposed to be due in part to adaptations in the brain regions that regulate emotional behavior, including the bed nucleus of the stria terminalis (BNST), a principal output nucleus of the amygdala. However, to date there have been no studies that have examined the impact of in vivo alcohol exposure on synaptic function in the BNST. To better understand how alcohol can alter neuronal function, we examined the ability of in vivo alcohol exposure to alter glutamatergic transmission in the BNST using whole-cell voltage clamp recordings and biochemistry in brain slices obtained from C57Bl6 mice. Chronic intermittent, but not continuous, ethanol vapor exposure increased temporal summation of NMDA receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs). Both electrophysiological and biochemical approaches suggest that this difference is not because of an alteration in glutamate release, but rather an increase in the levels of NR2B-containing NMDARs. Further, we found that ethanol modulation of NMDAR in the vBNST is altered after intermittent alcohol exposure. Our results support the hypothesis that NMDAR-mediated synaptic transmission is sensitized at key synapses in the extended amygdala and thus may be a suitable target for manipulation of the behavioral deficits associated with acute withdrawal from chronic alcohol exposure.

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Acute withdrawal from intermittent alcohol exposure leads to an up-regulation of levels of NR2B protein and a down-regulation of CaMKIIα in the vBNSTRepresentative brain slice demonstrating the location and size of the vBNST punches.There is no difference in NR1 protein expression between control and alcohol exposed mice.There is no difference in NR2A protein expression between control and alcohol exposed mice.There is a significant increase of NR2B protein expression in alcohol exposed mice compared to control mice. * p < 0.05, unpaired Student’s two-tailed t-test.There is no difference in GluR1 protein expression between control and alcohol exposed mice.There is a significant decrease in CaMKIIα protein expression in alcohol exposed mice compared to control mice. * p < 0.05,unpaired Student’s two-tailed t-test.
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Figure 6: Acute withdrawal from intermittent alcohol exposure leads to an up-regulation of levels of NR2B protein and a down-regulation of CaMKIIα in the vBNSTRepresentative brain slice demonstrating the location and size of the vBNST punches.There is no difference in NR1 protein expression between control and alcohol exposed mice.There is no difference in NR2A protein expression between control and alcohol exposed mice.There is a significant increase of NR2B protein expression in alcohol exposed mice compared to control mice. * p < 0.05, unpaired Student’s two-tailed t-test.There is no difference in GluR1 protein expression between control and alcohol exposed mice.There is a significant decrease in CaMKIIα protein expression in alcohol exposed mice compared to control mice. * p < 0.05,unpaired Student’s two-tailed t-test.

Mentions: The alteration of NMDA mediated synaptic transmission in the vBNST following alcohol exposure could be due to an alteration in the expression levels of NR2B. In order to test this possibility, we evaluated the expression levels of NR1, NR2A and NR2B in tissue punches enriched in the vBNST from intermittent alcohol-exposed and control mice (Figure 6). We found that NR2B expression was significantly increased approximately 1.7 fold in intermittent alcohol-exposed mice (t(33)= 2.865, p < 0.01), while NR1 (p = 0.61) and NR2A (p = 0.63) expression was unchanged. These results strongly support the possibility that the alteration in synaptic NMDAR function properties is due to increased levels of NR2B in the vBNST. We then compared the expression levels of the AMPA receptor subunit, GluR1, and found no differences in between intermittent alcohol exposed and control groups (p = 0.69). We next compared the expression levels of calcium/calmodulin-dependent protein kinase II (CaMKIIα) in control and intermittent alcohol-exposed mice. This protein is of particular interest because it interacts with and phosphorylates NR2B (Strack et al., 2000) and also modulates NMDAR channel kinetics (Sikes et al., 2005). Moreover, CaMKII binding to NR2B is critical for the induction of plasticity (Barria and Malinow, 2005). Intermittent alcohol-exposure significantly reduced the expression of CaMKIIα in the vBNST by approximately 19% (t(16)=2.240, p < 0.05).


Alcohol exposure alters NMDAR function in the bed nucleus of the stria terminalis.

Kash TL, Baucum AJ, Conrad KL, Colbran RJ, Winder DG - Neuropsychopharmacology (2009)

Acute withdrawal from intermittent alcohol exposure leads to an up-regulation of levels of NR2B protein and a down-regulation of CaMKIIα in the vBNSTRepresentative brain slice demonstrating the location and size of the vBNST punches.There is no difference in NR1 protein expression between control and alcohol exposed mice.There is no difference in NR2A protein expression between control and alcohol exposed mice.There is a significant increase of NR2B protein expression in alcohol exposed mice compared to control mice. * p < 0.05, unpaired Student’s two-tailed t-test.There is no difference in GluR1 protein expression between control and alcohol exposed mice.There is a significant decrease in CaMKIIα protein expression in alcohol exposed mice compared to control mice. * p < 0.05,unpaired Student’s two-tailed t-test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2864644&req=5

Figure 6: Acute withdrawal from intermittent alcohol exposure leads to an up-regulation of levels of NR2B protein and a down-regulation of CaMKIIα in the vBNSTRepresentative brain slice demonstrating the location and size of the vBNST punches.There is no difference in NR1 protein expression between control and alcohol exposed mice.There is no difference in NR2A protein expression between control and alcohol exposed mice.There is a significant increase of NR2B protein expression in alcohol exposed mice compared to control mice. * p < 0.05, unpaired Student’s two-tailed t-test.There is no difference in GluR1 protein expression between control and alcohol exposed mice.There is a significant decrease in CaMKIIα protein expression in alcohol exposed mice compared to control mice. * p < 0.05,unpaired Student’s two-tailed t-test.
Mentions: The alteration of NMDA mediated synaptic transmission in the vBNST following alcohol exposure could be due to an alteration in the expression levels of NR2B. In order to test this possibility, we evaluated the expression levels of NR1, NR2A and NR2B in tissue punches enriched in the vBNST from intermittent alcohol-exposed and control mice (Figure 6). We found that NR2B expression was significantly increased approximately 1.7 fold in intermittent alcohol-exposed mice (t(33)= 2.865, p < 0.01), while NR1 (p = 0.61) and NR2A (p = 0.63) expression was unchanged. These results strongly support the possibility that the alteration in synaptic NMDAR function properties is due to increased levels of NR2B in the vBNST. We then compared the expression levels of the AMPA receptor subunit, GluR1, and found no differences in between intermittent alcohol exposed and control groups (p = 0.69). We next compared the expression levels of calcium/calmodulin-dependent protein kinase II (CaMKIIα) in control and intermittent alcohol-exposed mice. This protein is of particular interest because it interacts with and phosphorylates NR2B (Strack et al., 2000) and also modulates NMDAR channel kinetics (Sikes et al., 2005). Moreover, CaMKII binding to NR2B is critical for the induction of plasticity (Barria and Malinow, 2005). Intermittent alcohol-exposure significantly reduced the expression of CaMKIIα in the vBNST by approximately 19% (t(16)=2.240, p < 0.05).

Bottom Line: These alterations are proposed to be due in part to adaptations in the brain regions that regulate emotional behavior, including the bed nucleus of the stria terminalis (BNST), a principal output nucleus of the amygdala.Both electrophysiological and biochemical approaches suggest that this difference is not because of an alteration in glutamate release, but rather an increase in the levels of NR2B-containing NMDARs.Further, we found that ethanol modulation of NMDAR in the vBNST is altered after intermittent alcohol exposure.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.

ABSTRACT
Chronic alcohol exposure can cause dramatic behavioral alterations, including increased anxiety-like behavior and depression. These alterations are proposed to be due in part to adaptations in the brain regions that regulate emotional behavior, including the bed nucleus of the stria terminalis (BNST), a principal output nucleus of the amygdala. However, to date there have been no studies that have examined the impact of in vivo alcohol exposure on synaptic function in the BNST. To better understand how alcohol can alter neuronal function, we examined the ability of in vivo alcohol exposure to alter glutamatergic transmission in the BNST using whole-cell voltage clamp recordings and biochemistry in brain slices obtained from C57Bl6 mice. Chronic intermittent, but not continuous, ethanol vapor exposure increased temporal summation of NMDA receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs). Both electrophysiological and biochemical approaches suggest that this difference is not because of an alteration in glutamate release, but rather an increase in the levels of NR2B-containing NMDARs. Further, we found that ethanol modulation of NMDAR in the vBNST is altered after intermittent alcohol exposure. Our results support the hypothesis that NMDAR-mediated synaptic transmission is sensitized at key synapses in the extended amygdala and thus may be a suitable target for manipulation of the behavioral deficits associated with acute withdrawal from chronic alcohol exposure.

Show MeSH
Related in: MedlinePlus