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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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Related in: MedlinePlus

Anxiety-related behavior as measured in the 5 minute duration Elevated plus maze (EPM) test was assessed 4–6 hours following the last chronic intermittent ethanol or air vapor (control) exposure. A) Total distance traveled during the 5 minute test session. B) Time (seconds) spent in the closed and open arm of the EPM. C) Number of open and closed arm entries on the EPM. D) Schematic diagram of illumination levels during the EPM test (numerical values in Lx). Each value represents the mean ± SEM. Control (n=8), Ethanol (n=5). *P<0.05 (control group compared to ethanol vapor exposed group), **P<0.01 (control group compared to ethanol vapor exposed group), unpaired Student’s two-tailed t-test
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Figure 1: Anxiety-related behavior as measured in the 5 minute duration Elevated plus maze (EPM) test was assessed 4–6 hours following the last chronic intermittent ethanol or air vapor (control) exposure. A) Total distance traveled during the 5 minute test session. B) Time (seconds) spent in the closed and open arm of the EPM. C) Number of open and closed arm entries on the EPM. D) Schematic diagram of illumination levels during the EPM test (numerical values in Lx). Each value represents the mean ± SEM. Control (n=8), Ethanol (n=5). *P<0.05 (control group compared to ethanol vapor exposed group), **P<0.01 (control group compared to ethanol vapor exposed group), unpaired Student’s two-tailed t-test

Mentions: Chronic intermittent ethanol vapor exposure has been shown to have numerous effects, including increased alcohol drinking behavior (Griffin et al., 2008) , handling induced convulsions (Becker et al., 1997) and anxiety (Kliethermes et al., 2004). The performance of mice during acute withdrawal (4–6 hours following removal) from intermittent alcohol or air exposure was evaluated in the elevated-plus maze to demonstrate that the animals that underwent chronic intermittent alcohol vapor exposure have altered behavior consistent with alcohol withdrawal (Figure 1). We focused on this time-point, as previous studies have shown that there is a significant increase in handling-induced convulsion (Becker et al., 1997), suggesting a hyperexcitable state in the CNS. We found that, at this time-point, mice exposed to intermittent alcohol (n = 5) traveled significantly less total distance than air exposed mice (n = 8) (Figure 1A, t(11) = 3.56, *p < 0.05), consistent with a recent report that motor impairment is a withdrawal phenotype in mice (Philibin et al., 2008). Further, alcohol exposed mice had a significant reduction in time spent in the open arm and open arm entries, consistent with an increase in anxiety-like behavior (Figure 1B and 1C, respectively, t (11) = 3.76, *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)

Anxiety-related behavior as measured in the 5 minute duration Elevated plus maze (EPM) test was assessed 4–6 hours following the last chronic intermittent ethanol or air vapor (control) exposure. A) Total distance traveled during the 5 minute test session. B) Time (seconds) spent in the closed and open arm of the EPM. C) Number of open and closed arm entries on the EPM. D) Schematic diagram of illumination levels during the EPM test (numerical values in Lx). Each value represents the mean ± SEM. Control (n=8), Ethanol (n=5). *P<0.05 (control group compared to ethanol vapor exposed group), **P<0.01 (control group compared to ethanol vapor exposed group), unpaired Student’s two-tailed t-test
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Related In: Results  -  Collection

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Figure 1: Anxiety-related behavior as measured in the 5 minute duration Elevated plus maze (EPM) test was assessed 4–6 hours following the last chronic intermittent ethanol or air vapor (control) exposure. A) Total distance traveled during the 5 minute test session. B) Time (seconds) spent in the closed and open arm of the EPM. C) Number of open and closed arm entries on the EPM. D) Schematic diagram of illumination levels during the EPM test (numerical values in Lx). Each value represents the mean ± SEM. Control (n=8), Ethanol (n=5). *P<0.05 (control group compared to ethanol vapor exposed group), **P<0.01 (control group compared to ethanol vapor exposed group), unpaired Student’s two-tailed t-test
Mentions: Chronic intermittent ethanol vapor exposure has been shown to have numerous effects, including increased alcohol drinking behavior (Griffin et al., 2008) , handling induced convulsions (Becker et al., 1997) and anxiety (Kliethermes et al., 2004). The performance of mice during acute withdrawal (4–6 hours following removal) from intermittent alcohol or air exposure was evaluated in the elevated-plus maze to demonstrate that the animals that underwent chronic intermittent alcohol vapor exposure have altered behavior consistent with alcohol withdrawal (Figure 1). We focused on this time-point, as previous studies have shown that there is a significant increase in handling-induced convulsion (Becker et al., 1997), suggesting a hyperexcitable state in the CNS. We found that, at this time-point, mice exposed to intermittent alcohol (n = 5) traveled significantly less total distance than air exposed mice (n = 8) (Figure 1A, t(11) = 3.56, *p < 0.05), consistent with a recent report that motor impairment is a withdrawal phenotype in mice (Philibin et al., 2008). Further, alcohol exposed mice had a significant reduction in time spent in the open arm and open arm entries, consistent with an increase in anxiety-like behavior (Figure 1B and 1C, respectively, t (11) = 3.76, *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