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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 does not alter glutamate release in the vBNSTRepresentative sEPSC traces from control and intermittent alcohol exposed mice demonstrating the lack of an effect of intermittent alcohol exposure on spontaneous glutamatergic transmission.Intermittent alcohol exposure does not alter the sEPSC frequency.Intermittent alcohol exposure does not alter sEPSC amplitude.Representative traces of evoked AMPA-EPSCs demonstrating the lack of an effect of intermittent alcohol treatment on the paired pulse ratio.E. Pooled data demonstrating the lack of an effect of intermittent alcohol exposure on the paired-pulse ratio across a range of interstimulus intervals.
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Figure 3: Acute withdrawal from intermittent alcohol exposure does not alter glutamate release in the vBNSTRepresentative sEPSC traces from control and intermittent alcohol exposed mice demonstrating the lack of an effect of intermittent alcohol exposure on spontaneous glutamatergic transmission.Intermittent alcohol exposure does not alter the sEPSC frequency.Intermittent alcohol exposure does not alter sEPSC amplitude.Representative traces of evoked AMPA-EPSCs demonstrating the lack of an effect of intermittent alcohol treatment on the paired pulse ratio.E. Pooled data demonstrating the lack of an effect of intermittent alcohol exposure on the paired-pulse ratio across a range of interstimulus intervals.

Mentions: We next sought to determine the mechanism underlying the alteration in temporal summation of NMDAR EPSCs in the vBNST during acute withdrawal from intermittent alcohol exposure. One potential mechanism underlying this enhancement could be through an increase in glutamate release (Yashiro et al., 2005). To evaluate this possibility, we assessed glutamate release using multiple complementary techniques. We first examined spontaneous AMPAR mediated glutamatergic synaptic transmission (sEPSCs) (Figure 3A). This technique is useful in such that if there were a large increase in synaptic glutamate release one would see an increase in the frequency of sEPSCs. We found that there was no significant difference in either the frequency (Figure 3B, p=.36) or the amplitude (Figure 3C, p = 1) of AMPAR mediated sEPSCs in mice exposed to intermittent alcohol (n = 10) when compared to control (n = 9) mice. We next examined the paired-pulse ratio (PPR) of evoked AMPAR-mediated EPSCs (Figure 3D). If there were an increase in the probability of glutamate release, one would expect a corresponding decrease in the PPR. Consistent with the lack of an alteration of sEPSC frequency, we found no significant alteration in the PPR at a variety of interstimulus intervals in mice exposed to intermittent alcohol (n = 12) when compared to controls (n =12) (Figure 3E). As a final means of investigating glutamate release following intermittent alcohol exposure, we examined the rate of blockade of the activity-dependent NMDAR antagonist MK-801 and found no significant differences from the control experiments (MK-801 blocking decay time in control mice (n = 3): 37 ± 4 seconds, intermittent alcohol mice (n = 3): 49 ± 14 seconds p = 0.49). In combination, these results suggest that the increase in temporal summation of NMDAR EPSCs in the vBNST during acute withdrawal from intermittent alcohol exposure is likely not due to an alteration in glutamate release.


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 does not alter glutamate release in the vBNSTRepresentative sEPSC traces from control and intermittent alcohol exposed mice demonstrating the lack of an effect of intermittent alcohol exposure on spontaneous glutamatergic transmission.Intermittent alcohol exposure does not alter the sEPSC frequency.Intermittent alcohol exposure does not alter sEPSC amplitude.Representative traces of evoked AMPA-EPSCs demonstrating the lack of an effect of intermittent alcohol treatment on the paired pulse ratio.E. Pooled data demonstrating the lack of an effect of intermittent alcohol exposure on the paired-pulse ratio across a range of interstimulus intervals.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2864644&req=5

Figure 3: Acute withdrawal from intermittent alcohol exposure does not alter glutamate release in the vBNSTRepresentative sEPSC traces from control and intermittent alcohol exposed mice demonstrating the lack of an effect of intermittent alcohol exposure on spontaneous glutamatergic transmission.Intermittent alcohol exposure does not alter the sEPSC frequency.Intermittent alcohol exposure does not alter sEPSC amplitude.Representative traces of evoked AMPA-EPSCs demonstrating the lack of an effect of intermittent alcohol treatment on the paired pulse ratio.E. Pooled data demonstrating the lack of an effect of intermittent alcohol exposure on the paired-pulse ratio across a range of interstimulus intervals.
Mentions: We next sought to determine the mechanism underlying the alteration in temporal summation of NMDAR EPSCs in the vBNST during acute withdrawal from intermittent alcohol exposure. One potential mechanism underlying this enhancement could be through an increase in glutamate release (Yashiro et al., 2005). To evaluate this possibility, we assessed glutamate release using multiple complementary techniques. We first examined spontaneous AMPAR mediated glutamatergic synaptic transmission (sEPSCs) (Figure 3A). This technique is useful in such that if there were a large increase in synaptic glutamate release one would see an increase in the frequency of sEPSCs. We found that there was no significant difference in either the frequency (Figure 3B, p=.36) or the amplitude (Figure 3C, p = 1) of AMPAR mediated sEPSCs in mice exposed to intermittent alcohol (n = 10) when compared to control (n = 9) mice. We next examined the paired-pulse ratio (PPR) of evoked AMPAR-mediated EPSCs (Figure 3D). If there were an increase in the probability of glutamate release, one would expect a corresponding decrease in the PPR. Consistent with the lack of an alteration of sEPSC frequency, we found no significant alteration in the PPR at a variety of interstimulus intervals in mice exposed to intermittent alcohol (n = 12) when compared to controls (n =12) (Figure 3E). As a final means of investigating glutamate release following intermittent alcohol exposure, we examined the rate of blockade of the activity-dependent NMDAR antagonist MK-801 and found no significant differences from the control experiments (MK-801 blocking decay time in control mice (n = 3): 37 ± 4 seconds, intermittent alcohol mice (n = 3): 49 ± 14 seconds p = 0.49). In combination, these results suggest that the increase in temporal summation of NMDAR EPSCs in the vBNST during acute withdrawal from intermittent alcohol exposure is likely not due to an alteration in glutamate release.

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