Alcohol Exposure Alters NMDAR Function in the Bed Nucleus of the Stria Terminalis

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. In order 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 EPSCs. Both electrophysiological and biochemical approaches suggest that this difference is not due to 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 following 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.

Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats

“…Therefore, it was important to determine whether DA acted on NMDAR of specific composition. Kash et al (2008aKash et al ( , 2009 showed that chronic passive (experimenter-controlled) exposure to alcohol alters the subunit composition of NMDAR throughout the dorsolateral BNST, which includes the ovBNST. We observed that NMDA-EPSC became insensitive to noncompetitive GluN2B antagonists, suggesting a loss of synaptic diheteromeric GluN1/ GluN2B 2 NMDAR (GluN2B non-competitive antagonists being ineffective at triheteromeric GluN1/GluN2A/GluN2B (Hatton and Paoletti, 2005)).…”

Synaptic Effects Induced by Alcohol

“…Direct examination of ion current through the NMDAR pore has revealed effects consistent with a chronic EtOH-induced upregulation of NMDAR function (Floyd et al 2003;Grover et al 1998). An increase in the component of current mediated by NR2B-containing receptors has also been observed (Floyd et al 2003;Kash et al 2009;Roberto et al 2004b. Interestingly, acute EtOH inhibition of NMDARs in most brain regions is still intact or even increased after chronic in vivo exposure (Floyd et al 2003;Roberto et al 2004b), although a small decrease in inhibition was observed in medial septum/diagonal band neurons (Grover et al 1998).…”

Ethanol Effects on N-Methyl-D-Aspartate Receptors in the Bed Nucleus of the Stria Terminalis

“…1B,D) (Wills et al 2012). Additionally, chronic ethanol exposure blunted the inhibitory effects of acute in vitro ethanol administration in the vBNST suggesting that NMDARs likely develop tolerance to the acute ethanol effects (Kash et al 2009). This is particularly curious given the key role of GluN2B in ethanol sensitivity of NMDARs in this region coupled with its increased expression after chronic exposure.…”

“…Wills and D.G. Winder levels and increased GluN2B antagonism on NMDAR EPSCs and decay kinetics (Kash et al 2009). These changes are consistent with functional up-regulation of GluN2B from chronic ethanol and it is this increase that likely contributes to enhanced temporal summation of NMDAR EPSCs.…”

“…In the vBNST, chronic intermittent ethanol exposure increases NMDAR EPSC temporal summation during the early withdrawal period (Kash et al 2009). In these chronically treated ethanol mice, there was no change in glutamate release but there were elevated GluN2B protein T.A.…”