Chronic intermittent ethanol and withdrawal differentially modulate basolateral amygdala AMPA-type glutamate receptor function and trafficking

Abstract

The amygdala plays a critical role in the generation and expression of anxiety-like behaviors including those expressed following withdrawal (WD) from chronic intermittent ethanol (CIE) exposure. In particular, the BLA glutamatergic system controls the expression of both innate and pathological anxiety. Recent data suggests that CIE and WD may functionally alter this system in a manner that closely parallels memory-related phenomena like long term potentiation (LTP). We therefore specifically dissected CIE/WD-induced changes in glutamatergic signaling using electrophysiological and biochemical approaches with a particular focus on the plasticity-related components of this neurotransmitter system. Our results indicate that cortical glutamatergic inputs arriving at BLA principal via the external capsule undergo predominantly post-synaptic alterations in AMPA receptor function following CIE and WD. Biochemical analysis revealed treatment-dependent changes in AMPA receptor surface expression and subunit phosphorylation that are complemented by changes in total protein levels and/or phosphorylation status of several key, plasticity-associated protein kinases such as calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC). Together, these data show that CIE- and WD-induced changes in BLA glutamatergic function both functionally and biochemically mimic plasticity-related states. These mechanisms likely contribute to long-term increases in anxiety-like behavior following chronic ethanol exposure.

Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines

“…The results from the proteomic analysis of Triton X-100-insoluble proteins show that withdrawal from CIE exposure produces more than just neuroadaptations in PSDs. Consistent with previous studies on synaptic proteins, we found that withdrawal from CIE exposure altered expression levels of PSD-95 (Carpenter-Hyland and Chandler, 2006; Spiga et al, 2014), GAP-43 (Casoli et al, 2001), and CaMKII (Christian et al, 2012; Kash et al, 2009). Evidence has also implicated some glial and ECM proteins in models of chronic ethanol exposure and intake (Coleman et al, 2014; Lee et al, 2013; Wright et al, 2003), and the data from our study provide additional evidence for adaptations in glia and the ECM.…”

Structural and functional characterization of dendritic arbors and GABAergic synaptic inputs on interneurons and principal cells in the rat basolateral amygdala

“…Posttraumatic stress disorder and other forms of chronic stress are often associated with increases in amygdala activity, resulting in the dysregulation of fear responses and causing sensitization to stressful stimuli (Mahan and Ressler 2012;Roozendaal et al 2009). Previous studies have shown that emotional responses generated by the BLA may result from increased excitatory input and changes in glutamate receptor ratios (Christian et al 2012;Hubert et al 2014;LeDoux 2003) and repeated restraint stress can cause changes in BLA spine localization (Padival et al 2013). It would be interesting to investigate whether these changes result from altered levels of not only excitatory input but also inhibitory synapses within the BLA and other nuclei within the amygdala.…”

Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats

“…Chronic intermittent access to ethanol increases surface concentrations of GluA1 in the striatum, which may promote alcohol self-administration by altering the reinforcement processes (Wang et al, 2012). Surface GluA1 in the amygdala is also upregulated after chronic intermittent alcohol vapor exposure (Christian et al, 2012). Furthermore, phosphorylation of GluA1 at serine 831 plays a crucial role in increasing AMPAR activity in various regions of the brain (Malinow, 2003).…”