Ethanol inhibition of kainate receptor-mediated excitatory neurotransmission in the rat basolateral nucleus of the amygdala

Abstract

The neurobiological mechanisms governing alcohol-induced alterations in anxiety-like behaviors are not fully understood. Given that the amygdala is a major emotional center in the brain and regulates the expression of both learned-fear and anxiety, neurotransmitter systems within the basolateral amygdala represent likely mechanisms governing the anxiety-related effects of acute ethanol exposure. It is well established that, within the glutamatergic system, N-methyl-D-aspartate (NMDA)-type receptors, are particularly sensitive to intoxicating concentrations of ethanol. However, recent evidence suggests that kainate-type glutamate receptors are sensitive to ethanol as well. Therefore, we examined the effect of acute ethanol on kainate receptor (KA-R)-mediated synaptic transmission in the basolateral amygdala (BLA) of Sprague Dawley rats. Acute ethanol decreased KA-R-mediated excitatory postsynaptic currents (EPSCs) in the BLA in a concentrationdependent manner. Ethanol also inhibited currents evoked by focal application of the kainate receptor agonist (R, S)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), and ethanol inhibition of kainate EPSCs was not associated with a change in paired-pulse ratio, suggesting a postsynaptic mechanism of ethanol action. The neurophysiological consequences of this acute sensitivity were tested by measuring ethanol's effects on KA-R-dependent modulation of synaptic plasticity. Acute ethanol, like the GluR5-specific antagonist (RS)-3-(2-carboxybenzyl)willardiine (UBP 296), robustly diminished ATPA-induced increases in synaptic efficacy. Lastly, to better understand the relationship between KA-R activity and anxiety-like behavior, we bilaterally microinjected ATPA directly into the BLA. We observed an increase in measures of anxiety-like behavior, assessed in the light/dark box, with no change in locomotor activity. This evidence suggests that kainate receptors in the BLA are inhibited by pharmacologically relevant concentrations of ethanol and may contribute to some of the acute anxiolytic effects of this drug.

Effects of a stressor and corticotrophin releasing factor on ethanol deprivation-induced ethanol intake and anxiety-like behavior in alcohol-preferring P rats

“…Previous studies have shown that acute injection of CRF into the NAC (Holahan et al 1997) or into the ventricles (Koob and Bloom 1985;Lowry et al 2009) increases locomotor activity. Likewise, local injection of CRF into the Amyg, DRN, or VTA can also have an acute activating action (Hiroi and Neumaier 2009;Kalivas et al 1987;Lack et al 2008;Lee and Tsai 1989;Meloni et al 2008;Wand 2005). However, since none of the brain regions previously associated with acute CRF-increased locomotion demonstrated an association with elevated locomotion during withdrawal after the ADE (Fig.…”

“…Brain regions implicated in CRF-induced and ethanol withdrawal-induced anxiety-like behavior are the amygdala (Amyg) (Huang et al 2010;Knapp et al 2007;Koob 2003Koob , 2008Lack et al 2008;Overstreet et al 2006;Rassnick et al 1993;Wand 2005;Silberman et al 2009) and the dorsal raphe nucleus (DRN) (Huang et al 2010;Overstreet et al 2006). The basolateral amygdala and dorsal bed nucleus of the stria terminalis were also implicated in withdrawalinduced anxiety-like behavior following repeated CRF and stressor presentations prior to exposure to chronic ethanolcontaining diets (Huang et al 2010).…”

Chronic Ethanol and Withdrawal Differentially Modulate Lateral/Basolateral Amygdala Paracapsular and Local GABAergic Synapses

“…However, intoxicated animals express decreased, not increased, anxiety-like behavior immediately after a chronic exposure despite exposure-induced increases in glutamatergic synaptic function. Because BLA glutamatergic synaptic responses are relatively insensitive to acute ethanol (Lä ck et al, 2008), the maintenance of an anxiolytic phenotype suggests contributions by neurotrans-mitter systems other than glutamate. In this regard, the expression of anxiety-like behavior (Sanders and Shekhar, 1995) and the activity of BLA principal neurons (Woodruff et al, 2006) are tightly regulated by GABAergic neurotransmission.…”

Synaptic Effects Induced by Alcohol

“…Inhibition of KAR-mediated responses has been observed at quite low EtOH concentrations (Costa et al 2000;Lack et al 2008;Valenzuela et al 1998a;Weiner et al 1999). However, direct examination of KAR-mediated ion current has yielded mixed results, at least for the receptor constructs examined to date (Dildy-Mayfield and Harris 1992;Valenzuela et al 1998a).…”

“…EtOH also inhibits LTP induced by kainate receptor activation in the basolateral amygdala (Lack et al 2008). …”