Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons

Abstract

We examined the interaction of ethanol with the ␥-aminobutyric acid (GABA)ergic system in neurons of slices of the rat central amygdala nucleus (CeA), a brain region thought to be critical for the reinforcing effects of ethanol. Brief superfusion of 11-66 mM ethanol significantly increased GABA type A (GABA A) receptormediated inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in most CeA neurons, with a low apparent EC50 of 20 mM. Acute superfusion of 44 mM ethanol increased the amplitude of evoked GABAA IPSPs and IPSCs in 70% of CeA neurons. The ethanol enhancement of IPSPs and IPSCs occurred to a similar extent in the presence of the GABA type B (GABA B) receptor antagonist CGP 55845A, suggesting that this receptor is not involved in the ethanol effect on CeA neurons. Ethanol superfusion also decreased pairedpulse facilitation of evoked GABAA IPSPs and IPSCs and always increased the frequency and sometimes the amplitude of spontaneous miniature GABA A IPSCs as well as responses to local GABA application, indicating both presynaptic and postsynaptic sites of action for ethanol. Thus, the CeA is the first brain region to reveal, without conditional treatments such as GABAB antagonists, consistent, low-dose ethanol enhancement of GABAergic transmission at both pre-and postsynaptic sites. These findings add further support to the contention that the ethanol-GABA interaction in CeA plays an important role in the reinforcing effects of ethanol.alcohol ͉ GABA IPSP͞Cs ͉ paired-pulse facilitation ͉ miniature synaptic current ͉ electrophysiology T he amygdala formation is a complex of interconnected nuclei that has been implicated in various physiological functions such as attention (1), memory (1-4), emotion (5-7), and autonomic control (3). This complex has been linked to the motivational effects of drugs of abuse and alcoholism in particular (8).The ␥-aminobutyric acid (GABA)ergic system, particularly in the central amygdala nucleus (CeA), has been implicated in the expression of emotionality, including behavioral states of fear and anxiety, as well as states associated with consummatory responses (9). The CeA is considered to be crucial in mediating the behavioral effects of acute and chronic ethanol consumption (10, 11). Because stress reduction has long been considered to contribute to ethanol-seeking behavior in humans, researchers hypothesized that the CeA and its connections might be sites for a GABA-like action of ethanol to mediate ethanol reinforcement. Behavioral studies indicate that injection of GABAergic antagonists directly into the CeA decreases motivated responding for oral self-administration of ethanol in rats, whereas infusion of GABA agonists and benzodiazepines decreased anxiety (11,12). Thus, these studies suggest that GABAergic systems in the CeA play a major role in the acute reinforcing effects of ethanol (13) and in the anxiogenic response to ethanol withdrawal (14).There has been a continuing controversy over the ability of ethanol to enhance GABAergic neurotransmission [inhib...

Microinjection of Naltrexone into the Central, but not the Basolateral, Amygdala Blocks the Anxiolytic Effects of Diazepam in the Plus Maze

“…These results suggest that the anxiolytic properties of ethanol in the elevated plus maze are not regulated by opioid receptor systems within CeA or BLA nuclei of the amygdala. This is surprising since ethanol increases GABA release, GABA A receptor function (Roberto et al, 2003), GABAergic neurotransmission (Nie et al, 2004), and c-fos expression in GABAergic neurons (Morales et al, 1998) in the CeA. These results are also somewhat discrepant with previous reports from this lab (Wilson et al, 2003); however, some important technical differences between the previous report and the current study warrant discussion.…”

“…Another potential problem is that ethanol is known to affect several neurotransmitter systems including GABA (Roberto et al, 2003), glutamate (Lovinger et al, 1989), neuroactive steroids (Sanna et al, 2004), and a variety of neuropeptides including opioids (de Gortari et al, 2000) and CRF (Nie et al, 2004). Therefore, even if opioid receptors modulate GABA A receptor function in the amygdala, the ability of ethanol to affect other neurotransmitter and neuromodulatory systems may be sufficient to circumvent any opioid receptor effects on GABA A receptor function localized selectively within the CeA or BLA.…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…Signore and Yeh (2000) found ethanol potentiation of GABA (410%) in a small number (nine of 44) of pyramidal neurons in the pyriform cortex. Roberto et al (2003) recently reported that 44 mM ethanol enhanced the effect of exogenously applied GABA to amygdaloid neurons, indicative that ethanol had a direct postsynaptic action on GABA A receptors at this site. Finally, the specific a 4 b X d and a 6 b X d GABA A receptor subunits (BZD-insensitive receptor subtypes), when expressed in oocytes, exhibited a direct action of low ethanol concentration enhancement of GABA responsiveness (Sundstrom-Poromaa et al, 2002;Wallner et al, 2003).…”

“…In contrast to work on dissociated neurons, several studies demonstrated that evoked release of GABA in a slice preparation was sensitive to ethanol (Carlen et al, 1982;Bloom and Siggins, 1987;Proctor et al, 1992;Roberto et al, 2003;Wan et al, 1996;Weiner et al, 1994aWeiner et al, , b, 1997a. Carlen et al (1982) reported enhanced inhibitory postsynaptic potentials (IPSPs) from CA1 hippocampal cells by ethanol, an observation later confirmed by a number of laboratories Wan et al, 1996;Weiner et al, 1994aWeiner et al, , b, 1997a.…”

“…Wan et al (1996) found that IPSCs from CA1 pyramidal cells were only sensitive to ethanol enhancement in the presence of a GABA B antagonist, providing a mechanism for the variability reported (see subsequent section on GABA B receptor influences). In another brain region, investigators (Nie et al, 2004;Roberto et al, 2003) reported that ethanol enhanced IPSCs from amygdaloid neurons.…”