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

Abstract

Withdrawal-related anxiety is cited as a major contributor to relapse in recovering alcoholics. Changes in lateral/basolateral amygdala (BLA) neurotransmission could directly influence anxiety-like behaviors after chronic ethanol exposure and withdrawal. We have shown that these treatments enhance BLA glutamatergic function and neurotransmission. However, the BLA GABAergic system tightly controls the expression of anxiety-like behavior, and additional neuroadaptations in this system are potentially important as well. The intrinsic BLA GABAergic system consists of at least two populations of interneurons: local feed-back interneurons scattered throughout the region and feed-forward interneurons concentrated within groups found in the lateral/paracapsular region of the BLA. In the present study, we found that withdrawal from chronic ethanol robustly decreased presynaptic function at feed-forward GABA synapses but did not alter neurotransmitter release from local interneurons. Differential presynaptic changes at these synapses were complemented by decreased zolpidem sensitivity at feed-forward synapses and decreased midazolam sensitivity at local synapses. Consistent with this, chronic ethanol/ withdrawal decreased expression of GABA ␣1-subunit total protein and increased surface expression of ␣4-subunit protein. We also found transient increases in GABA-receptor-associated protein levels and persistent increases in ␥2-subunit and gephyrin proteins that would suggest alterations in GABA A receptor trafficking that might help regulate changes in ␣4-subunit localization. These data together suggest that chronic ethanol and withdrawal differentially modulate local and lateral paracapsular cell GABAergic synapses via distinct presynaptic and postsynaptic mechanisms. These findings extend our understanding of the neurobiological mechanisms governing changes in anxiety-like behavior after chronic ethanol exposure and withdrawal.

Alcohol dependence: molecular and behavioral evidence

“…These acute effects of ethanol are reversible after a single exposure, but with chronic intermittent exposure leading to ethanol dependence, they become irreversible. Similar findings have been reported in basolateral amygdala after chronic ethanol exposure, although the changes in receptor subunits are synapse-specific, with reductions in α1 subunits occurring beneath inputs from lateral paracapsular amygdalar neurons and increases in α4 beneath inputs from local interneurons [59]. It is interesting that interneuronal expression of α1-containing GABA A receptors was implicated in the addictive properties of benzodiazepines [60], and such cell-type and subunit-specificity is also likely important in the addictive profile of alcohol on these and other LGICs.…”

Behavioural and neuroinflammatory effects of the combination of binge ethanol and MDMA in mice

“…These behavioural alterations could be explained by the important hormonal and neurotransmitter changes produced by ethanol, such as elevated levels of corticotrophin releasing factor (CRF) in the central nucleus of the amygdala (Merlo Pich et al 1995), and decreased levels of GABA, dopamine and 5-HT in different limbic areas (Díaz et al 2011;Weiss et al 1996;Diana et al 1993). Consistent with these data, the administration of CRF antagonists or serotonin 5-HT1A receptor stimulation ameliorated the anxiety-like effects of ethanol absence, as measured on the elevated plus-maze (Lal et al 1991;Rassnick et al 1993).…”

β1-Adrenoceptor Activation Is Required for Ethanol Enhancement of Lateral Paracapsular GABAergic Synapses in the Rat Basolateral Amygdala

“…Therefore, if EtOH does indeed act by increasing NE release, it seems plausible that endogenous NE may act predominantly on ␤1-ARs in the BLA. However, it is worth noting that repeated EtOH exposure as well as stress can profoundly influence GABAergic circuitry and AR function in the BLA (Braga et al, 2004;Buffalari and Grace, 2009;Diaz et al, 2011). Therefore, it will be important in future studies to more thoroughly characterize the contribution of all three ␤-AR subtypes in regulating in vitro and in vivo effects of EtOH, particularly after chronic exposure and withdrawal from this drug.…”