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Aberrant glucocorticoid signaling via glucocorticoid receptors (GR) plays a critical role in alcohol use disorder (AUD). Acute alcohol withdrawal and protracted abstinence in dependent rats are associated with increased GR signaling and changes in GR-mediated transcriptional activity in the rat central nucleus of the amygdala (CeA). The GR antagonist mifepristone decreases alcohol consumption in dependent rats during acute withdrawal and protracted abstinence. Regulation of CeA synaptic activity by GR is currently unknown. Here, we utilized mifepristone and the selective GR antagonist CORT118335 (both at 10 μM) as pharmacological tools to dissect the role of GR on GABA transmission in male, adult Sprague-Dawley rats using slice electrophysiology. We subjected rats to chronic intermittent alcohol vapor exposure for 5–7 weeks to induce alcohol dependence. A subset of dependent rats subsequently underwent protracted alcohol withdrawal for 2 weeks, and air-exposed rats served as controls. Mifepristone reduced the frequency of pharmacologically-isolated spontaneous inhibitory postsynaptic currents (sIPSC) in the CeA (medial subdivision) without affecting postsynaptic measures in all groups, suggesting decreased GABA release with the largest effect in dependent rats. CORT118335 did not significantly alter GABA transmission in naïve, but decreased sIPSC frequency in dependent rats. Similarly, mifepristone decreased amplitudes of evoked inhibitory postsynaptic potentials only in dependent rats and during protracted withdrawal. Collectively, our study provides insight into regulation of CeA GABAergic synapses by GR. Chronic ethanol enhances the efficiency of mifepristone and CORT118335, thus highlighting the potential of drugs targeting GR as a promising pharmacological avenue for the treatment of AUD. [ABSTRACT FROM AUTHOR]

Background: Women consume less alcohol than men, and yet they are more susceptible than men to the negative medical consequences of alcohol use, such as cirrhosis of the liver, cardiac disease, and cognitive impairments. This sex difference is also reflected in animal studies, in which male and female rats differ on both behavioral and electrophysiological measures. Given that one significant difference between males and females is the cycling fluctuations of the sex hormones, this study aimed to compare the relative sensitivity of adolescent and adult rats of both sexes and varying estrous stages to the behavioral and electrophysiological effects of ethanol. Methods: Adult female rats were lavaged daily for estrous cycle assessment. Following administration of 5 g/kg ethanol, adolescent and adult male and female animals were observed for loss of the righting reflex. Then, using whole-cell recording, we tested the response of spontaneous, gamma-aminobutyric acid (GABAA) receptor-mediated inhibitory postsynaptic currents (sIPSCs) in hippocampal slices from drug-naïve adult male and female rats. Results: Consistent with previous findings, adolescent animals were less sensitive than adults to the effect of ethanol on the righting reflex. In addition, adult proestrous and diestrous female rats were less sensitive than male rats to the sedative effects of ethanol. Finally, ethanol increased the frequency of sIPSCs in hippocampal pyramidal neurons and did so more potently in cells from male rats than in those from female rats. Conclusions: Female animals are less sensitive to the behavioral sedative effects of ethanol than adult male rats, and the effect is pronounced in the proestrous and diestrous states. This sex difference may be related to differential sensitivity of GABA receptor–mediated central nervous system function to ethanol in females. [ABSTRACT FROM AUTHOR]

The pituitary adenylate cyclase-activating polypeptide (PACAP) system plays a central role in the brain's emotional response to psychological stress by activating cellular processes and circuits associated with threat exposure. The neuropeptide PACAP and its main receptor PAC1 are expressed in the rodent central amygdala (CeA), a brain region critical in negative emotional processing, and CeA PACAPergic signaling drives anxiogenic and stress coping behaviors. Despite this behavioral evidence, PACAP's effects on neuronal activity within the medial subdivision of the CeA (CeM, the major output nucleus for the entire amygdala complex) during basal conditions and after psychological stress remain unknown. Therefore, in the present study, male Wistar rats were subjected to either restraint stress or control conditions, and PACAPergic regulation of CeM cellular function was assessed using immunohistochemistry and whole-cell patch-clamp electrophysiology. Our results demonstrate that PACAP-38 potentiates GABA release in the CeM of naïve rats, via its actions at presynaptic PAC1. Basal PAC1 activity also enhances GABA release in an action potential-dependent manner. Notably, PACAP-38's facilitation of CeM GABA release was attenuated after a single restraint stress session, but after repeated sessions returned to the level observed in naïve animals. A single restraint session also significantly decreased PAC1 levels in the CeM, with repeated restraint sessions producing a slight recovery. Collectively our data reveal that PACAP/PAC1 signaling enhances inhibitory control of the CeM and that psychological stress can modulate this influence to potentially disinhibit downstream effector regions that mediate anxiety and stress-related behaviors. This article is part of the special issue on 'Neuropeptides'. • PACAP-38/PAC1 signaling enhances GABA transmission in the central amygdala. • A single restraint stress reduced PAC1 immunoreactivity. • A single restraint stress dampened PACAP-38's effects on the GABA response. • Repeated restraint stress produced a functional recovery. [ABSTRACT FROM AUTHOR]

Myeloid differentiation primary response protein (MyD88) is a critical neuroimmune adaptor protein in TLR (Toll-like receptor) and IL-1R (Interleukin-1 receptor) signaling complexes. These two pro-inflammatory families play an important role in the neurobiology of alcohol use disorder, specifically MyD88 regulates ethanol drinking, ethanol-induced sedation, and ethanol-induced deficits in motor coordination. In this study, we examined the role of MyD88 in mediating the effects of IL-1β and ethanol on GABAergic transmission in the central amygdala (CeA) of male mice using whole-cell patch-clamp recordings in combination with pharmacological (AS-1, a mimetic that prevents MyD88 recruitment by IL-1R) and genetic (Myd88 knockout mice) approaches. We demonstrate through both approaches that IL-1β and ethanol's modulatory effects at CeA GABA synapses are not dependent on MyD88. Myd88 knockout potentiated IL-1β's actions in reducing postsynaptic GABAA receptor function. Pharmacological inhibition of MyD88 modulates IL-1β's action at CeA GABA synapses similar to Myd88 knockout mice. Additionally, ethanol-induced CeA GABA release was greater in Myd88 knockout mice compared to wildtype controls. Thus, MyD88 is not essential to IL-1β or ethanol regulation of CeA GABA synapses but plays a role in modulating the magnitude of their effects, which may be a potential mechanism by which it regulates ethanol-related behaviors. [ABSTRACT FROM AUTHOR]