Dynorphin-kappa opioid receptor activity in the central amygdala modulates binge-like alcohol drinking in mice

Abstract

Although previous research has demonstrated a role for kappa opioid receptor-mediated signaling in escalated alcohol consumption associated with dependence and stress exposure, involvement of the dynorphin/kappa opioid receptor (DYN/KOR) system in binge-like drinking has not been fully explored. Here we used pharmacological and chemogenetic approaches to examine the influence of DYN/KOR signaling on alcohol consumption in the drinking-in-the-dark (DID) model of binge-like drinking. Systemic administration of the KOR agonist U50,488 increased binge-like drinking (Experiment 1) while, conversely, systemic administration of the KOR antagonist nor-BNI reduced drinking in the DID model (Experiment 2). These effects of systemic KOR manipulation were selective for alcohol as neither drug influenced consumption of sucrose in the DID paradigm (Experiment 3). In Experiment 4, administration of the long-acting KOR antagonist nor-BNI into the central nucleus of the amygdala (CeA) decreased alcohol intake. Next, targeted "silencing" of DYN+ neurons in the CeA was accomplished using a chemogenetic strategy. Cre-dependent viral expression in DYN+ neurons was confirmed in CeA of Pdyn-IRES-Cre mice and functionality of an inhibitory (hM4Di) DREADD was validated (Experiment 5). Activating the inhibitory DREADD by CNO injection reduced binge-like alcohol drinking, but CNO injection did not alter alcohol intake in mice that were treated with control virus (Experiment 6). Collectively, these results demonstrate that DYN/KOR signaling in the CeA contributes to excessive alcohol consumption in a binge-drinking model.

Manipulations of central amygdala neurotensin neurons alter the consumption of ethanol and sweet fluids in mice

“…Nts CeA neurons also have a partial overlap with Pdyn CeA neurons. Dynorphin neurons in the CeA contribute to binge-drinking, a form of ethanol consumption that confers a high risk of developing alcohol use disorder (Anderson et al, 2019). We recently showed that dynorphin and NTS bi-directionally modulate synaptic inputs from the CeA to the BNST (Normandeau et al, 2018).…”

Leveraging Neural Networks in Preclinical Alcohol Research

“…For example, a reduction of alcohol consumption in mice was found by a suppression of activity in the NAc core with hM4Di-mediated inhibition [ 130 ]. Pharmacological antagonism of the k-opioid receptor and chemogenetic silencing of dynorphin signaling neurons was used to identify a role for dynorphin/k-opioid receptor signaling in the central amygdala in excessive alcohol consumption in a rodent model of binge drinking [ 131 ]. Specific neuronal ensembles critical for alcohol dependent drinking within the CEA were identified by the chemogenetic silencing of activated neurons using Daun02 [ 91 ].…”

Kappa Opioid Receptor and Dynorphin Signaling in the Central Amygdala Regulates Alcohol Intake

“…Manner Previous studies employing pharmacological approaches have shown that KOR antagonism in the CeA can decrease alcohol intake (Anderson et al, 2018;Kissler et al, 2014). However, it remains unclear whether this is mediated by KOR expression on CeA neurons or on presynaptic terminals from other brain regions.…”

“…In animal models, systemic treatment with KOR antagonists has been shown to reduce ethanol self-administration (Walker & Koob, 2007), stress-enhanced drinking (Anderson, Lopez, & Becker, 2016), and ethanol dependence-induced increases in anxiety (Valdez & Harshberger, 2012). Additionally site-specific KOR antagonism in the CeA decreases ethanol self-administration in dependent animals (Kissler et al, 2014) and alcohol consumption in a model of binge-like drinking (Anderson et al, 2018). Anderson et al (2018) also found that chemogenetic inhibition of preprodynorphin (PDYN) neurons in the CeA reduced binge-like drinking, suggesting that the source of dynorphin release may be within the CeA.…”

“…Additionally site-specific KOR antagonism in the CeA decreases ethanol self-administration in dependent animals (Kissler et al, 2014) and alcohol consumption in a model of binge-like drinking (Anderson et al, 2018). Anderson et al (2018) also found that chemogenetic inhibition of preprodynorphin (PDYN) neurons in the CeA reduced binge-like drinking, suggesting that the source of dynorphin release may be within the CeA. However, one limitation of these experiments is that PDYN neurons co-express a variety of other neuropeptides such as corticotropin releasing factor, somatostatin, and neurotensin (Kim, Zhang, Muralidhar, LeBlanc, & Tonegawa, 2017).…”