Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice.

Lara S Hwa,Waylin Yu,Melanie M Pina,Rachel Calloway,Thomas L Kash,Meghan E Flanigan,Olivia J Hon,Christina M Stanhope,Emily Kokush,Sofia Neira,Dipanwita Pati,Kristen Boyt

doi:10.7554/elife.59709

Abstract

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here, we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.

Highlights

Alcohol abuse exacts a tremendous toll on society, and long-term drinking can dysregulate stress systems in the brain
Given that we have previously reported increased glutamatergic transmission in the mPFC following acute TMT exposure (Hwa et al, 2019) and recent reports from the Radley lab indicated a key role in prefrontal cortex (PFC) inputs to the bed nucleus of the stria terminalis (BNST) in stress regulation, we wanted to investigate if EtOH and TMT together may strengthen the functional connection between mPFC and BNST Pdyn neurons
Using converging approaches of intra-BNST norBNI infusions and genetic deletion of BNSTPDYN using a floxed mouse line, we show that reducing Pdyn/kappa opioid receptor (KOR) signaling at the pre- or post-synaptic level, respectively, normalizes alcohol-induced impairments in TMT behavioral responses during protracted abstinence

Summary

Introduction

Alcohol abuse exacts a tremendous toll on society, and long-term drinking can dysregulate stress systems in the brain. Prolonged alcohol drinking and withdrawal experiences result in enhanced responsiveness and behavioral sensitivity to stress during protracted abstinence (Heilig et al, 2010). Chronic alcohol exposure engages brain stress signaling systems that influence drinking behaviors in a dynamic and complex manner (Koob and Kreek, 2007). One such stress system is the neuropeptide prodynorphin (Pdyn) and its receptor, the kappa opioid receptor (KOR), which has been studied in the contexts of both mood and alcohol use disorders (Lutz and Kieffer, 2013). The BNST is an integrative hub that may mediate the negative affective state associated with chronic alcohol use and withdrawal (Koob, 2009; Kash, 2012). KORs throughout the extended amygdala and the BNST alter anxietylike behavior in mice (Bruchas et al, 2009; Crowley et al, 2016) and mediate stress-induced reinstatement for alcohol reinforcement (Leet al., 2018)

Results

Discussion

Conclusion