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

AbstractMaladaptive 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 compared to drinking or stress alone. 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 from heavy drinking. 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.Impact StatementHeavy alcohol drinking primes dynorphin / kappa opioid systems in the bed nucleus of the stria terminalis to alter stress responses in mice.

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

eLife ◽

10.7554/elife.59709 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Lara S Hwa ◽

Sofia Neira ◽

Meghan E Flanigan ◽

Christina M Stanhope ◽

Melanie M Pina ◽

...

Keyword(s):

Opioid Receptor ◽

Stress Responses ◽

Alcohol Drinking ◽

Kappa Opioid Receptor ◽

Predator Odor ◽

Stria Terminalis ◽

Receptor Signaling ◽

Kappa Opioid ◽

Bed Nucleus ◽

Heavy Alcohol

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.

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Activation of the kappa opioid receptor / dynorphin system alters stress and threat responding during acute withdrawal from intermittent alcohol drinking in male mice

10.1101/2020.09.23.310284 ◽

2020 ◽

Author(s):

Lara S. Hwa ◽

Sofia Neira ◽

Dipanwita Pati ◽

Melanie M. Pina ◽

Morgan Bowling ◽

...

Keyword(s):

Opioid Receptor ◽

Alcohol Drinking ◽

Kappa Opioid Receptor ◽

Predator Odor ◽

List Type ◽

Kappa Opioid ◽

Swim Stress ◽

Acute Withdrawal ◽

Stress Behavior ◽

Forced Swim

AbstractThe dynorphin/kappa opioid receptor (KOR) system in the brain regulates both stressful experiences and negative, aversive states during withdrawal from drugs of abuse. We explored the role of this system during acute withdrawal from long-term alcohol drinking, focusing on the bed nucleus of the stria terminalis (BNST), a region strongly implicated in alcohol-withdrawal induced alterations of behavior. Male C57BL/6J mice were subjected to repeated forced swim tests, home cage exposure to a predator odor, and a visual threat after eight weeks intermittent access to alcohol or water. Systemic injection of KOR antagonist norBNI reversed alcohol-related differences in immobility time during the second swim test and reduced burying behavior in response to predator odor, but did not affect behavioral response to visual threat. In dynorphin-GFP reporter mice, c-Fos immunoreactivity was increased in dynorphin-containing neurons after repeated swim stress and alcohol drinking. Using dynorphin-GFP mice, there was enhanced spontaneous excitatory synaptic drive onto dynorphin neurons in the BNST after alcohol-drinking mice underwent forced swim stress. Finally, knockdown of dynorphin in the BNST using a viral shRNA affected swim stress behavior and responses to TMT in alcohol drinkers and controls, but did not affect alcohol drinking. These studies confirm BNST dynorphin recruitment during acute withdrawal as playing a key role in altered behavioral responses to stressful stimuli.HighlightsIntermittent alcohol drinking changed stress reactions in mice.KOR antagonist norBNI altered stress responses in alcohol drinkers.Alcohol and swim stress increased c-Fos immunoreactivity in BNST dynorphin neurons.Swim stress enhanced excitatory drive onto BNST dynorphin cells in alcohol mice.BNST dynorphin knockdown affected some stress behavior, but not alcohol drinking.

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