Dynorphin/Kappa Opioid Receptor Activity Within the Extended Amygdala Contributes to Stress-Enhanced Alcohol Drinking in 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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A review of salvinorin analogs and their kappa-opioid receptor activity

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2018.03.029 ◽

2018 ◽

Vol 28 (9) ◽

pp. 1436-1445 ◽

Cited By ~ 16

Author(s):

Jeremy J. Roach ◽

Ryan A. Shenvi

Keyword(s):

Opioid Receptor ◽

Kappa Opioid Receptor ◽

Receptor Activity ◽

Kappa Opioid

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mTORC1 pathway is involved in the kappa opioid receptor activation-induced increase in excessive alcohol drinking in mice

Pharmacology Biochemistry and Behavior ◽

10.1016/j.pbb.2020.172954 ◽

2020 ◽

Vol 195 ◽

pp. 172954 ◽

Cited By ~ 1

Author(s):

Yan Zhou ◽

Yupu Liang ◽

Mary Jeanne Kreek

Keyword(s):

Opioid Receptor ◽

Alcohol Drinking ◽

Receptor Activation ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Mtorc1 Pathway ◽

Excessive Alcohol

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

10.7554/elife.59709.sa1 ◽

2020 ◽

Author(s):

Nicholas Gilpin

Keyword(s):

Stress Response ◽

Opioid Receptor ◽

Alcohol Drinking ◽

Kappa Opioid Receptor ◽

Predator Odor ◽

Receptor Signaling ◽

Male Mice ◽

Kappa Opioid

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

10.7554/elife.59709.sa2 ◽

2020 ◽

Author(s):

Lara S Hwa ◽

Sofia Neira ◽

Meghan E Flanigan ◽

Christina M Stanhope ◽

Melanie M Pina ◽

...

Keyword(s):

Stress Response ◽

Opioid Receptor ◽

Alcohol Drinking ◽

Kappa Opioid Receptor ◽

Predator Odor ◽

Author Response ◽

Receptor Signaling ◽

Male Mice ◽

Kappa Opioid

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

10.1101/663666 ◽

2019 ◽

Cited By ~ 2

Author(s):

Daniel W. Bloodgood ◽

Dipanwita Pati ◽

Melanie M. Pina ◽

Sofia Neira ◽

J. Andrew Hardaway ◽

...

Keyword(s):

Opioid Receptor ◽

Alcohol Drinking ◽

Alcohol Intake ◽

Gene Knockout ◽

Kappa Opioid Receptor ◽

Conditional Knockout ◽

Central Nucleus ◽

Kappa Opioid ◽

Excessive Alcohol Consumption ◽

Excessive Alcohol

AbstractExcessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. We then examined the effects of DID on PDYN and KOR modulation of CeA circuit physiology. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.

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