Presynaptic Inhibition of Gamma-Aminobutyric Acid Release in the Bed Nucleus of the Stria Terminalis by Kappa Opioid Receptor Signaling

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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A midbrain dynorphin circuit promotes threat generalization

10.1101/2020.04.21.053892 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lizz Fellinger ◽

Yong S. Jo ◽

Avery C. Hunker ◽

Marta E. Soden ◽

Larry S. Zweifel

Keyword(s):

Ventral Tegmental Area ◽

Opioid Receptor ◽

Dorsal Raphe Nucleus ◽

Kappa Opioid Receptor ◽

Raphe Nucleus ◽

Stria Terminalis ◽

Kappa Opioid ◽

Bed Nucleus ◽

Ventral Tegmental ◽

Threat Stimuli

SummaryDiscrimination between predictive and non-predictive threat stimuli decrease as threat intensity increases. The central mechanisms that mediate the transition from discriminatory to generalized threat responding remain poorly resolved. Here, we identify the stress- and dysphoria-associated kappa opioid receptor (KOR) and its ligand dynorphin (Dyn), acting in the ventral tegmental area (VTA), as a key substrate for regulating threat generalization. We identified several dynorphinergic inputs to the VTA and demonstrate that projections from the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN) both contribute to anxiety-like behavior but differentially affect threat generalization. These data demonstrate that conditioned threat discrimination has an inverted ‘U’ relationship with threat intensity and establish a role for KOR/Dyn signaling in the midbrain for promoting threat generalization.

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