Dynorphin/Kappa Opioid Receptor Activity Within the Extended Amygdala Contributes to Stress-Enhanced Alcohol Drinking in Mice

While there is high comorbidity of stress-related disorders and alcohol use disorder, few effective treatments are available and elucidating underlying neurobiological mechanisms has been hampered by a general lack of reliable animal models. Here, we use a novel mouse model demonstrating robust and...

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Bibliographic Details
Published in:Biological psychiatry (1969) 2022-06, Vol.91 (12), p.1019-1028
Main Authors: Haun, Harold L., Lebonville, Christina L., Solomon, Matthew G., Griffin, William C., Lopez, Marcelo F., Becker, Howard C.
Format: Article
Language:English
Subjects:
Alcohol
Alcohol Drinking - genetics
Alcoholism - metabolism
Amygdala
Animals
Bed nucleus of the stria terminalis
Central Amygdaloid Nucleus - metabolism
Disease Models, Animal
Dynorphin
Dynorphins - metabolism
Ethanol - pharmacology
Kappa opioid receptor
Mice
Receptors, Opioid, kappa - metabolism
RNA, Messenger - metabolism
Stress
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Summary:While there is high comorbidity of stress-related disorders and alcohol use disorder, few effective treatments are available and elucidating underlying neurobiological mechanisms has been hampered by a general lack of reliable animal models. Here, we use a novel mouse model demonstrating robust and reproducible stress-enhanced alcohol drinking to examine the role of dynorphin/kappa opioid receptor (DYN/KOR) activity within the extended amygdala in mediating this stress-alcohol interaction. Mice received repeated weekly cycles of chronic intermittent ethanol exposure alternating with weekly drinking sessions ± forced swim stress exposure. Pdyn messenger RNA expression was measured in the central amygdala (CeA), and DYN-expressing CeA neurons were then targeted for chemogenetic inhibition. Finally, a KOR antagonist was microinjected into the CeA or bed nucleus of the stria terminalis to examine the role of KOR signaling in promoting stress-enhanced drinking. Stress (forced swim stress) selectively increased alcohol drinking in mice with a history of chronic intermittent ethanol exposure, and this was accompanied by elevated Pdyn messenger RNA levels in the CeA. Targeted chemogenetic silencing of DYN-expressing CeA neurons blocked stress-enhanced drinking, and KOR antagonism in the CeA or bed nucleus of the stria terminalis significantly reduced stress-induced elevated alcohol consumption without altering moderate intake in control mice. Using a novel and robust model of stress-enhanced alcohol drinking, a significant role for DYN/KOR activity within extended amygdala circuitry in mediating this effect was demonstrated, thereby providing further evidence that the DYN/KOR system may be a valuable target in the development of more effective treatments for individuals presenting with comorbidity of stress-related disorders and alcohol use disorder.
ISSN:0006-3223
1873-2402
DOI:10.1016/j.biopsych.2022.01.002