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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Alcohol; Amygdala; Bed nucleus of the stria terminalis; Dynorphin; Kappa opioid receptor; Stress.