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

Abstract

Excessive 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.

A midbrain dynorphin circuit promotes threat generalization

“…To inactivate Pdyn in inputs to the VTA, Pdyn lox/lox mice 34 were injected with CAV2-Cre 35 in the VTA (Figures 3F and 3G).…”

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice

“…Mice were tested unless when otherwise stated (rats); continuous, 24-h two-bottle choice alcohol consumption paradigm or 24-h progressive two-bottle free-choice alcohol consumption paradigm; DID, drinking in the dark; intermittent access, intermittent access two-bottle choice paradigm; limited, limited access procedures; Self-administration, operant alcohol self-administration; 4 bottles, four-bottle choice paradigm consumption in a two-bottle choice paradigm [150], total deletion of KORs in mice was associated with a reduced alcohol intake in the same paradigm [45,151]. Interestingly, conditional knockout of KORs in the central nucleus of the amygdala (CeA) resulted in reductions of alcohol intake in male but not female mice [152]. The fact that KOR conditional knockout within the CeA did not affect alcohol drinking in female mice may suggest that the mechanism of protective action of KOR deletion is likely different between sexes.…”

“…Pdyn knockout mice otherwise showed a normal increase in stress-induced alcohol preference [50,156] but developed stronger withdrawal signs after chronic alcohol [49]. Conditional knockout of Pdyn in CeA neurons resulted in decreased alcohol consumption in males and females and reduced pDyn neuron excitability in female mice following alcohol drinking [152]. In summary, these studies synthesize what is known about the role of KOR/pDyn in alcohol phenotype and point out the sex differences in dynorphin and KOR systems in the regulation of alcohol drinking behaviors.…”

A midbrain dynorphin circuit promotes threat generalization

“…To inactivate Pdyn in inputs to the VTA, Pdyn lox/lox mice [24] were injected with CAV2-Cre [25] into the VTA ( Figure 3F Figure S3). Improved threat discrimination was associated with a significant reduction in freezing to the CS-in CAV2-Cre::Pdyn lox/lox mice relative to controls ( Figure S3).…”