Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol.
- Authors
- Anderson, Rachel I; Becker, Howard C
- Year
- 2017
- Journal
- Alcoholism, clinical and experimental research
- PMID
- 28425121
- DOI
- 10.1111/acer.13406
- PMCID
- PMC5522623
Evidence has demonstrated that dynorphin (DYN) and the kappa opioid receptor (KOR) system contribute to various psychiatric disorders, including anxiety, depression, and addiction. More recently, this endogenous opioid system has received increased attention as a potential therapeutic target for treating alcohol use disorders. In this review, we provide an overview and synthesis of preclinical studies examining the influence of alcohol (ethanol [EtOH]) exposure on DYN/KOR expression and function, as well as studies examining the effects of DYN/KOR manipulation on EtOH's rewarding and aversive properties. We then describe work that has characterized effects of KOR activation and blockade on EtOH self-administration and EtOH dependence/withdrawal-related behaviors. Finally, we address how the DYN/KOR system may contribute to stress-EtOH interactions. Despite an apparent role for the DYN/KOR system in motivational effects of EtOH, support comes from relatively few studies. Nevertheless, review of this literature reveals several common themes: (i) rodent strains genetically predisposed to consume more EtOH generally appear to have reduced DYN/KOR tone in brain reward circuitry; (ii) acute and chronic EtOH exposure typically up-regulate the DYN/KOR system; (iii) KOR antagonists reduce behavioral indices of negative affect associated with stress and chronic EtOH exposure/withdrawal; and (iv) KOR antagonists are effective in reducing EtOH consumption, but are often more efficacious under conditions that engender high levels of consumption, such as dependence or stress exposure. These results support the contention that the DYN/KOR system plays a significant role in contributing to dependence- and stress-induced elevation in EtOH consumption. Overall, more comprehensive analyses (on both behavioral and mechanistic levels) are needed to provide additional insight into how the DYN/KOR system is engaged and adapts to influence the motivation effects of EtOH. This information will be critical for the development of new pharmacological agents targeting KORs as promising novel therapeutics for alcohol use disorders and comorbid affective disorders.
Conceptual schematic of adaptations in the DYN/KOR system in relation to motivational effects of ethanol. Under basal conditions, the rewarding effects of ethanol reflect an elevated (positive) hedonic state (gray line) whereby moderate levels of consumption are driven by positive reinforcement (i.e., drinking to achieve the rewarding effects of ethanol). Under these conditions, KOR antagonists do not affect basal hedonic state (or ethanol consumption). When the DYN/KOR system is activated pharmacologically via a KOR agonist (Panel A) or upregulated by stress or chronic ethanol exposure/withdrawal (Panel B), the basal hedonic state is depressed. Ethanol consumption now results in a relatively greater positive shift in hedonic value (red line). Under these conditions, ethanol consumption is elevated because it is driven by a combination of positive reinforcement (drinking for rewarding effects) and negative reinforcement (drinking to alleviate dysphoria). KOR antagonists restore balance to the hedonic state such that the relative rewarding effects of ethanol are no longer potentiated (blue line). In this circumstance, ethanol consumption returns to moderate levels since drinking is no longer driven by negative reinforcement.
LLM interpretation
This figure consists of two conceptual schematics (Panels A and B) using bar charts to illustrate the impact of the DYN/KOR system on the hedonic state and ethanol reward. The y-axis represents "Hedonic State," ranging from "Aversion" to "Reward," with a dashed baseline separating the two. The diagrams show that KOR activation (via agonists in A or stress/dependence in B) lowers the baseline hedonic state, increasing the relative reward value of ethanol; this effect is reversed by the administration of a KOR antagonist.
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