The One-Two Punch of Alcoholism: Role of Central Amygdala Dynorphins/Kappa-Opioid Receptors

doi:10.1016/j.biopsych.2013.03.014

Biological Psychiatry

Volume 75, Issue 10, 15 May 2014, Pages 774-782

https://doi.org/10.1016/j.biopsych.2013.03.014 Get rights and content

Background

The dynorphin (DYN)/kappa-opioid receptor (KOR) system undergoes neuroadaptations following chronic alcohol exposure that promote excessive operant self-administration and negative affective-like states; however, the exact mechanisms are unknown. The present studies tested the hypothesis that an upregulated DYN/KOR system mediates excessive alcohol self-administration that occurs during withdrawal in alcohol-dependent rats by assessing DYN A peptide expression and KOR function, in combination with site-specific pharmacologic manipulations.

Methods

Male Wistar rats were trained to self-administer alcohol using operant behavioral strategies and subjected to intermittent alcohol vapor or air exposure. Changes in self-administration were assessed by pharmacologic challenges during acute withdrawal. In addition, 22-kHz ultrasonic vocalizations were utilized to measure negative affective-like states. Immunohistochemical techniques assessed DYN A peptide expression and [³⁵S]GTPγS coupling assays were performed to assess KOR function.

Results

Alcohol-dependent rats displayed increased alcohol self-administration, negative affective-like behavior, DYN A-like immunoreactivity, and KOR signaling in the amygdala compared with nondependent control rats. Site-specific infusions of a KOR antagonist selectively attenuated self-administration in dependent rats, whereas a mu-opioid receptor/delta-opioid receptor antagonist cocktail selectively reduced self-administration in nondependent rats. A mu-opioid receptor antagonist/partial KOR agonist attenuated self-administration in both cohorts.

Conclusions

Increased DYN A and increased KOR signaling could set the stage for a one-two punch during withdrawal that drives excessive alcohol consumption in alcohol dependence. Importantly, intracentral nucleus of the amygdala pharmacologic challenges functionally confirmed a DYN/KOR system involvement in the escalated alcohol self-administration. Together, the DYN/KOR system is heavily dysregulated in alcohol dependence and contributes to the excessive alcohol consumption during withdrawal.

Section snippets

Animals

Eighty-four male Wistar rats approximately 70 days old were housed in an environmentally controlled vivarium with food and water ad libitum. All work adhered to the National Research Council Guide for the Care and Use of Laboratory Animals (27) and followed Institutional Animal Care and Use Committee Guidelines.

Operant Alcohol Self-Administration

Animals were trained to self-administer a 10% alcohol (wt/vol) solution using a sweetener-fade method. Standard operant chambers (Med Associates, St. Albans, Vermont) were utilized,

Chronic Alcohol Exposure Induces Negative Affective State and Increased DYN A-like Immunoreactivity in the CeA

Chronic intermittent alcohol vapor exposure induced dependence (6), escalated alcohol self-administration (Figures 2 and 3), and significantly elevated BACs compared with nondependent control animals (Figure 2). In separate groups of animals, the expression of DYN A in the CeA was assessed by immunohistochemistry. Rats were trained to self-administer alcohol (Figure 1B) and were divided into groups matched for alcohol consumption. Following dependence induction, animals were tested during acute

Discussion

To test the hypothesis that the DYN/KOR is dysregulated in dependence and contributes to escalated alcohol self-administration, dependence was induced using chronic intermittent alcohol vapor exposure and dependent animals exhibited escalated self-administration during withdrawal that yielded significantly increased BACs compared with control animals.

Negative affective states accompanying withdrawal are proposed to drive excessive alcohol seeking and consumption (29). Withdrawal-induced

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The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are reciprocally connected nodes of the extended amygdala thought to play an important role in alcohol consumption. Studies of immediate-early genes indicate that BNST and CeA are acutely activated following alcohol drinking and may signal alcohol reward in nondependent drinkers, while stress signaling in the extended amygdala following chronic alcohol exposure drives increased drinking via negative reinforcement. However, the temporal dynamics of neuronal activation in these regions during drinking behavior are poorly understood. In this study, we used fiber photometry and the genetically encoded calcium sensor GCaMP6s to assess acute changes in neuronal activity during alcohol consumption in BNST and CeA before and after a chronic drinking paradigm. Activity was examined in the pan-neuronal population and separately in dynorphinergic neurons. BNST and CeA showed increased pan-neuronal activity during acute consumption of alcohol and other fluid tastants of positive and negative valence, as well as highly palatable chow. Responses were greatest during initial consummatory bouts and decreased in amplitude with repeated consumption of the same tastant, suggesting modulation by stimulus novelty. Dynorphin neurons showed similar consumption-associated calcium increases in both regions. Following three weeks of continuous alcohol access (CA), calcium increases in dynorphin neurons during drinking were maintained, but pan-neuronal activity and BNST-CeA coherence were altered in a sex-specific manner. These results indicate that BNST and CeA, and dynorphin neurons specifically, are engaged during drinking behavior, and activity dynamics are influenced by stimulus novelty and chronic alcohol.
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The dynorphin (DYN)/kappa-opioid receptor (KOR) system is involved in dysphoria and negative emotional states. Dysregulation of KOR function promotes maladaptive behavioral regulation during withdrawal associated with alcohol dependence. Mesolimbic dopaminergic (DA) projections from the ventral tegmental area (VTA) innervate the extended amygdala circuitry and presynaptic KORs attenuate DA in these regions leading to an excessive alcohol consumption and negative affective-like behavior, whereas mesocortical KOR-regulated DA projections have been implicated in executive function and decision-making. Thus, the neuroadaptations occurring in DYN/KOR systems are important aspects to consider for the development of personalized therapeutic solutions. Herein, we study the contribution of the VTA DA neuron Oprk1 (KOR gene) in excessive alcohol consumption, negative emotional state, and executive function. To do so, Oprk1 mRNA expression and KOR function were characterized to confirm alcohol dependence-induced dysregulation in the VTA. Then, a transgenic Cre-Lox rat model (male and female TH::Cre rats) was used to allow for conditional and inducible overexpression of Oprk1 in VTA DA neurons. The effect of this overexpression was evaluated on operant alcohol self-administration, negative emotional states, and executive function. We found that VTA Oprk1 overexpression recapitulates some phenotypes of alcohol dependence including escalated alcohol self-administration and depressive-like behavior. However, working memory performance was not impacted following VTA Oprk1 overexpression in TH::Cre rats. This supports the hypothesis that dysregulated KOR signaling within the mesolimbic DA system is an important contributor to symptoms of alcohol dependence and shows that understanding Oprk1-mediated contributions to alcohol use disorder (AUD) should be an important future goal.
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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.
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: Authors JLK and SS contributed equally to this work.

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Archival ReportThe One-Two Punch of Alcoholism: Role of Central Amygdala Dynorphins/Kappa-Opioid Receptors

Background

Methods

Results

Conclusions

Section snippets

Animals

Operant Alcohol Self-Administration

Chronic Alcohol Exposure Induces Negative Affective State and Increased DYN A-like Immunoreactivity in the CeA

Discussion

Am J Prev Med

Drug Alcohol Depend

J Subst Abuse Treat

Neuropsychopharmacology

Alcohol

Trends Neurosci

Neuropharmacology

Alcohol

Pharmacol Biochem Behav

Alcohol

Neuroscience

Prog Neurobiol

Neurosci Biobehav Rev

Neurosci Biobehav Rev

Neurosci Biobehav Rev

Neuropharmacology

Pharmacol Ther

Neuroscience

Neurosci Lett

Alcohol

Brain Res

Dynamics of neuronal circuits in addiction: Reward, antireward, and emotional memory

Pharmacopsychiatry

Psychiatric disorders associated with alcoholism: 2 year follow-up of treatment

Actas Esp Psiquiatr

Effects of acute ethanol on opioid peptide release in the central amygdala: An in vivo microdialysis study

Psychopharmacology (Berl)

Dynorphin is a specific endogenous ligand of the kappa opioid receptor

Science

Inhibition of kappa opioid receptors attenuated increased cocaine intake in rats with extended access to cocaine

Psychopharmacology (Berl)

Stress-induced activation of the dynorphin/kappa-opioid receptor system in the amygdala potentiates nicotine conditioned place preference

J Neurosci

Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence

Neuropsychopharmacology

Archival Report
The One-Two Punch of Alcoholism: Role of Central Amygdala Dynorphins/Kappa-Opioid Receptors