scholarly journals Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcript variants by excessive ethanol drinking and dependence

2019 ◽  
Author(s):  
Rita Cervera-Juanes ◽  
Audrey E. Padula ◽  
Larry J. Wilhem ◽  
Byung Park ◽  
Kathleen A. Grant ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Drinking ◽  
Alcohol Intake ◽  
Heavy Drinking ◽  
Differentially Methylated Region ◽  
Sequencing Analysis ◽  
Alternative Promoters ◽  
Transcript Variants ◽  
Excessive Alcohol ◽  
Alcohol Dependent

ABSTRACTThe underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Given that small-conductance Ca2+-activated K+ (KCa2 or SK) channels encoded by the KCNN family of genes have emerged from preclinical studies as a crucial target that contributes to heavy drinking and alcohol-induced functional neuroadaptations, we performed a cross-species analysis of KCNN3 methylation, gene expression, and polymorphisms of alcohol-drinking monkeys and alcohol dependent mice. Because of the alternative promoters in KCNN3, we analyzed expression of the different transcript variants that when translated influence surface trafficking and function of KCa2 channels. In heavy drinking rhesus macaques and alcohol dependent C57BL/6J mice, bisulfite sequencing analysis of the nucleus accumbens revealed a differentially methylated region in exon 1A of KCNN3 that overlaps with a predicted promoter sequence. The hypermethylation of KCNN3 in monkey and mouse accumbens paralleled an increase in expression of alternative transcript variants that encode apamin-insensitive and dominant-negative KCa2 channel isoforms. A polymorphic repeat in macaque KCNN3 encoded by exon 1 did not correlate with alcohol drinking. At the protein level, KCa2.3 channel expression in the accumbens was significantly reduced in very heavy drinking monkeys. Together, our cross-species findings on epigenetic dysregulation of KCNN3 by heavy alcohol drinking and dependence represent a complex mechanism that utilizes alternative promoters to impact firing of accumbens neurons. Thus, these results provide support for hypermethylation of KCNN3 by excessive alcohol drinking as a possible key molecular mechanism underlying harmful alcohol intake and alcohol use disorder.

scholarly journals Bioinformatics identification and pharmacological validation of Kcnn3/KCa2 channels as a mediator of negative affective behaviors and excessive alcohol drinking in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Audrey E. Padula ◽  
Jennifer A. Rinker ◽  
Marcelo F. Lopez ◽  
Megan K. Mulligan ◽  
Robert W. Williams ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Mood Disorders ◽  
Alcohol Drinking ◽  
Heavy Drinking ◽  
Alcohol Exposure ◽  
Sk Channel ◽  
Affective Behaviors ◽  
Positive Modulator ◽  
Excessive Alcohol ◽  
Alcohol Dependent

AbstractMood disorders are often comorbid with alcohol use disorder (AUD) and play a considerable role in the development and maintenance of alcohol dependence and relapse. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy drinking and negative affective behaviors. In order to identify novel pharmacogenetic targets, a bioinformatics analysis was used to quantify the expression of amygdala K+ channel genes that covary with anxiety-related phenotypes in the well-phenotyped and fully sequenced family of BXD strains. We used a model of stress-induced escalation of drinking in alcohol-dependent mice to measure negative affective behaviors during abstinence. A pharmacological approach was used to validate the key bioinformatics findings in alcohol-dependent, stressed mice. Amygdalar expression of Kcnn3 correlated significantly with 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors and negative correlations with binge-like and voluntary alcohol drinking. Mice treated with chronic intermittent alcohol exposure and repeated swim stress consumed more alcohol in their home cages and showed hypophagia on the novelty-suppressed feeding test during abstinence. Pharmacologically targeting Kcnn gene products with the KCa2 (SK) channel-positive modulator 1-EBIO decreased drinking and reduced feeding latency in alcohol-dependent, stressed mice. Collectively, these validation studies provide central nervous system links into the covariance of stress, negative affective behaviors, and AUD in the BXD strains. Further, the bioinformatics discovery tool is effective in identifying promising targets (i.e., KCa2 channels) for treating alcohol dependence exacerbated by comorbid mood disorders.

scholarly journals Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking

2016 ◽  
Vol 10 ◽  
Author(s):  
Kelly Lei ◽  
Scott A. Wegner ◽  
Ji Hwan Yu ◽  
Arisa Mototake ◽  
Bing Hu ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Drinking ◽  
Nucleus Accumbens Shell ◽  
Excessive Alcohol

scholarly journals Differential importance of nucleus accumbens Ox1Rs and AMPARs for female and male mouse binge alcohol drinking

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claudina Kwok ◽  
Kelly Lei ◽  
Vincent Pedrozo ◽  
Lexy Anderson ◽  
Shahbaj Ghotra ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Binge Drinking ◽  
Ampa Receptors ◽  
Alcohol Drinking ◽  
Alcohol Intake ◽  
Problem Drinking ◽  
Therapeutic Interventions ◽  
Nucleus Accumbens Shell ◽  
Saccharin Intake ◽  
New Information

AbstractAlcohol use disorder exhausts substantial social and economic costs, with recent dramatic increases in female problem drinking. Thus, it is critically important to understand signaling differences underlying alcohol consumption across the sexes. Orexin-1 receptors (Ox1Rs) can strongly promote motivated behavior, and we previously identified Ox1Rs within nucleus accumbens shell (shell) as crucial for driving binge intake in higher-drinking male mice. Here, shell Ox1R inhibition did not alter female mouse alcohol drinking, unlike in males. Also, lower dose systemic Ox1R inhibition reduced compulsion-like alcohol intake in both sexes, indicating that female Ox1Rs can drive some aspects of pathological consumption, and higher doses of systemic Ox1R inhibition (which might have more off-target effects) reduced binge drinking in both sexes. In contrast to shell Ox1Rs, inhibiting shell calcium-permeable AMPA receptors (CP-AMPARs) strongly reduced alcohol drinking in both sexes, which was specific to alcohol since this did not reduce saccharin intake in either sex. Our results together suggest that the shell critically regulates binge drinking in both sexes, with shell CP-AMPARs supporting intake in both sexes, while shell Ox1Rs drove drinking only in males. Our findings provide important new information about sex-specific and -general mechanisms that promote binge alcohol intake and possible targeted therapeutic interventions.

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

2019 ◽  
Author(s):  
Daniel W. Bloodgood ◽  
Dipanwita Pati ◽  
Melanie M. Pina ◽  
Sofia Neira ◽  
J. Andrew Hardaway ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Alcohol Drinking ◽  
Alcohol Intake ◽  
Gene Knockout ◽  
Kappa Opioid Receptor ◽  
Conditional Knockout ◽  
Central Nucleus ◽  
Kappa Opioid ◽  
Excessive Alcohol Consumption ◽  
Excessive Alcohol

AbstractExcessive 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.

scholarly journals Toll-like receptor 3 activation increases voluntary alcohol intake in C57BL/6J male mice

2018 ◽  
Author(s):  
Anna S. Warden ◽  
Moatasem M. Azzam ◽  
Adriana DaCosta ◽  
Sonia Mason ◽  
Yuri A. Blednov ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Drinking ◽  
Alcohol Intake ◽  
Drinking Behavior ◽  
Ethanol Exposure ◽  
Innate Immune ◽  
Poly I:C ◽  
List Type ◽  
Toll Like Receptor ◽  
Excessive Alcohol

AbstractMany genes differentially expressed in brain tissue from human alcoholics and animals that have consumed large amounts of alcohol are components of the innate immune toll-like receptor (TLR) pathway. TLRs initiate inflammatory responses via two branches: (1) MyD88-dependent or (2) TRIF-dependent. All TLRs signal through MyD88 except TLR3. Prior work demonstrated a direct role for MyD88-dependent signaling in regulation of alcohol consumption. However, the role of TLR3 as a potential regulator of excessive alcohol drinking has not previously been investigated. To test the possibility TLR3 activation regulates alcohol consumption, we injected mice with the TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)) and tested alcohol consumption in an every-other-day two-bottle choice test. Poly(I:C) produced a persistent increase in alcohol intake that developed over several days. Repeated poly(I:C) and ethanol exposure altered innate immune transcript abundance; increased levels of TRIF-dependent pathway components correlated with increased alcohol consumption. Administration of poly(I:C) before exposure to alcohol did not alter alcohol intake, suggesting that poly(I:C) and ethanol must be present together to change drinking behavior. To determine which branch of TLR signaling mediates poly(I:C)-induced changes in drinking behavior, we tested either mice lacking MyD88 or mice administered a TLR3/dsRNA complex inhibitor. MyD88 null mutants showed poly(I:C)-induced increases in alcohol intake. In contrast, mice pretreated with a TLR3/dsRNA complex inhibitor reduced their alcohol intake, suggesting poly(I:C)-induced escalations in alcohol intake function are, at least partially, dependent on TLR3. Together, these results strongly suggest that TLR3-dependent signaling drives excessive alcohol drinking behavior.HighlightsActivation of TLR3 via poly(I:C) increased alcohol intake.Poly(I:C) and ethanol must be present together to change drinking behavior.Increased alcohol intake due to poly(I:C) is independent of MYD88.Increased alcohol intake due to poly(I:C) is dependent on TLR3.

scholarly journals The Loss of Metabolic Control on Alcohol Drinking in Heavy Drinking Alcohol-Dependent Subjects

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e38682 ◽  
Author(s):  
Philippe de Timary ◽  
Patrice D. Cani ◽  
Julie Duchemin ◽  
Audrey M. Neyrinck ◽  
Dominique Gihousse ◽  
...  
Keyword(s):  
Metabolic Control ◽  
Alcohol Drinking ◽  
Heavy Drinking ◽  
Drinking Alcohol ◽  
Alcohol Dependent

scholarly journals AKT Signaling Pathway in the Nucleus Accumbens Mediates Excessive Alcohol Drinking Behaviors

2011 ◽  
Vol 70 (6) ◽  
pp. 575-582 ◽  
Author(s):  
Jérémie Neasta ◽  
Sami Ben Hamida ◽  
Quinn V. Yowell ◽  
Sebastien Carnicella ◽  
Dorit Ron
Keyword(s):  
Nucleus Accumbens ◽  
Signaling Pathway ◽  
Alcohol Drinking ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Excessive Alcohol ◽  
Drinking Behaviors

scholarly journals Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Margaret A. Minnig ◽  
Tayun Park ◽  
Maria Echeveste Sanchez ◽  
Pietro Cottone ◽  
Valentina Sabino
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Drinking ◽  
Fixed Ratio ◽  
Loss Of Function ◽  
Nucleus Accumbens Shell ◽  
Self Administration ◽  
Pac1 Receptor ◽  
Excessive Alcohol Consumption ◽  
Excessive Alcohol ◽  
Shrna Knockdown

Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.

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