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 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 Alcohol dependence potentiates substance P/neurokinin-1 receptor signaling in the rat central nucleus of amygdala

2020 ◽  
Vol 6 (12) ◽  
pp. eaaz1050
Author(s):  
S. Khom ◽  
T. Steinkellner ◽  
T. S. Hnasko ◽  
M. Roberto
Keyword(s):  
Substance P ◽  
Alcohol Dependence ◽  
Critical Role ◽  
Alcohol Exposure ◽  
Gaba Release ◽  
Central Nucleus ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1 ◽  
Gaba Transmission ◽  
Alcohol Dependent

Behavioral and clinical studies suggest a critical role of substance P (SP)/neurokinin-1 receptor (NK-1R) signaling in alcohol dependence. Here, we examined regulation of GABA transmission in the medial subdivision of the central amygdala (CeM) by the SP/NK-1R system, and its neuroadaptation following chronic alcohol exposure. In naïve rats, SP increased action potential–dependent GABA release, and the selective NK-1R antagonist L822429 decreased it, demonstrating SP regulation of CeM activity under basal conditions. SP induced a larger GABA release in alcohol-dependent rats accompanied by decreased NK-1R expression compared to naïve controls, suggesting NK-1R hypersensitivity which persisted during protracted alcohol withdrawal. The NK-1R antagonist blocked acute alcohol-induced GABA release in alcohol-dependent and withdrawn but not in naïve rats, indicating that dependence engages the SP/NK-1R system to mediate acute effects of alcohol. Collectively, we report long-lasting CeA NK-1R hypersensitivity corroborating that NK-1Rs are promising targets for the treatment of alcohol use disorder.

The Role of Brief Motivational Intervention on Self-Efficacy and Abstinence in a Cohort of Patients with Alcohol Dependence

2009 ◽  
Vol 39 (3) ◽  
pp. 313-323 ◽  
Author(s):  
Lucia Romo ◽  
Yann Le Strat ◽  
Caroline Aubry ◽  
Sonia Marquez ◽  
Karine Houdeyer ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Self Efficacy ◽  
Controlled Trial ◽  
Heavy Drinking ◽  
Motivational Intervention ◽  
Prognosis Factor ◽  
Brief Motivational Intervention ◽  
Motivational Interventions ◽  
Alcohol Dependent

Objectives: Brief interventions are effective in reducing heavy drinking in the general population but few studies examined whether it is also effective in alcohol dependent patients, and whether brief intervention increases self-efficacy. Method: One hundred and seven patients with alcohol-dependence were randomized in a controlled trial examining the efficacy of a brief motivational intervention on both self-efficacy level and days of abstinence. Results: We found that brief motivational interventions had no effect on days of abstinence, nor on self-efficacy, but that high self-efficacy was consistently correlated with a longer period of abstinence, at all assessment-points. Conclusion: Self-efficacy appears to be a crucial prognosis factor, and is not influenced by brief motivational interventions. Other types of specific psychotherapy, probably more intensive, may be more efficient in alcohol-dependent patients than motivational interventions.

scholarly journals Central amygdala CRF pathways in alcohol dependence

2017 ◽  
Author(s):  
Giordano de Guglielmo ◽  
Marsida Kallupi ◽  
Matthew B. Pomrenze ◽  
Elena Crawford ◽  
Sierra Simpson ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Optical Fibers ◽  
Alcohol Drinking ◽  
Ethanol Vapor ◽  
Central Nucleus ◽  
Self Administration ◽  
Neuronal Ensemble ◽  
Excessive Alcohol ◽  
Crf Neurons

AbstractAlcohol withdrawal activates a neuronal ensemble in the central nucleus of the amygdala (CeA) that is responsible for high levels of uncontrolled alcohol drinking. However, the neuronal phenotypes and circuits controlled by these neurons are unknown. We investigated the cellular identity of this CeA neuronal ensemble and found that most neurons expressed corticotropin-releasing factor (CRF). Using Crh-Cre transgenic rats combined with in vivo optogenetics, we tested the role of CeA CRF neurons and their projections in excessive alcohol self-administration during withdrawal. Rats were injected with AAV-DIO-NpHR-eYFP or AAV-DIO-eYFP and implanted with optical fibers over the CeA. Animals were then exposed to chronic intermittent ethanol vapor to induce alcohol dependence. Inactivation of CeA CRF neurons decreased alcohol drinking in dependent rats to non-dependent levels and completely suppressed activation of the CeA neuronal ensemble (Fos+ neurons) during withdrawal. No effects were observed on water or saccharin self-administration. In a second experiment, CeA CRF neurons were infected with AAV-DIO-NpHR-eYFP and optical fibers were implanted into downstream projection regions, including the bed nucleus of the stria terminalis (BNST), lateral hypothalamus (LH), parasubthalamic nucleus (pSTN), substantia innominata (SI), and parabrachial nuclei (PBN). Optogenetic inactivation of CRF terminals in the BNST reduced alcohol drinking and withdrawal signs, whereas inactivation of all other projections had no effect. These results demonstrate that CeA CRF neurons and their projections to the BNST drive excessive alcohol drinking and withdrawal in dependent rats.

scholarly journals Recovery of Hippocampal-Dependent Learning Despite Blunting Reactive Adult Neurogenesis After Alcohol Dependence

2020 ◽  
Vol 6 (1) ◽  
pp. 83-101 ◽  
Author(s):  
Chelsea G. Nickell ◽  
K. Ryan Thompson ◽  
James R. Pauly ◽  
Kimberly Nixon
Keyword(s):  
Alcohol Dependence ◽  
Adult Neurogenesis ◽  
Alcohol Exposure ◽  
Cell Number ◽  
Male Rats ◽  
Proliferating Cells ◽  
Excessive Alcohol ◽  
Reactive Proliferation ◽  
Dependent Learning

Background: The excessive alcohol drinking that occurs in alcohol use disorder (AUD) causes neurodegeneration in regions such as the hippocampus, though recovery may occur after a period of abstinence. Mechanisms of recovery are not clear, though reactive neurogenesis has been observed in the hippocampal dentate gyrus following alcohol dependence and correlates to recovery of granule cell number. Objective: We investigated the role of neurons born during reactive neurogenesis in the recovery of hippocampal learning behavior after 4-day binge alcohol exposure, a model of an AUD. We hypothesized that reducing reactive neurogenesis would impair functional recovery. Methods: Adult male rats were subjected to 4-day binge alcohol exposure and two approaches were tested to blunt reactive adult neurogenesis, acute doses of alcohol or the chemotherapy drug, temozolomide (TMZ). Results: Acute 5 g/kg doses of EtOH gavaged T6 and T7 days post binge did not inhibit significantly the number of Bromodeoxyuridine-positive (BrdU+) proliferating cells in EtOH animals receiving 5 g/kg EtOH versus controls. A single cycle of TMZ inhibited reactive proliferation (BrdU+ cells) and neurogenesis (NeuroD+ cells) to that of controls. However, despite this blunting of reactive neurogenesis to basal levels, EtOH-TMZ rats were not impaired in their recovery of acquisition of the Morris water maze (MWM), learning similarly to all other groups 35 days after 4-day binge exposure. Conclusions: These studies show that TMZ is effective in decreasing reactive proliferation/neurogenesis following 4-day binge EtOH exposure, and baseline levels of adult neurogenesis are sufficient to allow recovery of hippocampal function.

Sex Differences in Acute Alcohol Sensitivity of Naïve and Alcohol Dependent Central Amygdala GABA Synapses

2021 ◽  
Author(s):  
Dean Kirson ◽  
Sophia Khom ◽  
Larry Rodriguez ◽  
Sarah A Wolfe ◽  
Florence P Varodayan ◽  
...  
Keyword(s):  
Sex Differences ◽  
Alcohol Use ◽  
Animal Models ◽  
Alcohol Dependence ◽  
Heavy Drinking ◽  
Gamma Aminobutyric Acid ◽  
Central Amygdala ◽  
Alcohol Sensitivity ◽  
Whole Cell Patch Clamp ◽  
Alcohol Dependent

Abstract Aims Alcohol use disorder (AUD) is linked to hyperactivity of brain stress systems, leading to withdrawal states which drive relapse. AUD differs among the sexes, as men are more likely to have AUD than women, but women progress from casual use to binge and heavy alcohol use more quickly and are more likely to relapse into repetitive episodes of heavy drinking. In alcohol dependence animal models of AUD, the central amygdala (CeA) functions as a hub of stress and anxiety processing and gamma-Aminobutyric acid (GABA)ergic signaling within the CeA is involved in dependence-induced increases in alcohol consumption. We have shown dysregulation of CeA GABAergic synaptic signaling in alcohol dependence animal models, but previous studies have exclusively used males. Methods Here, we used whole-cell patch clamp electrophysiology to examine basal CeA GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) and the effects of acute alcohol in both naïve and alcohol dependent rats of both sexes. Results We found that sIPSC kinetics differ between females and males, as well as between naïve and alcohol-dependent animals, with naïve females having the fastest current kinetics. Additionally, we find differences in baseline current kinetics across estrous cycle stages. In contrast to the increase in sIPSC frequency routinely found in males, acute alcohol (11–88 mM) had no effect on sIPSCs in naïve females, however the highest concentration of alcohol increased sIPSC frequency in dependent females. Conclusion These results provide important insight into sex differences in CeA neuronal function and dysregulation with alcohol dependence and highlight the need for sex-specific considerations in the development of effective AUD treatment.

scholarly journals Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daria Piacentino ◽  
Silvia Grant-Beurmann ◽  
Carlotta Vizioli ◽  
Xiaobai Li ◽  
Catherine F. Moore ◽  
...  
Keyword(s):  
Amino Acids ◽  
Alcohol Use ◽  
Alcohol Drinking ◽  
Gut Microbiome ◽  
Alcohol Exposure ◽  
Primate Model ◽  
Fecal Microbiome ◽  
Excessive Alcohol ◽  
Human Primate

AbstractA relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p’s < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p’s < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.

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

A case-comparison study of executive functions in alcohol-dependent adults with maternal history of alcoholism

2009 ◽  
Vol 24 (3) ◽  
pp. 195-200 ◽  
Author(s):  
Olivier Cottencin ◽  
Jean-Louis Nandrino ◽  
Laurent Karila ◽  
Caroline Mezerette ◽  
Thierry Danel
Keyword(s):  
Executive Functions ◽  
Alcohol Dependence ◽  
Cognitive Disorders ◽  
Alcohol Exposure ◽  
Executive Dysfunction ◽  
Comparison Study ◽  
Maternal History ◽  
Case Comparison ◽  
History Of ◽  
Alcohol Dependent

AbstractIntroductionAs executive dysfunctions frequently accompany alcohol dependence, we suggest that reports of executive dysfunction in alcoholics are actually due, in some case to a maternal history of alcohol misuse (MHA+). A history of maternal alcohol dependence increases the risk for prenatal alcohol exposure to unborn children. These exposures likely contribute to executive dysfunction in adult alcoholics. To assess this problem, we propose a case-comparison study of alcohol-dependent subjects with and without a MHA.MethodsTen alcohol-dependent subjects, with a maternal history of alcoholism (MHA) and paternal history of alcoholism (PHA), were matched with 10 alcohol-dependent people with only a paternal history of alcoholism (PHA). Executive functions (cancellation, Stroop, and trail-making A and B tests) and the presence of a history of three mental disorders (attention deficit hyperactivity disorder, violent behavior while intoxicated, and suicidal behavior) were evaluated in both populations.ResultsAlcohol-dependent subjects with MHA showed a significant alteration in executive functions and significantly more disorders related to these functions than PHA subjects. The major measures of executive functioning deficit are duration on task accomplishment in all tests. Rates of ADHD and suicidality were found to be higher in MHA patients compared to the controls.ConclusionA history of MHA, because of the high risk of PAE (in spite of the potential confounding factors such as environment) must be scrupulously documented when evaluating mental and cognitive disorders in a general population of alcoholics to ensure a better identification of these disorders. It would be helpful to replicate the study with more subjects.

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