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Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Systems Neuroscience".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 34906

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Special Issue Editor

Dr. Candice Contet

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Guest Editor

Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA
Interests: alcohol; dependence; self-administration; stress; negative affect; neuropeptides; ion channels; microtubules; parasubthalamic nucleus; mouse models

Special Issue Information

Dear Colleagues,

Alcoholic beverages are commonly consumed for the positively reinforcing properties of their molecular constituent, ethanol. At different doses, ethanol can produce a variety of behavioral effects, ranging from euphoria to anxiolysis, appetite stimulation, cognitive and motor alterations, aggression, sedation, and coma. Pathological patterns of alcohol consumption can alter the initial response to ethanol, and additional behavioral changes emerge during acute withdrawal and protracted abstinence from alcohol (e.g., seizures, craving, negative affect). Alcohol exposure during adolescence, gestation, and gametogenesis can also have a long-term impact on behaviors later in life and across generations, as a result of developmental and epigenetic effects. Identifying the stuctural and functional changes in specific brain regions, cell populations, or neural circuits which causally contribute to the behavioral phenotypes associated with ethanol exposure and withdrawal is essential to our understanding of the neurobiological mechanisms underlying alcohol’s action. It also represents a critical endeavor for the development of rational approaches to leverage the desirable properties of ethanol and to alleviate the burden associated with the detrimental consequences of excessive alcohol consumpion.

Original research articles advancing our understanding of the “Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Ethanol” are solicited for this Special Issue. Reviews providing an analytical perspective on the existing literature are also welcome.

Dr. Candice Contet
Guest Editor

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Keywords

intoxication
binge drinking
dependence
addiction
relapse
alcohol use disorders
genes
proteins
signaling pathways
medication development

Published Papers (10 papers)

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Research

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16 pages, 2171 KiB

Open AccessArticle

Alcohol Dependence in Rats Is Associated with Global Changes in Gene Expression in the Central Amygdala

by Brent R. Kisby, Sean P. Farris, Michelle M. McManus, Florence P. Varodayan, Marisa Roberto, R. Adron Harris and Igor Ponomarev

Brain Sci. 2021, 11(9), 1149; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11091149 - 29 Aug 2021

Cited by 6 | Viewed by 3326

Abstract

Alcohol dependence is associated with adverse consequences of alcohol (ethanol) use and is evident in most severe cases of alcohol use disorder (AUD). The central nucleus of the amygdala (CeA) plays a critical role in the development of alcohol dependence and escalation of alcohol consumption in dependent subjects. Molecular mechanisms underlying the CeA-driven behavioral changes are not well understood. Here, we examined the effects of alcohol on global gene expression in the CeA using a chronic intermittent ethanol (CIE) vapor model in rats and RNA sequencing (RNA-Seq). The CIE procedure resulted in robust changes in CeA gene expression during intoxication, as the number of differentially expressed genes (DEGs) was significantly greater than those expected by chance. Over-representation analysis of cell types, functional groups and molecular pathways revealed biological categories potentially important for the development of alcohol dependence in our model. Genes specific for astrocytes, myelinating oligodendrocytes, and endothelial cells were over-represented in the DEG category, suggesting that these cell types were particularly affected by the CIE procedure. The majority of the over-represented functional groups and molecular pathways were directly related to the functions of glial and endothelial cells, including extracellular matrix (ECM) organization, myelination, and the regulation of innate immune response. A coordinated regulation of several ECM metalloproteinases (e.g., Mmp2; Mmp14), their substrates (e.g., multiple collagen genes and myelin basic protein; Mbp), and a metalloproteinase inhibitor, Reck, suggests a specific mechanism for ECM re-organization in response to chronic alcohol, which may modulate neuronal activity and result in behavioral changes, such as an escalation of alcohol drinking. Our results highlight the importance of glial and endothelial cells in the effects of chronic alcohol exposure on the CeA, and demonstrate further insight into the molecular mechanisms of alcohol dependence in rats. These molecular targets may be used in future studies to develop therapeutics to treat AUD. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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13 pages, 1181 KiB

Open AccessArticle

Constitutive Genetic Deletion of Hcn1 Increases Alcohol Preference during Adolescence

by Michael C. Salling and Neil L. Harrison

Brain Sci. 2020, 10(11), 763; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10110763 - 22 Oct 2020

Cited by 4 | Viewed by 1760

Abstract

The hyperpolarization-activated cyclic nucleotide-gated channel (HCN), which underlies the hyperpolarization-activated cation current (I_h), has diverse roles in regulating neuronal excitability across cell types and brain regions. Recently, HCN channels have been implicated in preclinical models of substance abuse including alcohol. In the prefrontal cortex of rodents, HCN expression and I_h magnitude are developmentally regulated during adolescence and may be vulnerable to alcohol’s effects. In mice, binge alcohol consumption during the adolescent period results in a sustained reduction in I_h that coincides with increased alcohol consumption in adulthood, yet the direct role HCN channels have on alcohol consumption are unknown. Here, we show that the genetic deletion of Hcn1 causes an increase in alcohol preference on intermittent 2-bottle choice task in homozygous null (HCN1^−/−) male mice compared to wild-type littermates without affecting saccharine or quinine preference. The targeted viral deletion of HCN1 in pyramidal neurons of the medial prefrontal cortex resulted in a gradual loss of Hcn1 expression and a reduction in I_h magnitude during adolescence, however, this did not significantly affect alcohol consumption or preference. We conclude that while HCN1 regulates alcohol preference, the genetic deletion of Hcn1 in the medial prefrontal cortex does not appear to be the locus for this effect. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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16 pages, 2417 KiB

Open AccessArticle

Adolescent Intermittent Ethanol Exposure Effects on Kappa Opioid Receptor Mediated Dopamine Transmission: Sex and Age of Exposure Matter

by Mary B. Spodnick, Raymond T. Amirault, Trevor T. Towner, Elena I. Varlinskaya, Linda P. Spear and Anushree N. Karkhanis

Brain Sci. 2020, 10(8), 472; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10080472 - 23 Jul 2020

Cited by 9 | Viewed by 2940

Abstract

Underage alcohol drinking increases the risk of developing alcohol use disorder (AUD). In rodents, adolescent ethanol exposure augments ethanol consumption and anxiety-like behavior while reducing social interaction. However, the underlying mechanisms driving these adaptations are unclear. The dopamine and kappa opioid receptor (KOR) systems in the nucleus accumbens (NAc) are implicated in affective disorders, including AUD, with studies showing augmented KOR function and reduced dopamine transmission in ethanol-dependent adult animals. Thus, here we examine the impact of adolescent intermittent ethanol (AIE) exposure on dopamine transmission and KOR function in the NAc. Rats were exposed to water or ethanol (4 g/kg, intragastrically) every other day during early (postnatal day (PD) 25–45) or late (PD 45–65) adolescence. While AIE exposure during early adolescence (early-AIE) did not alter dopamine release in male and female rats, AIE exposure during late adolescence (late-AIE) resulted in greater dopamine release in males and lower dopamine release in females. To determine the impact of AIE on KOR function, we measured the effect of KOR activation using U50,488 (0.01–1.00 µM) on dopamine release. Early-AIE exposure potentiated KOR-mediated inhibition of dopamine release in females, while late-AIE exposure attenuated this effect in males. Interestingly, no differences in KOR function were observed in early-AIE exposed males and late-AIE exposed females. Together, these data suggest that AIE exposure impact on neural processes is dependent on sex and exposure timing. These differences likely arise from differential developmental timing in males and females. This is the first study to show changes in KOR function following AIE exposure. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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27 pages, 3846 KiB

Open AccessArticle

Incubation of Negative Affect during Protracted Alcohol Withdrawal Is Age-, but Not Sex-Selective

by C. Leonardo Jimenez Chavez, Michal A. Coelho, Lindsey W. Brewin, Isaiah Swauncy, Tori Tran, Taylor Albanese, Angie Laguna, Ivette Gabriela and Karen K. Szumlinski

Brain Sci. 2020, 10(6), 405; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10060405 - 26 Jun 2020

Cited by 12 | Viewed by 2690

Abstract

A prior history of excessive drinking induces a negative affective state in both humans and laboratory rodents, the manifestation of which varies with the age of drinking-onset. In adolescent male mice, negative affect incubates over the course of a 30-day alcohol withdrawal period. In contrast, the negative affect exhibited by adult male mice is robust at 1 day withdrawal, but dissipates with the passage of time. As females tend to consume more alcohol than males, we aimed to explore the affective disturbances exhibited by adolescent and adult C57BL/6J mice of both sexes during more protracted alcohol withdrawal and to relate any behavioral changes observed to plasma corticosterone levels as a biochemical index of stress. Male and female, adolescent and adult, mice were subjected to 14 consecutive days of binge alcohol-drinking using a multi-bottle-choice Drinking-in-the-Dark (DID) procedure (5, 10, 20 and 40% v/v). Age- and sex-matched control mice consumed water only. On either withdrawal day 1 or 70, subgroups of animals were subjected a to 1-day behavioral test battery that included the light–dark box shuttle test, marble-burying test, and Porsolt forced swim test. As expected, adolescent mice consumed more alcohol than adults and females consumed more alcohol than males. However, despite binge-like levels of alcohol consumption, we detected relatively few signs of alcohol withdrawal-induced negative affect and there was no correlation between affective behavior and circulating corticosterone levels. We discuss these findings within the context of our published work, highlighting procedural differences that might account for the relatively weak effect of binge-drinking history upon anxiety and depressive-like behavior observed herein. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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22 pages, 3233 KiB

Open AccessArticle

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

by Dar’ya Y. Pozhidayeva, Sean P. Farris, Calla M. Goeke, Evan J. Firsick, Kayla G. Townsley, Marina Guizzetti and Angela R. Ozburn

Brain Sci. 2020, 10(2), 109; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10020109 - 18 Feb 2020

Cited by 24 | Viewed by 3803

Abstract

Binge drinking is a dangerous pattern of behavior. We tested whether chronically manipulating nucleus accumbens (NAc) activity (via clozapine-N-oxide (CNO) and Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) could produce lasting effects on ethanol binge-like drinking in mice selectively bred to drink to intoxication. We found chronically increasing NAc activity (4 weeks, via CNO and the excitatory DREADD, hM3Dq) decreased binge-like drinking, but did not observe CNO-induced changes in drinking with the inhibitory DREADD, hM4Di. The CNO/hM3Dq-induced reduction in ethanol drinking persisted for at least one week, suggesting adaptive neuroplasticity via transcriptional and epigenetic mechanisms. Therefore, we defined this plasticity at the morphological and transcriptomic levels. We found that chronic binge drinking (6 weeks) altered neuronal morphology in the NAc, an effect that was ameliorated with CNO/hM3Dq. Moreover, we detected significant changes in expression of several plasticity-related genes with binge drinking that were ameliorated with CNO treatment (e.g., Hdac4). Lastly, we found that LMK235, an HDAC4/5 inhibitor, reduced binge-like drinking. Thus, we were able to target specific molecular pathways using pharmacology to mimic the behavioral effects of DREADDs. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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13 pages, 1238 KiB

Open AccessArticle

Individual Differences in Ethanol Drinking and Seeking Behaviors in Rats Exposed to Chronic Intermittent Ethanol Vapor Exposure is Associated with Altered CaMKII Autophosphorylation in the Nucleus Accumbens Shell

by Sucharita S. Somkuwar and Chitra D. Mandyam

Brain Sci. 2019, 9(12), 367; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci9120367 - 11 Dec 2019

Cited by 3 | Viewed by 2935

Abstract

Chronic intermittent ethanol vapor exposure (CIE) in rodents produces reliable and high blood ethanol concentration and behavioral symptoms associated with moderate to severe alcohol use disorder (AUD)—for example, escalation of operant ethanol self-administration, a feature suggestive of transition from recreational to addictive use, is a widely replicated behavior in rats that experience CIE. Herein, we present evidence from a subset of rats that do not demonstrate escalation of ethanol self-administration following seven weeks of CIE. These low responders (LR) maintain low ethanol self-administration during CIE, demonstrate lower relapse to drinking during abstinence and reduced reinstatement of ethanol seeking triggered by ethanol cues when compared with high responders (HR). We examined the blood ethanol levels in LR and HR rats during CIE and show higher levels in LR compared with HR. We also examined peak corticosterone levels during CIE and show that LR rats have higher levels compared with HR rats. Lastly, we evaluated the levels of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) in the nucleus accumbens shell and reveal that the activity of CaMKII, which is autophosphorylated at site Tyr-286, is significantly reduced in HR rats compared with LR rats. These findings demonstrate that dysregulation of the hypothalamic–pituitary–adrenal axis activity and plasticity-related proteins regulating molecular memory in the nucleus accumbens shell are associated with higher ethanol-drinking and -seeking in HR rats. Future mechanistic studies should evaluate CaMKII autophosphorylation-dependent remodeling of glutamatergic synapses in the ventral striatum as a plausible mechanism for the CIE-induced enhanced ethanol drinking and seeking behaviors. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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13 pages, 1331 KiB

Open AccessArticle

Corticotropin Releasing Factor Type 1 and 2 Receptor Signaling in the Medial Prefrontal Cortex Modulates Binge-Like Ethanol Consumption in C57BL/6J Mice

by Stacey L. Robinson, Carlos A. Perez-Heydrich and Todd E. Thiele

Brain Sci. 2019, 9(7), 171; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci9070171 - 19 Jul 2019

Cited by 11 | Viewed by 3777

Abstract

Corticotropin releasing factor (CRF) signaling via limbic CRF1 and 2 receptors (CRF1R and CRF2R, respectively) is known to modulate binge-like ethanol consumption in rodents. Though CRF signaling in the medial prefrontal cortex (mPFC) has been shown to modulate anxiety-like behavior and ethanol seeking, its role in binge ethanol intake is unknown. Here, we used “drinking-in-the-dark” (DID) procedures in male and female C57BL/6J mice to address this gap in the literature. First, the role of CRF1R and CRF2R signaling in the mPFC on ethanol consumption was evaluated through site-directed pharmacology. Next, we evaluated if CRF1R antagonist reduction of binge-intake was modulated in part through CRF2R activation by co-administration of a CRF1R and CRF2R antagonist. Intra-mPFC inhibition of CRF1R and activation of CRF2R resulted in decreased binge-like ethanol intake. Further, the inhibitory effect of the CRF1R antagonist was attenuated by co-administration of a CRF2R antagonist. We provide novel evidence that (1) inhibition of CRF1R or activation of CRF2R in the mPFC reduces binge-like ethanol intake; and (2) the effect of CRF1R antagonism may be mediated via enhanced CRF2R activation. These observations provide the first direct behavioral pharmacological evidence that CRF receptor activity in the mPFC modulates binge-like ethanol consumption. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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16 pages, 2371 KiB

Open AccessArticle

Sex Differences in the Effect of Alcohol Drinking on Myelinated Axons in the Anterior Cingulate Cortex of Adolescent Rats

by Elizabeth R. Tavares, Andrea Silva-Gotay, Wanette Vargas Riad, Lynn Bengston and Heather N. Richardson

Brain Sci. 2019, 9(7), 167; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci9070167 - 16 Jul 2019

Cited by 16 | Viewed by 5012

Abstract

Cognitive deficits associated with teenage drinking may be due to disrupted myelination of prefrontal circuits. To better understand how alcohol affects myelination, male and female Wistar rats (n = 7–9/sex/treatment) underwent two weeks of intermittent operant self-administration of sweetened alcohol or sweetened water early in adolescence (postnatal days 28–42) and we tested for macro- and microstructural changes to myelin. We previously reported data from the males of this study showing that alcohol drinking reduced myelinated fiber density in layers II–V of the anterior cingulate division of the medial prefrontal cortex (Cg1); herein, we show that myelinated fiber density was not significantly altered by alcohol in females. Alcohol drinking patterns were similar in both sexes, but males were in a pre-pubertal state for a larger proportion of the alcohol exposure period, which may have contributed to the differential effects on myelinated fiber density. To gain more insight into how alcohol impacts myelinated axons, brain sections from a subset of these animals (n = 6/sex/treatment) were used for microstructural analyses of the nodes of Ranvier. Confocal analysis of nodal domains, flanked by immunofluorescent-labeled contactin-associated protein (Caspr) clusters, indicated that alcohol drinking reduced nodal length-to-width ratios in layers II/III of the Cg1 in both sexes. Despite sex differences in the underlying cause (larger diameter axons after alcohol in males vs. shorter nodal lengths after alcohol in females), reduced nodal ratios could have important implications for the speed and integrity of neural transmission along these axons in both males and females. Alcohol-induced changes to myelinated axonal populations in the Cg1 may contribute to long-lasting changes in prefrontal function associated with early onset drinking. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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19 pages, 3844 KiB

Open AccessArticle

Paternal Preconception Every-Other-Day Ethanol Drinking Alters Behavior and Ethanol Consumption in Offspring

by Erik Beeler, Zachary L. Nobile and Gregg E. Homanics

Brain Sci. 2019, 9(3), 56; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci9030056 - 06 Mar 2019

Cited by 20 | Viewed by 4847

Abstract

Alcohol use disorder is a devastating disease with a complex etiology. Recent preclinical studies have revealed that paternal preconception chronic intermittent ethanol (EtOH) exposure via vaporized EtOH altered drinking behaviors and sensitivity to EtOH selectively in male offspring. In the current study, we used a voluntary oral route of paternal preconception EtOH exposure, i.e., intermittent every-other-day two-bottle choice drinking, and tested offspring for behavioral alterations. Fifteen EtOH drinking sires and 10 control sires were mated to EtOH naïve females to produce EtOH-sired and control-sired offspring. These offspring were tested using the elevated plus maze, open field, drinking in the dark, and unlimited access two-bottle choice assays. We found that paternal preconception every-other-day two-bottle choice drinking resulted in reduced EtOH consumption selectively in male offspring in the drinking in the dark assay compared to control-sired offspring. No differences were detected in either sex in the unlimited access two-bottle choice and elevated plus maze assays. Open field analysis revealed complex changes in basal behavior and EtOH-induced behaviors that were sex specific. We concluded that paternal preconception voluntary EtOH consumption has persistent effects that impact the next generation. This study adds to a growing appreciation that one’s behavioral response to EtOH and EtOH drinking behavior are impacted by EtOH exposure of the prior generation. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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Review

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21 pages, 1108 KiB

Open AccessReview

Leveraging Neural Networks in Preclinical Alcohol Research

by Lauren C. Smith and Adam Kimbrough

Brain Sci. 2020, 10(9), 578; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10090578 - 21 Aug 2020

Cited by 5 | Viewed by 3002

Abstract

Alcohol use disorder is a pervasive healthcare issue with significant socioeconomic consequences. There is a plethora of neural imaging techniques available at the clinical and preclinical level, including magnetic resonance imaging and three-dimensional (3D) tissue imaging techniques. Network-based approaches can be applied to imaging data to create neural networks that model the functional and structural connectivity of the brain. These networks can be used to changes to brain-wide neural signaling caused by brain states associated with alcohol use. Neural networks can be further used to identify key brain regions or neural “hubs” involved in alcohol drinking. Here, we briefly review the current imaging and neurocircuit manipulation methods. Then, we discuss clinical and preclinical studies using network-based approaches related to substance use disorders and alcohol drinking. Finally, we discuss how preclinical 3D imaging in combination with network approaches can be applied alone and in combination with other approaches to better understand alcohol drinking. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms Mediating the Behavioral Effects of Alcohol)

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