Correction: Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption.
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ABSTRACT:
SUBMITTER: Smith ML
PROVIDER: S-EPMC6581262 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
Correction: Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption.
Smith Maren L ML Lopez Marcelo F MF Archer Kellie J KJ Wolen Aaron R AR Becker Howard C HC Miles Michael F MF
PloS one 20190618 6
[This corrects the article DOI: 10.1371/journal.pone.0146257.]. ...[more]
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Project description:Adolescent alcohol use may interfere with neurodevelopment, increasing the likelihood of adult alcohol use disorders (AUDs). We investigated whether adolescent intermittent ethanol (AIE) exposure alters the adult reward response to ethanol. Adolescent rats were administered ethanol once (moderate exposure; Cohort 1) or three times per day (severe exposure; Cohort 2) in a 2 days on/2 days off pattern. In adulthood, subjects responded for electrical stimulation directed at the posterior lateral hypothalamus in a discrete-trial intracranial self-stimulation (ICSS) procedure that provides current-intensity thresholds as a measure of brain reward function. The effects of ethanol administration and withdrawal were assessed. Control rats showed dose-dependent threshold elevations after acute ethanol, indicating reward deficits. A majority of moderately AIE-exposed rats (Cohort 1) showed threshold lowering after ethanol, suggesting ethanol-induced reward enhancement in this sub-set of rats. Rats exposed to severe AIE (Cohort 2) showed no threshold elevation or lowering, suggesting a blunted affective ethanol response. Daily ethanol induced threshold elevations 24h after administration in control rats but not in either group of AIE-exposed rats, suggesting decreased sensitivity to the negative affective state of ethanol withdrawal. Withdrawal from a 4-day ethanol binge produced robust and enduring threshold elevations in all rats, although threshold elevations were diminished in rats exposed to severe AIE. These results indicate that AIE exposure diminished reward deficits associated with ethanol intoxication and withdrawal and may have increased ethanol-induced reward enhancement in a sub-set of rats. In humans, enhanced ethanol reward accompanied by reduced withdrawal severity may contribute to the development of AUDs.
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Project description:BackgroundAlcohol is among the most commonly abused drugs worldwide. Cessation of chronic alcohol consumption can result in the appearance of withdrawal symptoms that commonly promote relapse in individuals with alcohol use disorder (AUD). Thus, preclinical models of voluntary alcohol consumption, in which animals manifest spontaneous signs of withdrawal after alcohol cessation, can be useful for studying AUD and its treatment. The intermittent two-bottle choice paradigm (I2BC) has been used extensively to examine alcohol intake in rodents. However, previous studies have reported conflicting observations regarding its potential to result in the spontaneous manifestation of withdrawal upon alcohol cessation.MethodsWe employed a battery of behavioral tests to examine the emergence of affective and physical signs of withdrawal in female and male mice exposed to alcohol in the I2BC for 10 weeks. Specifically, mice of both sexes undergoing 24-h withdrawal from the I2BC were tested for physical signs of withdrawal, anxiety-like behavior in the open field arena (OFA) and elevated plus maze (EPM), and anxiety/compulsive-like behavior in the marble burying test (MBT). The main outcomes from these tests were combined into a behavioral severity score to describe the overall behavioral phenotype.ResultsBoth female and male mice undergoing withdrawal from the I2BC displayed elevated physical signs of withdrawal and anxiety-associated behavior in the EPM and MBT. Analysis of the overall behavioral severity score revealed more severe phenotypes in female and male mice undergoing withdrawal from the I2BC than controls. Additionally, stratification of the mice based on severity scores demonstrated a differential distribution of severities between the exposure groups.ConclusionsWe confirmed that a significant fraction of mice chronically exposed to alcohol in the I2BC display spontaneous withdrawal. In addition, we showed that computing a severity score from a combination of behavioral metrics can be useful in preclinical research to model evaluation tools used in patients with AUD.
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Project description:BackgroundPrkcz has been identified as a gene whose expression is positively correlated with ethanol (EtOH) consumption in mice and is also induced by EtOH. Two proteins are produced from Prkcz: protein kinase M zeta (PKMζ), which is expressed in the nervous system and protein kinase C zeta (PKCζ), which is expressed in other tissues. We examined Prkcz(-/-) mice that lack PKCζ and PKMζ to investigate the role of this gene in behavioral responses to EtOH.MethodsMale Prkcz(-/-) and wild-type littermates were tested for EtOH consumption using 4 procedures: 24-hour intermittent access, 4-hour limited intermittent access, 4-day drinking-in-the-dark, and 24-hour continuous access. We also assessed the acute hypnotic effect of EtOH, EtOH reward, and taste preference for sweet-, bitter-, salty-, and umami-flavored solutions. Finally, we determined whether EtOH could increase PKMζ and PKCζ transcripts and protein expression in wild-type mice using quantitative PCR and Western blot analysis.ResultsPrkcz(-/-) mice consumed more EtOH than their wild-type littermates in both intermittent access procedures, but not in the drinking-in-the-dark or 24-hour continuous access procedures. EtOH exposure increased Prkcz transcripts in cultured PC12 cells, and intermittent EtOH consumption increased PKMζ protein in the ventral striatum of wild-type mice.ConclusionsAbsence of PKMζ in the brain is associated with increased EtOH intake during procedures that incorporate intermittent consumption sessions every other day. Our data suggest that EtOH induces PKMζ, which acts in a negative feedback loop to limit binge-like EtOH consumption.
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