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Adolescent Alcohol Exposure Reduces Behavioral Flexibility, Promotes Disinhibition, and Increases Resistance to Extinction of Ethanol Self-Administration in Adulthood
Open accessAbstract
The prefrontal cortex (PFC) is a brain region that is critically involved in cognitive function and inhibitory control of behavior, and adolescence represents an important period of continued PFC development that parallels the maturation of these functions. Evidence suggests that this period of continued development of the PFC may render it especially vulnerable to environmental insults that impact PFC function in adulthood. Experimentation with alcohol typically begins during adolescence when binge-like consumption of large quantities is common. In the present study, we investigated the effects of repeated cycles of adolescent intermittent ethanol (AIE) exposure (postnatal days 28-42) by vapor inhalation on different aspects of executive functioning in the adult rat. In an operant set-shifting task, AIE-exposed rats exhibited deficits in their ability to shift their response strategy when the rules of the task changed, indicating reduced behavioral flexibility. There were no differences in progressive ratio response for the reinforcer suggesting that AIE did not alter reinforcer motivation. Examination of performance on the elevated plus maze under conditions designed to minimize stress revealed that AIE exposure enhanced the number of entries into the open arms, which may reflect either reduced anxiety and/or disinhibition of exploratory-like behavior. In rats that trained to self-administer ethanol in an operant paradigm, AIE increased resistance to extinction of ethanol-seeking behavior. This resistance to extinction was reversed by positive allosteric modulation of mGluR5 during extinction training, an effect that is thought to reflect promotion of extinction learning mechanisms within the medial PFC. Consistent with this, CDPPB was also observed to reverse the deficits in behavioral flexibility. Finally, diffusion tensor imaging with multivariate analysis of 32 brain areas revealed that while there were no differences in the total brain volume, the volume of a subgroup of regions (hippocampus, thalamus, dorsal striatum, neocortex, and hypothalamus) were significantly different in AIE-exposed adults compared with litter-matched Control rats. Taken together, these findings demonstrate that binge-like exposure to alcohol during early to middle adolescence results in deficits in PFC-mediated behavioral control in adulthood.
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“Similar adult deficits in behavioral flexibility, due to adolescent ethanol exposure, have also been observed using the Morris water maze (Coleman et al. 2011) and set shifting models (Gass et al. 2014).”
From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Gass et al. 2014
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“Moreover, binge-like alcohol exposure in adolescent rats reduces adult hippocampus, thalamus, dorsal striatum (STR), and cortex volumes compared to littermate controls (Gass et al., 2014; see Gulley and Juraska, 2013 for further review).”
From Sensitive periods of substance abuse: Early risk for the transition to dependence (2017) · cites this paper as Gass et al., 2014
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Metadata
- Authors
- Gass, J. T., Glen, W. B., McGonigal, J. T., Trantham-Davidson, H., Lopez, M. F., Randall, P. K., Yaxley, R., Floresco, S. B., & Chandler, L. J.
- Affiliations
- Medical University of South Carolina (US)
- University of North Carolina at Chapel Hill (US)
- University of British Columbia (CA)
- Corresponding author
- Gass, Justin T
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2014-05-13
- Volume
- 39
- Issue
- 11
- Pages
- 2570-2583
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4207336
- OpenAlex
- W2059163032
- Cited by
- 197
- References
- 65
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 14 · 2023: 19 · 2022: 19 · 2021: 22 · 2020: 23 · 2019: 18 · 2018: 15 · 2017: 22 · 2016: 15 · 2015: 4 · 2014: 1
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (5u54ca151652-05)
- Canadian Institutes of Health Research (MOP102478, 89861_1)
- National Institute on Alcohol Abuse and Alcoholism (U01AA019967, U01AA020023, K99AA020537, R01AA010983, R00AA020537, K01AA022475, F32AA021642, U24AA020024, U24AA020023, P50AA010761)
- National Cancer Institute (U54CA151652-01-04, U54‐CA151652, P30CA016086-35-37, P30CA016086)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- adolescent intermittent ethanol exposure, binge drinking, prefrontal cortex development, behavioral flexibility, set-shifting, disinhibition, ethanol self-administration, extinction resistance, mGluR5, CDPPB, executive function, anxiety, brain structure, hippocampus, dorsal striatum, medial prefrontal cortex
- MeSH terms
- Administration, Inhalation, Ethanol, Animals, Anxiety, Benzamides, Brain, Central Nervous System Agents, Central Nervous System Depressants, Conditioning, Operant, Exploratory Behavior, Extinction, Psychological, Male, Motivation, Pyrazoles, Reinforcement Schedule, Self Administration, Maze Learning, Rats, Long-Evans, Diffusion Tensor Imaging, Executive Function, Drug-Seeking Behavior, Receptor, Metabotropic Glutamate 5
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