title: Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood.
abstract: 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.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Gass
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: William Bailey
authors.initials: WB
authors.lastname: Glen
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: McGonigal
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Trantham-Davidson
authors.affiliation: Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Lopez
authors.affiliation: Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Randall
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Yaxley
authors.affiliation: Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Floresco
authors.affiliation: 1] Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA [2] Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: L Judson
authors.initials: LJ
authors.lastname: Chandler
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D002491:Central Nervous System Agents / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D056324:Diffusion Tensor Imaging; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage*; D056344:Executive Function / Q000187:drug effects* / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects* / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D020318:Rats, Long-Evans; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D001549:Benzamides; D002491:Central Nervous System Agents; D002492:Central Nervous System Depressants; C578937:Grm5 protein, rat; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D000431:Ethanol