title: Chronic alcohol produces neuroadaptations to prime dorsal striatal learning.
abstract: Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptor-dependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism.
authors: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, MD 20814, USA.
authors: Lauren
authors: L
authors: DePoy
authors: Rachel
authors: R
authors: Daut
authors: Jonathan L
authors: JL
authors: Brigman
authors: Kathryn
authors: K
authors: MacPherson
authors: Nicole
authors: N
authors: Crowley
authors: Ozge
authors: O
authors: Gunduz-Cinar
authors: Charles L
authors: CL
authors: Pickens
authors: Resat
authors: R
authors: Cinar
authors: Lisa M
authors: LM
authors: Saksida
authors: George
authors: G
authors: Kunos
authors: David M
authors: DM
authors: Lovinger
authors: Timothy J
authors: TJ
authors: Bussey
authors: Marguerite C
authors: MC
authors: Camp
authors: Andrew
authors: A
authors: Holmes
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007858:Learning / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D013997:Time Factors
chemical_list: D002492:Central Nervous System Depressants; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol
keywords: PFC; abuse; cannabinoid; dependence; touchscreen
references: Nat Neurosci. 2009 Mar;12(3):333-41
references: 19198605
references: Alcohol Clin Exp Res. 2010 Sep 1;34(9):1565-73
references: 20586757
references: Neurosci Lett. 1999 Jun 18;268(2):81-4
references: 10400083
references: J Biol Chem. 1998 Jul 3;273(27):16865-73
references: 9642247
references: Neuropharmacology. 2008 Jul;55(1):55-62
references: 18501388
references: Nat Neurosci. 2013 Jan;16(1):16-24
references: 23201973
references: Biol Psychiatry. 2008 Feb 1;63(3):256-62
references: 17719014
references: Addict Biol. 2009 Jan;14(1):108-18
references: 18855799
references: Neuropsychopharmacology. 2009 May;34(6):1578-89
references: 19078949
references: Science. 2010 Jun 25;328(5986):1709-12
references: 20576893
references: Psychopharmacology (Berl). 2005 Oct;181(4):688-96
references: 16001125
references: Psychopharmacology (Berl). 2009 Nov;207(1):163-72
references: 19727677
references: Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6323-8
references: 21383171
references: Behav Brain Res. 1995 Sep;70(1):77-94
references: 8519431
references: Neuropharmacology. 2011 Dec;61(7):1160-5
references: 21251919
references: Ann N Y Acad Sci. 2004 Oct;1025:515-27
references: 15542757
references: Neurosignals. 2006-2007;15(2):91-101
references: 16874009
references: Biol Psychiatry. 2010 May 1;67(9):823-30
references: 20132926
references: Neuropsychology. 2008 Mar;22(2):196-208
references: 18331162
references: PLoS One. 2011 Jan 10;6(1):e15536
references: 21249214
references: Mol Psychiatry. 2013 Aug;18(8):916-21
references: 22776901
references: J Neurosci. 2003 Sep 24;23(25):8771-80
references: 14507977
references: Behav Neurosci. 2011 Dec;125(6):879-91
references: 22122149
references: Drug Alcohol Depend. 2004 Jun 11;74(3):223-34
references: 15194200
references: J Psychiatr Res. 2010 Jul;44(9):591-7
references: 20015515
references: Nat Neurosci. 2006 Jul;9(7):868-9
references: 16732275
references: Cereb Cortex. 2011 Sep;21(9):2056-64
references: 21263035
references: Neuropsychopharmacology. 2010 Jan;35(1):48-69
references: 19776734
references: Alcohol Clin Exp Res. 2006 Dec;30(12):1957-65
references: 17117959
references: Learn Mem. 2008 Jan 28;15(2):50-4
references: 18230672
references: Q J Exp Psychol B. 2002 Oct;55(4):331-48
references: 12350285
references: Nat Neurosci. 2013 Aug;16(8):1101-10
references: 23831965
references: Alcohol Clin Exp Res. 2006 May;30(5):819-24
references: 16634850
references: Cereb Cortex. 2010 Aug;20(8):1955-63
references: 20032063
references: Pharmacol Ther. 2006 Sep;111(3):855-76
references: 16545872
references: Neuropsychopharmacology. 2008 Jan;33(1):166-80
references: 17805308
references: Neuropharmacology. 2010 Jun;58(7):951-61
references: 20096294
references: J Neurosci. 2010 Jul 28;30(30):10187-98
references: 20668202
references: Behav Brain Res. 2006 Aug 10;171(2):181-8
references: 16713639
references: Neuropharmacology. 2004;47 Suppl 1:33-46
references: 15464124
references: Pharmacol Ther. 2011 Feb;129(2):149-71
references: 20951730
references: Neuropsychopharmacology. 2012 May;37(6):1534-47
references: 22334122
references: Nat Neurosci. 2012 Oct;15(10):1359-61
references: 22941108
references: J Neurosci. 2007 Mar 28;27(13):3593-602
references: 17392475
references: Alcohol Clin Exp Res. 2011 Apr;35(4):671-88
references: 21223304
references: Neuropsychopharmacology. 2000 Jun;22(6):581-94
references: 10788758
references: Addiction. 2010 Oct;105(10):1741-9
references: 20670348
references: Nat Neurosci. 2011 Nov 06;14(12):1507-9
references: 22057192
references: Neurochem Int. 2006 Nov;49(6):619-25
references: 16822589
references: Eur J Neurosci. 2003 Jul;18(2):441-8
references: 12887426
references: Nat Neurosci. 2005 Nov;8(11):1481-9
references: 16251991
references: Pharmacol Biochem Behav. 2002 Jun;72(3):521-32
references: 12175448
references: Addict Biol. 2012 Jan;17(1):132-40
references: 22026443
references: Psychopharmacology (Berl). 1999 Oct;146(4):373-90
references: 10550488
references: Pharmacol Biochem Behav. 1999 Apr;62(4):719-25
references: 10208378
references: Addict Biol. 2014 Jan;19(1):87-101
references: 23710649
references: J Neurosci. 2010 Apr 14;30(15):5357-67
references: 20392957
references: Brain Res. 1999 Jan 2;815(1):89-97
references: 9974126
references: Alcohol Clin Exp Res. 2012 Jul;36(7):1180-7
references: 22309159
references: J Neurosci. 1992 Nov;12(11):4224-33
references: 1359031
references: Biol Psychiatry. 2012 Sep 1;72(5):389-95
references: 22440617
references: Alcohol Clin Exp Res. 2003 Feb;27(2):232-43
references: 12605072
references: J Neurosci. 2012 Oct 24;32(43):15124-32
references: 23100433
references: Neurosci Biobehav Rev. 2013 Mar;37(3):300-16
references: 23253945
references: Am J Psychiatry. 2005 Aug;162(8):1403-13
references: 16055761
references: Neuropharmacology. 2011 Dec;61(7):1070-87
references: 21669214