title: When a good taste turns bad: Neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine.
abstract: An important feature of cocaine addiction in humans is the emergence of negative affect (e.g., dysphoria, irritability, anhedonia), postulated to play a key role in craving and relapse. Indeed, the DSM-IV recognizes that social, occupational and/or recreational activities become reduced as a consequence of repeated drug use where previously rewarding experiences (e.g., food, job, family) become devalued as the addict continues to seek and use drug despite serious negative consequences. Here, research in the Carelli laboratory is reviewed that examined neurobiological mechanisms that may underlie these processes using a novel animal model. Oromotor responses (taste reactivity) were examined as rats learned that intraoral infusion of a sweet (e.g., saccharin) predicts impending but delayed access to cocaine self-administration. We showed that rats exhibit aversive taste reactivity (i.e., gapes/rejection responses) during infusion of the sweet paired with impending cocaine, similar to aversive responses observed during infusion of quinine, a bitter tastant. Critically, the expression of this pronounced aversion to the sweet predicted the subsequent motivation to self-administer cocaine. Electrophysiology studies show that this shift in palatability corresponds to an alteration in nucleus accumbens (NAc) cell firing; neurons that previously responded with inhibition during infusion of the palatable sweet shifted to excitatory activity during infusion of the cocaine-devalued tastant. This excitatory response profile is typically observed during infusion of quinine, indicating that the once palatable sweet becomes aversive following its association with impending but delayed cocaine, and NAc neurons encode this aversive state. We also review electrochemical studies showing a shift (from increase to decrease) in rapid NAc dopamine release during infusion of the cocaine-paired tastant as the aversive state developed, again, resulting in responses similar to quinine infusion. Collectively, our findings suggest that cocaine-conditioned cues elicit a cocaine-need state that is aversive, is encoded by a distinct subset of NAc neurons and rapid dopamine signaling, and promotes cocaine-seeking behavior. Finally, we present data showing that experimentally induced abstinence (30 days) exacerbates this natural reward devaluation by cocaine, and this effect is correlated with a greater motivation to lever press during extinction. Dissecting the neural mechanisms underlying these detrimental consequences of addiction is critical since it may lead to novel treatments that ameliorate negative affective states associated with drug use and decrease the drive (craving) for the drug. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
authors: Department of Psychology, The University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, The University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: rcarelli@unc.edu.
authors: Regina M
authors: RM
authors: Carelli
authors: Elizabeth A
authors: EA
authors: West
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D004576:Electromyography; D006801:Humans; D023421:Models, Animal; D009415:Nerve Net / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012201:Reward; D013649:Taste / Q000502:physiology*
chemical_list: D003042:Cocaine
keywords: Accumbens; Addiction; Anhedonia; Behavior; Dopamine; Reward
references: Psychopharmacology (Berl). 2011 Sep;217(2):221-30
references: 21487661
references: Curr Opin Investig Drugs. 2010 Jan;11(1):63-71
references: 20047160
references: Brain Res. 2000 Jun 2;866(1-2):44-54
references: 10825479
references: Behav Neurosci. 2002 Apr;116(2):321-33
references: 11996317
references: Neuron. 2000 Mar;25(3):515-32
references: 10774721
references: Behav Neurosci. 1997 Feb;111(1):129-36
references: 9109631
references: Eur J Neurosci. 2009 Dec 3;30(11):2121-33
references: 20128849
references: Eur J Neurosci. 2003 Sep;18(6):1645-51
references: 14511343
references: J Neurosci. 2003 Dec 3;23(35):11214-23
references: 14657180
references: J Neurophysiol. 2011 Sep;106(3):1537-44
references: 21697439
references: Neuron. 2004 Nov 18;44(4):729-40
references: 15541319
references: Front Neurosci. 2012 Sep 25;6:137
references: 23055953
references: Nature. 2000 Jan 27;403(6768):430-4
references: 10667795
references: Eur J Neurosci. 2011 Jan;33(2):308-21
references: 21198983
references: Brain Res. 2001 Jul 13;907(1-2):156-61
references: 11430899
references: Prog Neurobiol. 1994 Apr;42(6):719-61
references: 7938546
references: Synapse. 2006 Feb;59(2):69-73
references: 16270303
references: Brain Res. 1978 Mar 24;143(2):263-79
references: 630409
references: Neuron. 2005 Feb 17;45(4):587-97
references: 15721244
references: Eur J Neurosci. 2006 Jun;23(11):3109-18
references: 16820001
references: Synapse. 2008 Mar;62(3):219-28
references: 18088061
references: J Neurosci. 1999 Oct 15;19(20):RC35
references: 10516337
references: Brain Res. 2002 Mar 8;929(2):226-35
references: 11864628
references: Cell Mol Neurobiol. 2003 Oct;23(4-5):727-38
references: 14514027
references: Trends Neurosci. 2011 Aug;34(8):411-20
references: 21764143
references: Neuroscience. 2010 Sep 1;169(3):1186-98
references: 20570714
references: Ann N Y Acad Sci. 1992 Jun 28;654:400-15
references: 1632593
references: Nature. 2003 Apr 10;422(6932):614-8
references: 12687000
references: Science. 1998 Oct 9;282(5387):298-300
references: 9765157
references: Trends Cogn Sci. 1999 Feb;3(2):65-73
references: 10234229
references: J Comp Neurol. 2002 Dec 2;454(1):15-33
references: 12410615
references: J Neurochem. 2002 Sep;82(5):1290-9
references: 12358776
references: Learn Mem. 2010 Oct 22;17(11):539-46
references: 20971936
references: Addict Behav. 2003 Jun;28(4):817-21
references: 12726795
references: Ann N Y Acad Sci. 2003 Apr;985:294-307
references: 12724166
references: Neuropsychopharmacology. 2009 Apr;34(5):1162-71
references: 18769473
references: Annu Rev Neurosci. 2006;29:565-98
references: 16776597
references: Neuropsychopharmacology. 2013 Jan;38(1):248
references: 23147490
references: Nature. 2013 Apr 18;496(7445):359-62
references: 23552889
references: Neuropharmacology. 2009;56 Suppl 1:149-59
references: 18625253
references: Neuroscience. 1982 Mar;7(3):615-30
references: 7070669
references: Brain Res. 1993 Oct 29;626(1-2):14-22
references: 8281424
references: Neuropsychopharmacology. 2010 Jan;35(1):217-38
references: 19710631
references: Neurosci Biobehav Rev. 1995 Spring;19(1):143-57
references: 7770194
references: Synapse. 2001 Mar 1;39(3):257-66
references: 11169774
references: Neuropsychopharmacology. 2008 Mar;33(4):796-805
references: 17568398
references: Neuropharmacology. 2004;47 Suppl 1:180-9
references: 15464136
references: Drug Discov Today Dis Models. 2008 Winter;5(4):227-233
references: 20016772
references: Behav Neurosci. 2012 Aug;126(4):563-74
references: 22845705
references: Nat Neurosci. 2008 Dec;11(12):1376-7
references: 18978779
references: J Neurosci. 1996 Aug 15;16(16):5256-65
references: 8756453
references: Biol Psychiatry. 2010 Apr 15;67(8):737-44
references: 20044074
references: Drug Alcohol Depend. 1995 Apr;38(1):11-8
references: 7648992
references: Nat Neurosci. 2006 Aug;9(8):1050-6
references: 16829955
references: Biol Psychiatry. 2010 Aug 1;68(3):306-9
references: 20452572
references: J Neurosci. 2003 Sep 10;23(23):8204-11
references: 12967981
references: Curr Opin Neurobiol. 2004 Dec;14(6):763-8
references: 15582381
references: J Neurosci. 2003 Apr 15;23(8):3498-505
references: 12716959
references: Psychol Rev. 2004 Jan;111(1):33-51
references: 14756584
references: J Neurosci. 2004 Feb 11;24(6):1265-71
references: 14960596
references: Trends Neurosci. 2003 Sep;26(9):507-13
references: 12948663
references: Ann N Y Acad Sci. 2003 Nov;1003:169-75
references: 14684444
references: Prog Neurobiol. 1980;14(2-3):69-97
references: 6999537
references: Eur J Neurosci. 2012 Mar;35(6):940-51
references: 22356698
references: Neuropharmacology. 2004;47 Suppl 1:214-26
references: 15464139
references: J Neurosci. 2007 Mar 28;27(13):3535-9
references: 17392469
references: Psychopharmacology (Berl). 2005 Jul;180(3):473-90
references: 15731896
references: Synapse. 1996 Nov;24(3):308-11
references: 8923672
references: Neuropharmacology. 2004;47 Suppl 1:33-46
references: 15464124
references: Neuropsychopharmacology. 2005 Aug;30(8):1464-74
references: 15856078
references: Biol Psychiatry. 2011 Jun 1;69(11):1067-74
references: 21481843
references: Nature. 2008 Jul 3;454(7200):118-21
references: 18500330
references: Psychol Rev. 1974 Mar;81(2):119-45
references: 4817611
references: Nat Neurosci. 2003 Jul;6(7):743-9
references: 12778052
references: Appetite. 2000 Aug;35(1):89-91
references: 10896765
references: J Neurosci. 2006 Apr 5;26(14):3855-63
references: 16597740
references: Science. 2004 Mar 26;303(5666):2040-2
references: 15044807
references: Biol Psychiatry. 2012 Feb 1;71(3):199-205
references: 22055017
references: Eur J Neurosci. 2007 Oct;26(7):2046-54
references: 17868375
references: Psychopharmacology (Berl). 2011 Nov;218(1):29-37
references: 21336579
references: J Neurosci. 1994 Dec;14(12):7735-46
references: 7996208
references: Behav Brain Res. 2013 Mar 1;240:87-90
references: 23174208
references: Neuron. 2008 Mar 13;57(5):774-85
references: 18341996
references: J Neurosci. 2003 Jan 15;23(2):666-75
references: 12533626
references: Science. 1991 Mar 29;251(5001):1580-6
references: 2011738
references: Psychopharmacology (Berl). 2003 Oct;170(1):62-72
references: 12845411
references: Neuropharmacology. 2004;47 Suppl 1:3-13
references: 15464121
references: Brain Res. 2000 Apr 28;863(1-2):52-8
references: 10773192
references: J Neurosci. 2000 Jun 1;20(11):4255-66
references: 10818162
references: Neuropharmacology. 2009;56 Suppl 1:177-85
references: 18565549
references: J Neurochem. 2003 Jun;85(6):1604-13
references: 12787079
references: Am J Psychiatry. 1999 Jan;156(1):11-8
references: 9892292
references: Synapse. 2000 Mar 1;35(3):238-42
references: 10657032
references: Science. 1976 Mar 26;191(4233):1273-5
references: 1257748
references: Science. 1997 Oct 3;278(5335):52-8
references: 9311926
references: Nature. 1997 Apr 24;386(6627):830-3
references: 9126741
references: Nature. 1996 Feb 1;379(6564):449-51
references: 8559249
references: Nat Neurosci. 2012 Jun 24;15(8):1105-7
references: 22729176
references: Nature. 2012 Nov 8;491(7423):212-7
references: 23064228
references: Biol Psychiatry. 2012 Feb 15;71(4):327-34
references: 22115620
references: Curr Psychiatry Rep. 2004 Oct;6(5):323-31
references: 15355754
references: Nat Protoc. 2007;2(11):2987-95
references: 18007634
references: Am J Psychiatry. 2005 Aug;162(8):1403-13
references: 16055761
references: J Neurosci. 2004 Feb 18;24(7):1551-60
references: 14973230
references: Neurosci Biobehav Rev. 2004 Jan;27(8):739-49
references: 15019424