title: Compound stimulus presentation and the norepinephrine reuptake inhibitor atomoxetine enhance long-term extinction of cocaine-seeking behavior.
abstract: Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Janak
authors.forename: M Scott
authors.initials: MS
authors.lastname: Bowers
authors.forename: Laura H
authors.initials: LH
authors.lastname: Corbit
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009638:Norepinephrine / Q000819:agonists / Q000378:metabolism*; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D009638:Norepinephrine
references.citation: Annu Rev Neurosci. 2004;27:1-28
references.pmid: 15217324
references.citation: Prog Brain Res. 1991;88:571-85
references.pmid: 1813935
references.citation: Biol Psychiatry. 2002 Nov 15;52(10):976-86
references.pmid: 12437938
references.citation: Neurobiol Learn Mem. 1996 Nov;66(3):253-7
references.pmid: 8946419
references.citation: Eur J Pharmacol. 2005 Dec 5;526(1-3):36-50
references.pmid: 16289451
references.citation: J Psychopharmacol. 1998;12(1):15-22
references.pmid: 9584964
references.citation: Learn Mem. 2008 Jan 29;15(2):88-92
references.pmid: 18235109
references.citation: Psychopharmacology (Berl). 1996 Jun;125(3):202-8
references.pmid: 8815954
references.citation: Learn Mem. 2010 Mar 23;17(4):168-75
references.pmid: 20332188
references.citation: J Exp Anal Behav. 2003 Jan;79(1):111-35
references.pmid: 12696744
references.citation: Pharmacol Biochem Behav. 2009 Jan;91(3):473-80
references.pmid: 18824018
references.citation: Learn Mem. 2009 Nov 25;16(12):777-89
references.pmid: 19940038
references.citation: Drug Alcohol Depend. 1999 Nov 1;57(1):41-9
references.pmid: 10617312
references.citation: Annu Rev Neurosci. 2000;23:473-500
references.pmid: 10845072
references.citation: Brain Res Bull. 1994;35(5-6):457-65
references.pmid: 7859103
references.citation: Brain Res Brain Res Rev. 2003 Apr;42(1):33-84
references.pmid: 12668290
references.citation: Nat Rev Neurosci. 2009 Jun;10(6):410-22
references.pmid: 19455173
references.citation: J Exp Psychol Anim Behav Process. 2006 Apr;32(2):135-44
references.pmid: 16634656
references.citation: Neuropsychopharmacology. 2004 Apr;29(4):686-93
references.pmid: 14872205
references.citation: Addict Behav. 1990;15(4):395-9
references.pmid: 2248112
references.citation: Am J Drug Alcohol Abuse. 2008;34(1):109-21
references.pmid: 18161649
references.citation: Learn Mem. 2008 Aug 26;15(9):643-8
references.pmid: 18772251
references.citation: J Exp Psychol Anim Behav Process. 2000 Jul;26(3):251-60
references.pmid: 10913990
references.citation: Neuroreport. 2006 Sep 18;17(13):1443-7
references.pmid: 16932155
references.citation: Learn Mem. 2008 Aug 26;15(9):667-76
references.pmid: 18772254
references.citation: Neuropsychopharmacology. 2010 Oct;35(11):2165-78
references.pmid: 20613718
references.citation: Neuropharmacology. 2009;56 Suppl 1:186-95
references.pmid: 18708077
references.citation: Nature. 2001 Jul 12;412(6843):141-2
references.pmid: 11449260
references.citation: J Neurosci. 2008 Jun 4;28(23):6046-53
references.pmid: 18524910
references.citation: Psychopharmacology (Berl). 2004 Oct;176(1):101-8
references.pmid: 15071719
references.citation: Brain Res Brain Res Rev. 2000 Aug;33(1):13-33
references.pmid: 10967352
references.citation: Addiction. 2001 Jan;96(1):33-46
references.pmid: 11177518
references.citation: Neurobiol Learn Mem. 2006 Sep;86(2):123-32
references.pmid: 16458544
references.citation: Learn Mem. 2009 Feb 04;16(2):155-60
references.pmid: 19196909
references.citation: J Neurosci. 2004 Mar 10;24(10):2475-80
references.pmid: 15014123
references.citation: Brain Res. 2008 May 13;1209:65-73
references.pmid: 18396264
references.citation: J Neurosci. 2003 Jan 1;23(1):12-6
references.pmid: 12514195
references.citation: Psychopharmacology (Berl). 1981;75(2):134-43
references.pmid: 6798603
references.citation: Proc Natl Acad Sci U S A. 1980 May;77(5):3033-7
references.pmid: 6771765
references.citation: Biol Psychiatry. 2004 Jun 1;55(11):1082-9
references.pmid: 15158427
references.citation: Psychopharmacology (Berl). 2011 Nov;218(1):89-99
references.pmid: 21318567
references.citation: PLoS One. 2011 Feb 23;6(2):e16573
references.pmid: 21373180
references.citation: J Neurosci Res. 1997 Dec 15;50(6):1040-6
references.pmid: 9452019
references.citation: Psychopharmacology (Berl). 2006 Nov;189(1):1-16
references.pmid: 17019567
references.citation: Neuroscience. 2010 Aug 25;169(2):628-36
references.pmid: 20639130
references.citation: Learn Mem. 2010 Dec 14;18(1):1-10
references.pmid: 21224211
references.citation: Learn Mem. 2004 Mar-Apr;11(2):179-87
references.pmid: 15054133
references.citation: Behav Neurosci. 2007 Jun;121(3):501-14
references.pmid: 17592941
references.citation: Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3277-86
references.pmid: 18640914
references.citation: Biol Psychiatry. 2011 Feb 1;69(3):266-74
references.pmid: 21109233
references.citation: Eur J Neurosci. 2002 Feb;15(3):553-60
references.pmid: 11876783
references.citation: Behav Brain Res. 2006 Nov 1;174(1):1-8
references.pmid: 16920204
references.citation: Nat Neurosci. 2005 Nov;8(11):1481-9
references.pmid: 16251991
references.citation: Science. 1999 Jan 22;283(5401):549-54
references.pmid: 9915705
references.citation: Neuroimage. 2008 Feb 1;39(3):1266-73
references.pmid: 18024160
references.citation: Nature. 1994 Oct 20;371(6499):702-4
references.pmid: 7935815
references.citation: Addict Behav. 1992;17(3):297-300
references.pmid: 1353283
references.citation: Behav Neurosci. 2010 Apr;124(2):204-10
references.pmid: 20364880
references.citation: J Neurosci. 1999 Jun 15;19(12):5119-23
references.pmid: 10366644
references.citation: Am J Psychiatry. 1999 Jan;156(1):11-8
references.pmid: 9892292
references.citation: Behav Neurosci. 2000 Oct;114(5):957-62
references.pmid: 11085610
references.citation: Biol Psychiatry. 2011 Apr 1;69(7):708-11
references.pmid: 20817135
references.citation: Pharmacol Biochem Behav. 2011 Aug;99(2):229-44
references.pmid: 21295059
references.citation: Psychopharmacology (Berl). 2011 Jan;213(1):19-27
references.pmid: 20827461
references.citation: J Neurosci. 2008 Jan 9;28(2):369-75
references.pmid: 18184779
references.citation: JAMA. 2000 Oct 4;284(13):1689-95
references.pmid: 11015800
references.citation: J Neurosci. 2006 Sep 27;26(39):10051-6
references.pmid: 17005868
references.citation: Behav Brain Res. 2010 Mar 17;208(1):1-11
references.pmid: 19931568