Incubation of nicotine seeking is associated with enhanced protein kinase A-regulated signaling of dopamine- and cAMP-regulated phosphoprotein of 32 kDa in the insular cortex.
A recent clinical study demonstrated that damage to the insular cortex can disrupt tobacco addiction. The neurobiological mechanisms for this effect are not yet understood. In this study we used an animal model of nicotine addiction to examine the possibility that changes in insular cortex levels of dopamine (DA)- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a phosphoprotein enriched in DA neurons containing DA D1 receptors, may be associated with changes in vulnerability to nicotine addiction. Once rats acquired self-administration, they were given unlimited access to nicotine (0.01 mg/kg/infusion) for 23 h/day for a total of 10 days. Each infusion was paired with a visual cue (stimulus light) and auditory cue (sound of pump). Nicotine seeking, as assessed under a cue-induced reinstatement paradigm, and markers of DARPP-32 signaling, as assessed using western blot analysis, were examined in separate groups of rats at two different abstinent intervals: 1 and 7 days. Consistent with findings with other drugs of abuse, rats in the 7-day abstinence group took longer to extinguish and responded at higher levels during reinstatement testing as compared with rats in the 1-day reinstatement group. Relative to saline controls, rats in the 7-day but not the 1-day abstinence group had higher levels of DARPP-32 phosphorylated at the protein kinase A site in the insular cortex. These results demonstrate incubation of drug seeking following extended access to nicotine self-administration and suggest that enhanced protein kinase A signaling in the insular cortex via phosphorylation of DARPP-32 at Thr34 is associated with this effect.
Abdolahi
Amir
A
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Charlottesville, VA 22911, USA.
Acosta
Glen
G
Breslin
Florence J
FJ
Hemby
Scott E
SE
Lynch
Wendy J
WJ
D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D003463:Cues; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D005108:Extinction, Psychological; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009538:Nicotine; D017868:Cyclic AMP-Dependent Protein Kinases
Eur J Neurosci. 2006 Dec;24(11):3285-98
17156389
Science. 2007 Oct 26;318(5850):655-8
17962567
Psychopharmacology (Berl). 2007 Sep;194(1):103-16
17541779
J Neurosci. 2006 Mar 8;26(10):2645-51
16525043
J Comp Neurol. 1992 Sep 8;323(2):209-18
1328330
Brain Res. 1997 Nov 14;775(1-2):30-6
9439825
Neuropharmacology. 2004;47 Suppl 1:14-23
15464122
Psychopharmacology (Berl). 2008 Feb;196(3):365-75
17932656
Eur J Pharmacol. 2005 Dec 5;526(1-3):36-50
16289451
J Neurosci. 2007 Dec 19;27(51):14035-40
18094242
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4147-52
17360491
Eur J Neurosci. 2005 Sep;22(5):1214-20
16176364
J Pharmacol Exp Ther. 2005 Nov;315(2):872-8
16040813
Psychopharmacology (Berl). 2003 Oct;170(1):23-32
12768275
J Neurosci. 1999 Aug 1;19(15):6610-4
10414988
Cereb Cortex. 2000 Mar;10(3):318-25
10731226
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19480-5
19033203
Psychopharmacology (Berl). 2003 Jul;168(1-2):3-20
12402102
Arch Gen Psychiatry. 1986 Feb;43(2):107-13
3947206
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12840-5
11050161
Psychopharmacology (Berl). 1997 Oct;133(3):300-4
9361337
Science. 2007 Jan 26;315(5811):531-4
17255515
Neuron. 2005 Mar 3;45(5):647-50
15748840
AAPS J. 2005 Oct 05;7(2):E353-60
16353915
Behav Pharmacol. 2000 Aug;11(5):365-76
11103888
Psychopharmacology (Berl). 2000 Feb;148(2):196-200
10663435
J Comp Neurol. 1990 Sep 15;299(3):327-48
2229482
Nature. 2001 Jul 12;412(6843):141-2
11449260
J Neurosci. 1998 Mar 1;18(5):1848-59
9465009
J Neurosci. 2004 Jul 21;24(29):6600-10
15269272
Nicotine Tob Res. 1999;1 Suppl 2:S133-7; discussion S139-40
11768171
Nature. 2003 Jan 2;421(6918):70-5
12511956
Psychopharmacology (Berl). 2008 Sep;200(1):81-91
18584153
Nature. 2008 Jul 3;454(7200):118-21
18500330
Trends Neurosci. 2009 Jan;32(1):56-67
18986715
J Neurosci. 2003 Feb 1;23(3):742-7
12574402
Psychopharmacology (Berl). 2008 Apr;197(2):237-46
18066534
Neuropharmacology. 2009;56 Suppl 1:177-85
18565549
Neuropsychopharmacology. 2008 Jul;33(8):1807-17
17851536
J Neurosci. 2005 Apr 13;25(15):3932-9
15829645