title: Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice.
abstract: OBJECTIVE
  Allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene, CHRNA5, increases vulnerability to tobacco addiction. Here, we investigated the role of α5* nAChRs in the effects of nicotine on brain reward systems.
  
  
  METHODS
  Effects of acute (0.03125-0.5 mg/kg SC) or chronic (24 mg/kg per day; osmotic minipump) nicotine and mecamylamine-precipitated withdrawal on intracranial self-stimulation (ICSS) thresholds were assessed in wild-type and α5 nAChR subunit knockout mice. Noxious effects of nicotine were further investigated using a conditioned taste aversion procedure.
  
  
  RESULTS
  Lower nicotine doses (0.03125-0.125 mg/kg) decreased ICSS thresholds in wild-type and α5 knockout mice. At higher doses (0.25-0.5 mg/kg), threshold-lowering effects of nicotine were diminished in wild-type mice, whereas nicotine lowered thresholds across all doses tested in α5 knockout mice. Nicotine (1.5 mg/kg) conditioned a taste aversion to saccharine equally in both genotypes. Mecamylamine (5 mg/kg) elevated ICSS thresholds by a similar magnitude in wild-type and α5 knockout mice prepared with minipumps delivering nicotine. Unexpectedly, mecamylamine also elevated thresholds in saline-treated α5 knockout mice.
  
  
  CONCLUSIONS
  α5* nAChRs are not involved in reward-enhancing effects of lower nicotine doses, the reward-inhibiting effects of nicotine withdrawal, or the general noxious effects of higher nicotine doses. Instead, α5* nAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of α5* nAChR signaling greatly expands the range of nicotine doses that facilitate brain reward activity, which may help explain the increased tobacco addiction vulnerability associated with CHRNA5 risk alleles.
authors: Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute-Florida, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors: Christie D
authors: CD
authors: Fowler
authors: Luis
authors: L
authors: Tuesta
authors: Paul J
authors: PJ
authors: Kenny
references: Pharmacol Biochem Behav. 2001 Dec;70(4):531-49
references: 11796152
references: Psychopharmacology (Berl). 2012 Mar;220(1):43-54
references: 21894487
references: Neuropsychopharmacology. 2009 Jan;34(2):266-81
references: 18418357
references: J Pharmacol Exp Ther. 2008 Apr;325(1):302-12
references: 18184829
references: Fed Proc. 1982 Feb;41(2):216-20
references: 7060749
references: Naunyn Schmiedebergs Arch Pharmacol. 2013 Mar;386(3):197-204
references: 23274455
references: Trends Pharmacol Sci. 2007 Mar;28(3):135-41
references: 17276521
references: Neuropharmacology. 2002 Mar;42(4):530-9
references: 11955523
references: Arch Gen Psychiatry. 1991 Jan;48(1):52-9
references: 1984762
references: Neuron. 2011 May 12;70(3):522-35
references: 21555077
references: Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3517-25
references: 19029397
references: Neuropsychopharmacology. 2006 Jun;31(6):1203-11
references: 16192981
references: Behav Neurosci. 1997 Feb;111(1):129-36
references: 9109631
references: Neuropharmacology. 2000 Oct;39(13):2840-7
references: 11044754
references: Neuropsychopharmacology. 2012 Nov;37(12):2661-70
references: 22828747
references: Nature. 2011 Mar 31;471(7340):597-601
references: 21278726
references: Mol Psychiatry. 2009 May;14(5):501-10
references: 18414406
references: Trends Pharmacol Sci. 2010 Jan;31(1):46-51
references: 19896728
references: PLoS Genet. 2008 Jul 11;4(7):e1000125
references: 18618000
references: Psychopharmacology (Berl). 1995 Jan;117(1):2-10; discussion 14-20
references: 7724697
references: Mol Psychiatry. 2008 Apr;13(4):368-73
references: 18227835
references: J Pharmacol Exp Ther. 1983 Feb;224(2):334-40
references: 6822959
references: Pharmacol Biochem Behav. 2008 Sep;90(3):409-15
references: 18466962
references: J Abnorm Psychol. 1998 May;107(2):238-51
references: 9604553
references: J Neurosci. 2009 Mar 11;29(10):3014-8
references: 19279237
references: Nature. 1999 Apr 29;398(6730):805-10
references: 10235262
references: Hum Mol Genet. 2007 Jan 1;16(1):36-49
references: 17135278
references: Eur Neuropsychopharmacol. 2007 May-Jun;17(6-7):377-93
references: 17169534
references: Neuropharmacology. 2008 Jun;54(8):1223-32
references: 18452957
references: Ann N Y Acad Sci. 1995 May 10;757:48-72
references: 7611705
references: Pharmacol Biochem Behav. 2008 Oct;90(4):598-607
references: 18556053
references: Mol Pharmacol. 1992 Jan;41(1):31-7
references: 1732720
references: Addiction. 2008 Sep;103(9):1544-52
references: 18783506
references: Pharmacol Biochem Behav. 1995 Jun-Jul;51(2-3):457-61
references: 7667368
references: Neuropharmacology. 2004 Sep;47(4):572-9
references: 15380374
references: Pharmacol Biochem Behav. 1983 Dec;19(6):1011-20
references: 6657719
references: Neuroreport. 2004 Jun 28;15(9):1479-81
references: 15194878
references: J Pharmacol Exp Ther. 2010 Jul;334(1):137-46
references: 20400469
references: Behav Genet. 2012 May;42(3):423-36
references: 22009521
references: J Pharmacol Exp Ther. 1982 Nov;223(2):402-8
references: 7131295
references: J Abnorm Psychol. 2003 Feb;112(1):14-27
references: 12653410
references: J Neurosci. 1992 Jul;12(7):2765-84
references: 1613557
references: Biol Psychiatry. 2008 Dec 1;64(11):922-9
references: 18519132
references: Science. 1981 Oct 30;214(4520):573-5
references: 7291998
references: Cell. 1994 Nov 18;79(4):705-15
references: 7954834
references: Behav Neural Biol. 1990 May;53(3):428-40
references: 2161651
references: Psychopharmacology (Berl). 1995 May;119(2):171-8
references: 7659764
references: Pharmacol Biochem Behav. 1983 Dec;19(6):1021-6
references: 6657720
references: Pharmacol Biochem Behav. 2005 Dec;82(4):751-7
references: 16412500
references: J Neurobiol. 2002 Dec;53(4):447-56
references: 12436412
references: Behav Genet. 2002 Nov;32(6):435-43
references: 12467341
references: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3501-6
references: 11248107
references: Int J Epidemiol. 2010 Apr;39(2):563-77
references: 19776245
references: Eur J Pharmacol. 2008 Aug 20;590(1-3):163-9
references: 18573248
references: Addict Behav. 1975 Jul;1(1):55-64
references: 1234709
references: J Physiol Paris. 1998 Apr;92(2):63-74
references: 9782446
references: Pharmacol Biochem Behav. 2005 Jan;80(1):135-43
references: 15652389
references: Neuropsychopharmacology. 1999 Oct;21(4):560-74
references: 10481840
references: Am J Psychiatry. 2008 Sep;165(9):1163-71
references: 18519524
references: Psychopharmacology (Berl). 1976 Oct 20;50(1):35-9
references: 827760
references: NIDA Res Monogr. 1986;67:54-65
references: 3092098
references: J Neurosci. 2009 Aug 19;29(33):10410-5
references: 19692616
references: J Pharmacol Exp Ther. 1994 Oct;271(1):125-33
references: 7965705