title: Nicotinic receptor modulation to treat alcohol and drug dependence.
abstract: Alcohol and drug dependence are serious public health problems worldwide. The prevalence of alcohol and drug dependence in the United States and other parts of the world is significant. Given the limitations in the efficacy of current pharmacotherapies to treat these disorders, research in developing alternative pharmacotherapies continues. Preclinical and clinical evidence thus far has indicated that brain nicotinic acetylcholine receptors (nAChRs) are important pharmacological targets for the development of medications to treat alcohol and drug dependence. The nAChRs are a super family of ligand gated ion channels, and are expressed throughout the brain with twelve neuronal nAChR subunits (α2-α10 and β2-β4) identified. Here, we review preclinical and clinical evidence involving a number of nAChR ligands that target different nAChR subtypes in alcohol and nicotine addiction. The important ligands include cytisine, lobeline, mecamylamine, varenicline, sazetidine A and others that target α4β2(*) nAChR subtypes as small molecule modulators of the brain nicotinic cholinergic system are also discussed. Taken together, both preclinical and clinical data exist that support nAChR-based ligands as promising therapeutic agents for the treatment of alcohol and drug dependence.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University Brookings, SD, USA.
authors: Shafiqur
authors: S
authors: Rahman
authors: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Eric A
authors: EA
authors: Engleman
authors: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Richard L
authors: RL
authors: Bell
keywords: CNS disorders; alcohol dependence; animal models; drug addiction; drug development; nicotine addiction; nicotinic receptor
references: Genes Brain Behav. 2009 Aug;8(6):631-7
references: 19500157
references: Alcohol Clin Exp Res. 2006 Dec;30(12):2017-25
references: 17117967
references: Alcohol Clin Exp Res. 2002 Mar;26(3):326-31
references: 11923584
references: Physiol Rev. 2009 Jan;89(1):73-120
references: 19126755
references: Am J Med Genet B Neuropsychiatr Genet. 2011 Apr;156B(3):275-84
references: 21268243
references: Alcohol Clin Exp Res. 2002 Feb;26(2):280-6
references: 11964569
references: Biochem Pharmacol. 2009 Oct 1;78(7):703-11
references: 19481063
references: J Pharmacol Exp Ther. 2009 Feb;328(2):364-70
references: 19023041
references: Brain Cogn. 2007 Oct;65(1):135-42
references: 17669569
references: Nicotine Tob Res. 2011 Sep;13(9):833-9
references: 21511889
references: Nebr Symp Motiv. 2009;55:131-41
references: 19013942
references: J Neurosci. 1998 Nov 1;18(21):8571-9
references: 9786965
references: Mol Pharmacol. 2004 Jun;65(6):1526-35
references: 15155845
references: Hum Genet. 2014 May;133(5):575-86
references: 24253422
references: Psychopharmacology (Berl). 2013 Mar;226(1):35-43
references: 23100170
references: Pharmacol Biochem Behav. 2012 Jul;102(1):36-43
references: 22741175
references: Trends Cogn Sci. 2002 Sep 1;6(9):361
references: 12200169
references: PLoS One. 2014 Jan 30;9(1):e87141
references: 24498031
references: Psychopharmacology (Berl). 2006 Aug;187(2):181-8
references: 16826402
references: Neuropsychopharmacology. 2011 Feb;36(3):603-15
references: 21048701
references: Neuropsychopharmacology. 2010 Aug;35(9):1921-31
references: 20485328
references: Nicotine Tob Res. 2011 Oct;13(10 ):982-8
references: 21690317
references: Prog Neurobiol. 2000 May;61(1):75-111
references: 10759066
references: Eur J Pharmacol. 2000 Mar 30;393(1-3):51-8
references: 10770997
references: J Neurosci. 2002 Oct 15;22(20):8785-9
references: 12388584
references: Alcohol Alcohol. 1999 Mar-Apr;34(2):231-43
references: 10344783
references: J Mol Neurosci. 2006;30(1-2):95-6
references: 17192644
references: Eur J Pharmacol. 1998 Oct 9;358(3):189-96
references: 9822883
references: Psychopharmacology (Berl). 2012 Sep;223(2):159-68
references: 22526534
references: Front Mol Neurosci. 2012 Aug 03;5:83
references: 22876217
references: Behav Pharmacol. 2008 Sep;19(5-6):461-84
references: 18690103
references: J Neurosci. 1998 Jun 15;18(12):4461-72
references: 9614223
references: Psychopharmacology (Berl). 2009 Jul;204(4):563-72
references: 19247637
references: Hum Mol Genet. 2012 Feb 1;21(3):647-55
references: 22042774
references: J Neurosci. 2001 Mar 1;21(5):1452-63
references: 11222635
references: Pharmacol Biochem Behav. 2010 Aug;96(2):141-7
references: 20451547
references: Biol Psychiatry. 2013 Apr 15;73(8):738-46
references: 23141806
references: Prog Neuropsychopharmacol Biol Psychiatry. 2012 Apr 27;37(1):141-6
references: 22230648
references: J Neurosci. 2010 Jul 28;30(30):10169-76
references: 20668200
references: Neuron. 2002 Mar 14;33(6):905-19
references: 11906697
references: Psychopharmacology (Berl). 2007 Sep;194(1):53-61
references: 17530475
references: J Med Chem. 2005 May 19;48(10):3474-7
references: 15887955
references: Eur J Pharmacol. 1996 Oct 31;314(3):257-67
references: 8957244
references: Nat Rev Neurosci. 2010 Jun;11(6):389-401
references: 20485364
references: Int J Neuropsychopharmacol. 2014 Feb;17(2):223-33
references: 24393456
references: Nicotine Tob Res. 2012 Jun;14(6):720-33
references: 22241830
references: Pharmacol Biochem Behav. 2012 Nov;103(1):119-55
references: 22841890
references: Alcohol Clin Exp Res. 2013 May;37(5):804-10
references: 23240586
references: J Neurosci. 2003 Apr 15;23(8):3176-85
references: 12716925
references: Neuropharmacology. 2007 Mar;52(3):755-63
references: 17097117
references: Alcohol Clin Exp Res. 1998 Aug;22(5):1170-6
references: 9726292
references: Nicotine Tob Res. 2011 Aug;13(8):686-90
references: 21498873
references: Br J Pharmacol. 1996 Feb;117(4):595-606
references: 8646402
references: Alcohol Clin Exp Res. 2000 Feb;24(2):155-63
references: 10698366
references: Expert Opin Emerg Drugs. 2006 Sep;11(3):429-44
references: 16939383
references: Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):257-64
references: 21111768
references: CNS Neurol Disord Drug Targets. 2010 Mar;9(1):60-76
references: 20201817
references: Psychopharmacology (Berl). 2010 Mar;208(4):613-26
references: 20072781
references: J Neurosci. 2007 May 23;27(21):5615-20
references: 17522306
references: Addict Biol. 2012 May;17(3):513-27
references: 22458728
references: Eur J Pharmacol. 2002 Mar 1;438(1-2):99-105
references: 11906717
references: Drug Alcohol Depend. 2012 Jan 1;120(1-3):7-13
references: 21764527
references: J Pharmacol Exp Ther. 2009 Apr;329(1):225-30
references: 19126781
references: J Neurosci. 2003 Aug 27;23(21):7820-9
references: 12944511
references: Mol Pharmacol. 1992 Jan;41(1):31-7
references: 1732720
references: PLoS One. 2014 Feb 05;9(2):e88240
references: 24505444
references: Alcohol Clin Exp Res. 2012 Jan;36(1):43-54
references: 21689122
references: Biochem Pharmacol. 2009 Oct 1;78(7):744-55
references: 19523928
references: Behav Brain Res. 2011 Jun 20;220(1):100-5
references: 21277332
references: Psychopharmacology (Berl). 2013 May;227(2):287-98
references: 23344555
references: J Psychopharmacol. 2010 Jan;24(1):51-5
references: 20130110
references: Pharmacol Ther. 2013 Jan;137(1):22-54
references: 22925690
references: J Neurochem. 2002 Aug;82(3):468-81
references: 12153472
references: Neurosci Biobehav Rev. 2004 Jan;27(8):713-20
references: 15019421
references: Psychopharmacology (Berl). 2014 Aug;231(15):2989-98
references: 24682499
references: Biochem Pharmacol. 2009 Oct 1;78(7):732-43
references: 19523455
references: Neuropsychopharmacology. 2014 Jan;39(2):254-62
references: 24121188
references: Alcohol Clin Exp Res. 2005 Jan;29(1):58-65
references: 15654292
references: Alcohol Clin Exp Res. 2009 Jan;33(1):31-42
references: 18945225
references: Psychopharmacology (Berl). 2006 Mar;184(3-4):426-34
references: 16220336
references: J Neurosci. 2002 May 1;22(9):3332-7
references: 11978808
references: Curr Opin Neurobiol. 2013 Aug;23(4):632-8
references: 23395462
references: Biochem Pharmacol. 2008 Jan 1;75(1):323-33
references: 17632086
references: Chin Med J (Engl). 2011 Jun;124(11):1634-8
references: 21740768
references: Addiction. 2012 Nov;107(11):2019-28
references: 22524403
references: Alcohol. 2013 Jun;47(4):299-307
references: 23601929
references: Biol Psychiatry. 2009 Jul 15;66(2):185-90
references: 19249750
references: Neuropsychopharmacology. 2007 Mar;32(3):710-8
references: 16794568
references: Neuropharmacology. 2014 Jan;76 Pt B:235-49
references: 23688927
references: Psychopharmacology (Berl). 2003 Jul;168(1-2):216-21
references: 12536264
references: Trends Pharmacol Sci. 2007 Jul;28(7):316-25
references: 17573127
references: J Pharmacol Exp Ther. 1997 Dec;283(3):1396-411
references: 9400016
references: J Addict Med. 2013 Jul-Aug;7(4):277-86
references: 23728065
references: Neuropsychopharmacology. 2010 Jan;35(1):217-38
references: 19710631
references: Neuropsychopharmacology. 2012 Jan;37(1):290-2
references: 22157859
references: Eur J Cancer Prev. 2012 Mar;21(2):111-7
references: 21955800
references: Neuropsychopharmacology. 2012 Feb;37(3):641-50
references: 22048466
references: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12518-23
references: 17626178
references: J Natl Cancer Inst. 2011 Sep 7;103(17 ):1342-6
references: 21747048
references: J Pharmacol Exp Ther. 1997 Jul;282(1):410-9
references: 9223582
references: Nature. 1995 Mar 2;374(6517):65-7
references: 7870173
references: J Neurosci. 2000 Sep 1;20(17 ):6431-41
references: 10964949
references: Pharmacopsychiatry. 2013 Mar;46(2):77-82
references: 23037950
references: J Popul Ther Clin Pharmacol. 2014;21(1):e1-e30
references: 24639410
references: Alcohol Clin Exp Res. 2003 May;27(5):780-6
references: 12766622
references: Behav Brain Res. 2000 Aug;113(1-2):85-96
references: 10942035
references: Mol Pharmacol. 2006 Sep;70(3):801-5
references: 16766716
references: Nicotine Tob Res. 2011 Nov;13(11):1076-83
references: 21810735
references: Mol Pharmacol. 2006 Oct;70(4):1454-60
references: 16857741
references: Science. 2004 Nov 5;306(5698):1029-32
references: 15528443
references: Pharmacology. 2010;86(3):168-73
references: 20714207
references: Psychopharmacology (Berl). 2010 Aug;211(2):161-74
references: 20535453
references: CNS Neurol Disord Drug Targets. 2013 Aug;12(5):633-40
references: 23574176
references: Biochem Soc Trans. 1993 May;21(2):429-31
references: 8359505
references: Drugs Today (Barc). 2007 Feb;43(2):65-75
references: 17353944
references: Mol Pharmacol. 2003 Feb;63(2):332-41
references: 12527804
references: Front Psychiatry. 2013 Apr 30;4:29
references: 23641218
references: Alcohol. 2009 Dec;43(8):581-92
references: 20004336
references: Psychopharmacology (Berl). 2012 Oct;223(3):299-306
references: 22547331
references: Behav Pharmacol. 2010 Mar;21(2):96-103
references: 20093928
references: Biochem Pharmacol. 2011 Oct 15;82(8):984-95
references: 21740894
references: Drug Alcohol Depend. 2012 Feb 1;121(1-2):163-6
references: 21925806
references: Alcohol Clin Exp Res. 2014 Feb;38(2):376-83
references: 24033702
references: Physiol Behav. 2000 Dec;71(5):565-70
references: 11239676
references: Pharmacopsychiatry. 2009 May;42(3):89-94
references: 19452376
references: Biochem Pharmacol. 2007 Oct 15;74(8):1102-11
references: 17597586
references: Pharmacol Ther. 2014 Mar;141(3):335-46
references: 24189489
references: J Pharmacol Exp Ther. 1996 Feb;276(2):482-9
references: 8632313
references: Eur J Hum Genet. 2011 May;19(5):593-6
references: 21248747
references: J Pharmacol Exp Ther. 2011 Nov;339(2):678-86
references: 21856860
references: Nature. 1998 Jan 8;391(6663):173-7
references: 9428762
references: J Neurobiol. 2002 Dec;53(4):457-78
references: 12436413
references: Genes Brain Behav. 2013 Apr;12(3):297-304
references: 23350800
references: J Addict Med. 2012 Sep;6(3):191-5
references: 22722381
references: Addict Biol. 2011 Jul;16(3):440-9
references: 21392178
references: Neuropsychopharmacology. 2012 May;37(6):1367-76
references: 22278092
references: Alcohol Clin Exp Res. 2013 Jan;37(1):8-15
references: 22671690
references: Prog Neuropsychopharmacol Biol Psychiatry. 2011 Dec 1;35(8):1827-30
references: 21803113
references: Pharmacol Ther. 1995;68(1):113-28
references: 8604434
references: Behav Brain Res. 2006 Mar 15;168(1):120-6
references: 16313978
references: Neuropsychopharmacology. 2001 May;24(5):576-89
references: 11282258
references: Eur J Neurosci. 1996 Nov;8(11):2428-39
references: 8950106
references: Psychopharmacology (Berl). 2011 Jul;216(2):267-77
references: 21331520
references: Alcohol. 2002 Nov;28(3):157-67
references: 12551757
references: Behav Genet. 2012 Jul;42(4):636-46
references: 22382757
references: Neuropsychopharmacology. 2012 Sep;37(10):2310-21
references: 22669169
references: Hum Genet. 2010 Nov;128(5):491-9
references: 20725741
references: Neuropharmacology. 2009 Jan;56(1):237-46
references: 18723036
references: J Pharmacol Exp Ther. 2010 Mar;332(3):933-9
references: 20007754
references: Adv Pharmacol. 2014;69:513-51
references: 24484986
references: Eur J Pharmacol. 1993 Nov 9;249(2):207-13
references: 8287902
references: Recent Pat CNS Drug Discov. 2012 Aug;7(2):145-50
references: 22574675
references: Pharmacol Biochem Behav. 2000 Jul;66(3):637-43
references: 10899382
references: Rev Physiol Biochem Pharmacol. 2003;147:1-46
references: 12783266
references: Br J Pharmacol. 2010 May;160(2):334-45
references: 20331614
references: Psychopharmacology (Berl). 1992;107(2-3):285-9
references: 1615127
references: Pharmacol Rep. 2006 Nov-Dec;58(6):777-98
references: 17220536
references: Annu Rev Pharmacol Toxicol. 2007;47:699-729
references: 17009926
references: Addiction. 2013 Oct;108(10 ):1818-28
references: 23692359
references: Psychopharmacology (Berl). 2009 Mar;203(1):99-108
references: 18987848
references: Pharmacol Biochem Behav. 2013 Sep;110:161-7
references: 23872372
references: J Neurochem. 1992 Sep;59(3):848-56
references: 1494911
references: Pharmacol Biochem Behav. 2004 Nov;79(3):439-50
references: 15582015
references: Alcohol. 2012 May;46(3):205-15
references: 22459873
references: Alcohol Clin Exp Res. 2013 Apr;37(4):655-62
references: 23164049
references: Annu Rev Pharmacol Toxicol. 2009;49:57-71
references: 18834313
references: J Neurosci. 2002 Feb 15;22(4):1208-17
references: 11850448