title: The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies.
abstract: OBJECTIVE
  Recent data have indicated that α3β4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal.
  
  
  METHODS
  To assess the role of α3β4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence.
  
  
  RESULTS
  BXD recombinant mouse lines demonstrated an increased expression of α3, β4 and α5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, α5 and β4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective α3β4* nACh receptor antagonists, α-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the α3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the α4β2* nACh receptor subtype is not involved in morphine somatic withdrawal signs.
  
  
  CONCLUSIONS
  Overall, our findings suggest an important role for the α3β4* nACh receptor subtype in morphine physical dependence.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Muldoon
authors.forename: K J
authors.initials: KJ
authors.lastname: Jackson
authors.forename: E
authors.initials: E
authors.lastname: Perez
authors.forename: J L
authors.initials: JL
authors.lastname: Harenza
authors.forename: S
authors.initials: S
authors.lastname: Molas
authors.forename: B
authors.initials: B
authors.lastname: Rais
authors.forename: H
authors.initials: H
authors.lastname: Anwar
authors.forename: N T
authors.initials: NT
authors.lastname: Zaveri
authors.forename: R
authors.initials: R
authors.lastname: Maldonado
authors.forename: U
authors.initials: U
authors.lastname: Maskos
authors.forename: J M
authors.initials: JM
authors.lastname: McIntosh
authors.forename: M
authors.initials: M
authors.lastname: Dierssen
authors.forename: M F
authors.initials: MF
authors.lastname: Miles
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: De Biasi
authors.forename: M I
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000818:Animals; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009021:Morphine Dependence / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016548:Prosencephalon / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; C447159:CHRNB4 protein, human; C403530:nicotinic receptor alpha3beta4; C523972:CHRNA5 protein, mouse
references.citation: Neuropharmacology. 2004 Sep;47(3):401-7
references.pmid: 15275829
references.citation: Pharmacol Biochem Behav. 2013 Aug;109:77-83
references.pmid: 23651795
references.citation: Eur J Pharmacol. 2005 Apr 25;513(3):207-18
references.pmid: 15862802
references.citation: Nat Genet. 2012 Jul 22;44(8):955-9
references.pmid: 22820512
references.citation: J Neurosci. 2009 Mar 11;29(10):3014-8
references.pmid: 19279237
references.citation: J Pharmacol Exp Ther. 2010 Jul;334(1):137-46
references.pmid: 20400469
references.citation: Neuropsychopharmacology. 2010 Aug;35(9):1921-31
references.pmid: 20485328
references.citation: Drug Alcohol Depend. 2009 Oct 1;104 Suppl 1:S64-9
references.pmid: 19596527
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Neuron. 2011 May 12;70(3):522-35
references.pmid: 21555077
references.citation: Addiction. 1998 Apr;93(4):549-59
references.pmid: 9684393
references.citation: Hum Genet. 2010 Nov;128(5):491-9
references.pmid: 20725741
references.citation: Neuropsychopharmacology. 2012 May;37(6):1367-76
references.pmid: 22278092
references.citation: J Med Chem. 2010 Nov 25;53(22):8187-91
references.pmid: 20979364
references.citation: J Neurosci. 1999 Nov 1;19(21):9298-305
references.pmid: 10531434
references.citation: J Neurosci. 2004 Nov 10;24(45):10035-9
references.pmid: 15537871
references.citation: Br J Pharmacol. 2013 Dec;170(8):1582-606
references.pmid: 24528238
references.citation: J Neurosci. 2002 Apr 1;22(7):2522-9
references.pmid: 11923417
references.citation: G3 (Bethesda). 2011 Nov;1(6):457-70
references.pmid: 22384356
references.citation: Eur J Pharmacol. 2005 Nov 21;525(1-3):98-104
references.pmid: 16289028
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12126-31
references.pmid: 10518587
references.citation: Psychopharmacology (Berl). 2005 Apr;178(4):353-66
references.pmid: 15696323
references.citation: Pain Physician. 2012 Jul;15(3 Suppl):ES9-38
references.pmid: 22786464
references.citation: Neuropharmacology. 2011 Sep;61(4):798-806
references.pmid: 21651919
references.citation: Brain Res. 1990 Aug 27;526(1):45-53
references.pmid: 2078817
references.citation: Neuroreport. 1998 May 11;9(7):1283-5
references.pmid: 9631413
references.citation: Neuropharmacology. 2013 Jul;70:228-35
references.pmid: 23416040
references.citation: PLoS Genet. 2009 Jun;5(6):e1000529
references.pmid: 19543373
references.citation: Amino Acids. 2012 Aug;43(2):897-909
references.pmid: 22101982
references.citation: Neuropharmacology. 2009 Jan;56(1):237-46
references.pmid: 18723036
references.citation: Br J Pharmacol. 2010 Aug;160(7):1577-9
references.pmid: 20649561
references.citation: Am J Hum Genet. 2004 Apr;74(4):765-9
references.pmid: 14997420
references.citation: Neuropharmacology. 1999 Jun;38(6):769-83
references.pmid: 10465681
references.citation: J Neurosci. 1998 Nov 1;18(21):8571-9
references.pmid: 9786965
references.citation: J Pharmacol Exp Ther. 1992 May;261(2):669-77
references.pmid: 1578378
references.citation: BMC Bioinformatics. 2010 May 28;11:288
references.pmid: 20509871
references.citation: Neurosci Lett. 1999 May 7;266(2):113-6
references.pmid: 10353340
references.citation: J Neurosci. 1995 Mar;15(3 Pt 1):1912-39
references.pmid: 7891142
references.citation: Br J Pharmacol. 2010 Aug;160(7):1573-6
references.pmid: 20649560
references.citation: Nature. 2003 Mar 20;422(6929):297-302
references.pmid: 12646919
references.citation: Genes Brain Behav. 2010 Mar 1;9(2):129-59
references.pmid: 19958391
references.citation: Clin Pharmacol Ther. 1999 Jun;65(6):685-94
references.pmid: 10391674
references.citation: Neuropsychopharmacology. 2012 Jan;37(1):306-7
references.pmid: 22157872