title: Long-term upregulation of protein kinase A and adenylate cyclase levels in human smokers.
abstract: Repeated injections of cocaine and morphine in laboratory rats cause a variety of molecular neuroadaptations in the cAMP signaling pathway in nucleus accumbens and ventral tegmental area. Here we report similar neuroadaptations in postmortem tissue from the brains of human smokers and former smokers. Activity levels of two major components of cAMP signaling, cAMP-dependent protein kinase A (PKA) and adenylate cyclase, were abnormally elevated in nucleus accumbens of smokers and in ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of the catalytic subunit of PKA were correspondingly higher in the ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of other candidate neuroadaptations, including glutamate receptor subunits, tyrosine hydroxylase, and other protein kinases, were within normal range. These findings extend our understanding of addiction-related neuroadaptations of cAMP signaling to tobacco smoking in human subjects and suggest that smoking-induced brain neuroadaptations can persist for significant periods in former smokers.
authors.affiliation: Behavioral Neuroscience Branch, Intramural Research Program/National Institute on Drug Abuse/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland 21224, USA. bhope@intra.nida.nih.gov
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Hope
authors.forename: Deepti
authors.initials: D
authors.lastname: Nagarkar
authors.forename: Sherry
authors.initials: S
authors.lastname: Leonard
authors.forename: Roy A
authors.initials: RA
authors.lastname: Wise
mesh_terms: D000222:Adaptation, Physiological; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002102:Cadaver; D020134:Catalytic Domain; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009714:Nucleus Accumbens / Q000201:enzymology*; D012907:Smoking; D013681:Tegmentum Mesencephali / Q000201:enzymology*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases