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The Journal of Neuroscience, February 21, 2007, 27(8):1964-1972; doi:10.1523/JNEUROSCI.3661-06.2007

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Cellular/Molecular
Long-Term Upregulation of Protein Kinase A and Adenylate Cyclase Levels in Human Smokers

Bruce T. Hope,¹ Deepti Nagarkar,¹ Sherry Leonard,² and Roy A. Wise¹

¹Behavioral Neuroscience Branch, Intramural Research Program/National Institute on Drug Abuse/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland 21224, and ²Department of Psychiatry, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045

Correspondence should be addressed to Dr. Bruce T. Hope, The National Institute on Drug Abuse, Behavioral Neuroscience Branch, 5500 Nathan Shock Drive, Building C, Baltimore, MD 21224. Email: bhope{at}intra.nida.nih.gov

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.

Key words: cAMP; nicotine; nucleus accumbens; addiction; neuroadaptations; PKA

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Received Aug. 23, 2006; revised Jan. 12, 2007; accepted Jan. 18, 2007.

Correspondence should be addressed to Dr. Bruce T. Hope, The National Institute on Drug Abuse, Behavioral Neuroscience Branch, 5500 Nathan Shock Drive, Building C, Baltimore, MD 21224. Email: bhope{at}intra.nida.nih.gov

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