Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite

Contributed by Derek A. Denton, June 7, 2011 (sent for review April 1, 2011)
July 11, 2011
108 (30) 12509-12514

Abstract

Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats’ lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational–medical implications.

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Data Availability

Data deposition: The microarray data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE29451, GSM729057–GSM729100, and GSM729100).

Acknowledgments

The authors appreciate valuable discussions with Drs. Marc Caron, Nicole Calakos, Sidney Simon, and Sayan Mukherjee and the expert technical assistance of James M. Friedman (all of Duke University). Support for this work was given by The G. Harold and Leila Y. Mathers Foundation, The Robert J. Jr and Helen C. Kleberg Foundation, the Search Foundation, Ms. Diana Gibson, Mr. Robert Albert, Mr. Baillieu Myer, Dr. Mark Nelson, Duke University (to W.B.L.), National Health and Medical Research Council (Australia) Fellowships 454369 (to M.J.M.) and 454303 (to A.J.L.), The Derek Denton Endowment Fund, a Trinity College Undergraduate Fellowship (to S.J.H.), and a Robert H. Ebert Clinical Scholarship of the Klingenstein Fund (to W.B.L.).

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 108 | No. 30
July 26, 2011
PubMed: 21746918

Classifications

Data Availability

Data deposition: The microarray data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE29451, GSM729057–GSM729100, and GSM729100).

Submission history

Published online: July 11, 2011
Published in issue: July 26, 2011

Acknowledgments

The authors appreciate valuable discussions with Drs. Marc Caron, Nicole Calakos, Sidney Simon, and Sayan Mukherjee and the expert technical assistance of James M. Friedman (all of Duke University). Support for this work was given by The G. Harold and Leila Y. Mathers Foundation, The Robert J. Jr and Helen C. Kleberg Foundation, the Search Foundation, Ms. Diana Gibson, Mr. Robert Albert, Mr. Baillieu Myer, Dr. Mark Nelson, Duke University (to W.B.L.), National Health and Medical Research Council (Australia) Fellowships 454369 (to M.J.M.) and 454303 (to A.J.L.), The Derek Denton Endowment Fund, a Trinity College Undergraduate Fellowship (to S.J.H.), and a Robert H. Ebert Clinical Scholarship of the Klingenstein Fund (to W.B.L.).

Authors

Affiliations

Wolfgang B. Liedtke1 [email protected]
Departments of aMedicine/Neurology and
Neurobiology, Duke University, Durham, NC 27710;
Michael J. McKinley
Florey Neuroscience Institutes,
Department of Physiology,
Lesley L. Walker2
Florey Neuroscience Institutes,
Hao Zhang2
Neurobiology, Duke University, Durham, NC 27710;
Andreas R. Pfenning2
Neurobiology, Duke University, Durham, NC 27710;
John Drago
Florey Neuroscience Institutes,
Center for Neuroscience, and
Sarah J. Hochendoner
Departments of aMedicine/Neurology and
Neurobiology, Duke University, Durham, NC 27710;
Donald L. Hilton
Department of Neurosurgery, University of Texas Health Science Center, San Antonio, TX 78229; and
Andrew J. Lawrence
Florey Neuroscience Institutes,
Center for Neuroscience, and
Derek A. Denton1 [email protected]
Florey Neuroscience Institutes,
Office of the Dean, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Parkville, VIC 3010, Australia;
Baker Heart Research Institute, Melbourne, Victoria 3004, Australia

Notes

1
To whom correspondence may be addressed. E-mail: [email protected] or [email protected].
Author contributions: W.B.L., M.J.M., L.L.W., H.Z., J.D., S.J.H., D.L.H., A.J.L., and D.A.D. designed research; W.B.L., M.J.M., L.L.W., H.Z., S.J.H., and A.J.L. performed research; J.D. contributed new reagents/analytic tools; W.B.L., M.J.M., L.L.W., A.R.P., and A.J.L. analyzed data; W.B.L. and D.A.D. wrote the paper; and W.B.L. and A.R.P. performed biocomputation.
2
L.L.W., H.Z., and A.R.P. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

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    Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite
    Proceedings of the National Academy of Sciences
    • Vol. 108
    • No. 30
    • pp. 12187-12559

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