(L) A classic instinct – salt appetite – is linked to drug addiction (2011)

Comments: It’s common knowledge among addiction researchers that behavioral addictions and substance addictions involve the same pathways and similar or overlapping mechanisms. This is another study corroborating this paradigm. Addictions hijack our normal pathways in the hub of the reward circuit, which is why they affect us in so many ways.


Durham, N.C., U.S. and Melbourne, Australia — A team of Duke University Medical Center and Australian scientists has found that addictive drugs may have hijacked the same nerve cells and connections in the brain that serve a powerful, ancient instinct: the appetite for salt.

Their rodent research shows how certain genes are regulated in a part of the brain that controls the equilibrium of salt, water, energy, reproduction and other rhythms – the hypothalamus. The scientists found that the gene patterns activated by stimulating an instinctive behavior, salt appetite, were the same groups of genes regulated by cocaine or opiate (such as heroin) addiction.

“We were surprised and gratified to see that blocking addiction-related pathways could powerfully interfere with sodium appetite,” said co-lead author Wolfgang Liedtke, M.D., Ph.D., an Assistant Professor of Medicine and Neurobiology at Duke University. “Our findings have profound and far-reaching medical implications, and could lead to a new understanding of addictions and the detrimental consequences when obesity-generating foods are overloaded with sodium.”

The study was published in the Proceedings of the National Academy of Sciences early edition online on July 11.

“Though instincts like salt appetite are basically genetic neural programs, they may be substantially changed by learning and cognition,” said co-lead author Professor Derek Denton, of the University of Melbourne and the Florey Neuroscience Institute, who is renowned for his pioneering work in the field of instinctive behavior. “Once the genetic program is operating, experiences that are part of the execution of the program become embodied in the overall patterns of an individual’s behavior, and some scientists have theorized that drug addiction may use nerve pathways of instinct. In this study, we have demonstrated that one classic instinct, the hunger for salt, is providing neural organization that subserves addiction to opiates and cocaine.”

Deeply embedded pathways of an ancient instinct may explain why addiction treatment with the chief objective of abstinence is so difficult, said Denton. Liedtke said that this might be relevant given the appreciable success of maintenance approaches that don’t involve abstinence, like replacing heroin with methadone and cigarettes with nicotine gum or patches.

“The work opens new pathways of experimental approach to addiction,” Denton said.

The study was the first to examine gene regulation in the hypothalamus for salt appetite. The team used two techniques to induce the instinctive behavior in mice – they withheld salt for a while combined with a diuretic and they also used the stress hormone ACTH to increase salt needs.

Liedtke, who is also affiliated with the Duke Center for Translational Neuroscience and the Duke Pain Clinics, said the researchers were surprised that they could detect that genes were “turned on” or “turned off” in salt appetite, these patterns were often substantially reversed within ten minutes of the animals’ drinking salt solution, well before any significant salt could be absorbed from the gut into the bloodstream. The question of how this occurs is perplexing, and opens an entirely new field for exploration, Liedtke said.

In terms of survival advantage of this behavior, fast satisfaction of salt appetite makes sense. Among wild animals, the ability to rapidly compensate for salt need by avidly lapping a salty solution means that depleted animals can drink to gratification and leave quickly, reducing their vulnerability to predators.

The Duke-Melbourne research team found that when the animal harbors a robust sodium appetite, a certain region of the hypothalamus seems to become susceptible to the effects of dopamine, which is the brain’s internal currency for reward. That suggests that the state of the instinctive need, the sodium-depleted state, “spring-loads” the hypothalamus for the subjective experience of reward which follows when animals gratify the need – a satisfied feeling. This concept is substantiated by their finding that the local actions of dopamine on a sub-region of the hypothalamus are critical for the animals’ instinctive behavior.


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


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.