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Allostasis and Addiction

An overall conceptual framework throughout this review is that drug dependence represents a break with homeostatic brain regulatory mechanisms that regulate the emotional state of the animal. However, the nature of engagement of the brain stress and antistress systems produced by repeated self-administration of drugs of abuse argues that the view of drug addiction representing a simple break with homeostasis is not sufficient to explain a number of key elements of addiction. Drug addiction, similar to other chronic physiological disorders, such as high blood pressure, worsens over time, is subject to significant environmental influences (e.g., external stressors), and leaves a residual neural trace that allows rapid ?readdiction? even months and years after detoxification and abstinence. These characteristics of drug addiction have led to a reconsideration of drug addiction as more than simply homeostatic dysregulation of emotional function but rather as a dynamic break with homeostasis of these systems, termed allostasis.

Allostasis is defined as ?stability through change? and is different from homeostasis because feed-forward, rather than negative feedback, mechanisms are hypothesized to be engaged (Sterling and Eyer, 1988). However, precisely this ability to mobilize resources quickly and to use feed-forward mechanisms leads to an allostatic state if the systems do not have sufficient time to reestablish homeostasis. An allostatic state can be defined as a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level.

The brain stress systems respond rapidly to anticipated challenges to homeostasis but are slow to habituate or do not readily shut off once engaged (Koob, 1999). Thus, the very physiological mechanism that allows a rapid and sustained response to environmental challenge becomes the engine of pathology if adequate time or resources are not available to shut off the response. Thus, the interaction between CRF and norepinephrine in the brainstem and basal forebrain, the interaction between orexin and CRF in the hypothalamus and basal forebrain, and the interaction between CRF and vasopressin and/or orexin could lead to chronically dysregulated emotional states (Koob, 1999). Similar allostatic mechanisms can be hypothesized to be involved in driving the pathology associated with the brain stress and antistress systems in addiction (Koob and Le Moal, 2001). Repeated challenges (e.g., with drugs of abuse) lead to attempts of the brain via molecular, cellular, and neurocircuitry changes to maintain stability, but at a cost. For the drug addiction framework elaborated here, the residual deviation from normal brain reward threshold regulation is termed an allostatic state. This state represents a combination of chronic elevation of reward set point fueled by numerous neurobiological changes, including decreased function of reward circuits, loss of executive control, and facilitation of stimulus-response associations, but also recruitment of the brain stress systems and compromises to the brain antistress systems. All of these effects contribute to the compulsivity of drug seeking and drug taking known as addiction (Koob and Le Moal, 2008).

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Acknowledgments

This work was supported by National Institutes of Health funding from the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute of Diabetes and Digestive and Kidney Diseases, and private funding from the Pearson Center for Alcoholism and Addiction Research. The author would like to thank Michael Arends and Mellany Santos for their help with manuscript preparation, Janet Hightower for her invaluable assistance with the figures, Dr. Charles Neal for his work on the neuroanatomical distribution of nociceptin (Neal et al., 1999) and for his help with Figure 9, and Dr. Michel Le Moal for discussions and the conceptual framework. The author also would like to thank the following people for critical comments and discussions on the manuscript: Dr. Heather Richardson, Dr. Scott Edwards, Dr. Dong Ji, Dr. Kaushik Misra, Dr. Laura Orio, Dr. Nick Gilpin, Dr. Olivier George, Dr. Marisa Roberto, Dr. Sunmee Wee, and Dr. Benjamin Boutrel. This is publication number 19397 from The Scripps Research Institute.

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Footnotes

SUPPLEMENTAL DATA

The Supplemental Data can be found with this article online at http://www.neuron.org/cgi/content/full/59/1/11/DC1/.

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