Peter R. Martin: Historical Vocabulary of Addiction, Vol. II



        According to the electronic version of the Oxford English Dictionary (OED), the noun allostasis is formed within English by compounding of the noun stasis with the combining form allo.   The noun stasis is a borrowing from Latin derived from the Greek στάσις (meaning “standing, station, stoppage”) and στα- (meaning “to stand”) that has acquired meanings and uses in English in subjects as varied as Pathology (mid 1700s) to Psychoanalysis (1940s).  Of relevance to our discussion are two meanings documented in OED. 

        The first meaning (“A stagnation or stoppage of the circulation of any of the fluids of the body, especially of the blood in some part of the blood vessels.”) is exemplified by a quotation of the English physician Robert James (1703–1776) in his renowned treatise (Grange 1962) A medicinal dictionary; including physic, surgery, anatomy, chymistry, and botany, in all their branches relative to  (James 1743): “Stasis,..a Stagnation.”  The second, more general use (“Inactivity; stagnation; a state of motionless or unchanging equilibrium.”) is as employed by the American novelist John Updike (1932–2009) in The Coup (Updike 1979): “A religion whose antipodes are motion and stasis.”  The combining form allo which is “a borrowing from Greek ἀλλο-” is used for “Forming nouns and adjectives with the sense ‘other, different(ly).’”  Compounding of these components of the word provides the noun allostasis its meaning in OED: “The continual process of reaction and adaptation to environmental changes and demands required for an organism to maintain physiological stability.” 

        The combining form to which stasis is joined can be employed to convey distinctly different viewpoints of how biological systems maintain (relative) equilibrium when exposed to multiple stressors in the course of their very existence.  The noun equilibrium must first be examined as it is through this fundamental physical concept that the biological ideas here under discussion were conceived.   

        The word is a borrowing from the Latin aequilībrium derived from aequus (“equal) and lībra (“balance”).  In the physical sense and also as relevant to biologic systems, the OED definition of equilibrium is: “The condition of equal balance between opposing forces; that state of a material system in which the forces acting upon the system, or those of them which are taken into consideration, are so arranged that their resultant at every point is zero. A body is said to be in stable equilibrium, when it returns to its original position after being disturbed; in unstable when it continues to move in the direction given to it by the disturbing force; in neutral, when it remains stationary in its new position.”  An example of the first use of equilibrium in the English language is attributed to the Anglo-Irish natural philosopher Robert Boyle (1627–1691), for whom is named the law defining the inversely proportional relationship between the absolute pressure and volume of a gas, if the temperature is kept constant within a closed system (Boyle, Flesher and Davis 1682): “The pressure on all hands being reduced as it were to an Æquilibrium.”    

        Historically, the first major combining word to be linked to stasis was homeo, derived from the Greek ὅμοιος (“of the same kind, like, similar”) to form homeostasis.  In OED, homeostasis is defined as: “The maintenance of a dynamically stable state within a system by means of internal regulatory processes that tend to counteract any disturbance of the stability by external forces or influences; the state of stability so maintained; specifically, in Physiology, the maintenance of relatively constant conditions in the body (e.g., as regards blood temperature) by physiological processes that act to counter any departure from the normal.”  

        The recognition of the vital importance of maintaining equilibrium in biological systems dates to the work of the French physiologist Claude Bernard (1813–1878).  Bernard coined the term milieu intérieur to describe the relative constancy of the biological environment within the cells of the body that is fundamental to all living organisms (Bernard 1865).  Bernard (1854) wrote: “The stability of the internal environment [the milieu intérieur] is the condition for the free and independent life.”  He proceeded to explain:

        “The living body, though it has need of the surrounding environment, is nevertheless relatively independent of it. This independence which the organism has of its external environment, derives from the fact that in the living being, the tissues are in fact withdrawn from direct external influences and are protected by a veritable internal environment which is constituted, in particular, by the fluids circulating in the body.

        The constancy of the internal environment is the condition for free and independent life: the mechanism that makes it possible is that which assured the maintenance, within the internal environment, of all the conditions necessary for the life of the elements.

        The constancy of the environment presupposes a perfection of the organism such that external variations are at every instant compensated and brought into balance. In consequence, far from being indifferent to the external world, the higher animal is on the contrary in a close and wise relation with it, so that its equilibrium results from a continuous and delicate compensation established as if the most sensitive of balances.”

        The term milieu intérieur is defined in OED as: “The extracellular fluid forming the environment of cells in a multicellular organism; (also) the homeostatically maintained internal environment of the body.” 

        This notion of equilibrium within individual cells within the body is a foreshadowing of the biological concept of homeostasis, a term coined in 1929 (Dale 1947) by the eminent American physiologist Walter Bradford Cannon (1871–1945), intended to consider the entire body through complex communications among organ systems in a veritable symphony of responses to environmental stressors that may include pain, hunger, fear and rage among others to maintain integrity (Cannon 1929):  

        “The constant conditions which are maintained in the body might be termed equilibria. That word, however, has come to have fairly exact meaning as applied to relatively simple physico-chemical states, in closed systems, where known forces are balanced. The coordinated physiological processes which maintain most of the steady states in the organism are so complex and so peculiar to living beings - involving, as they may, the brain and nerves, the heart, lungs, kidneys and spleen, all working cooperatively - that I have suggested a special designation for these states, homeostasis. The word does not imply something set and immobile, a stagnation. It means a condition - a condition which may vary, but which is relatively constant.”

        This model of homeostatic adaptation to maintain integrity of organisms has been extensively utilized in the 21st century to expand our understanding of biological systems and the human body in health and disease (Davies 2016).  The concept that stressful experiences encountered repeatedly during the course of life may change the body in multiple ways rather bouncing back to as it was initially has origins in the work of Hans Selye (1907–1982), the pioneering Hungarian-Canadian endocrinologist (Selye 1956). 

        He theorized that there were three phases of responding to stress by organisms, incorporating and progressing beyond the ideas of Cannon.  Selye believed that while acute stressors affect an organism almost reversibly, chronic stressors may exert their effects over the longer term by remodeling the system.  According to the General Adaptation Syndrome (GAS) of Selye, organisms respond to stress first in a nonspecific mobilization phase, which promotes sympathetic nervous system activity much as articulated by Cannon; then follows a resistance phase, during which the organism makes efforts to cope with the threat; and finally, an exhaustion phase, which depletes its physiological resources and probably makes irreversible alterations to the entire body, including the brain, the behavioral governor of the organism and wherein mental illnesses such as addiction or mood disorders originate.

        The study of chronic exposures to stressful stimuli or toxins led to recognition that homeostasis may have conceptual limitations in explaining lasting (or irreversible) adaptive changes in biological systems.  Hans Selye (1975) employed the combining word hetero (often used before a vowel from the Greek ἕτερος, meaning “the other of two, other, different; a formative of many scientific and other terms, often in opposition to homo-, sometimes to auto-, homoeo-, iso-, ortho-, syn-,”) linked to stasis to form heterostasis to indicate that the system may be irreversibly transformed.  He wrote: “I propose to speak of heterostasis (heteros = other; stasis = fixity) as the establishment of a new steady state by exogenous (pharmacologic) stimulation of adaptive mechanisms through the development and maintenance of dormant tissue reactions.” 

        Of note, heterostasis is not defined in OED and is not commonly used, despite the validity of the notion as expressed by Selye.  Rather, this more evolved perspective of biological adaptation distinct from homeostasis, representing the notion of predictive regulation, quite similar to heterostasis, has come to be specifically termed allostasis.  The word allostasis implies that it is the brain that accounts for the lasting or irreversible biological systems changes within the body as a whole. 

        The earliest evidence for use of the word allostasis in OED is from the American neuroscientist Peter Sterling (1940—) and his colleague Joseph Eyer (1944—2017) in Handbook of Life Stress, Cognition & Health (Sterling and Eyer 1988): “To maintain stability an organism must vary all the parameters of its internal milieu and match them appropriately to environmental demands. We refer to this principle as allostasis, meaning ‘stability through change’.”  Accordingly, as articulated by Sterling (2012), the allostatic model is one that minimizes the frequency and size of errors during biological adaptation; thus, it is intrinsically moreefficient than homeostasis, which waits for errors to occur and then corrects them by negative feedback.  As he continues to explain further:

        “The premise of the standard regulatory model, “homeostasis”, is flawed: the goal of regulation is not to preserve constancy of the internal milieu. Rather, it is to continually adjust the milieu to promote survival and reproduction. Regulatory mechanisms need to be efficient, but homeostasis (error-correction by feedback) is inherently inefficient. Thus, although feedbacks are certainly ubiquitous, they could not possibly serve as the primary regulatory mechanism.

        “A newer model, “allostasis”, proposes that efficient regulation requires anticipating needs and preparing to satisfy them before they arise. The advantages: (i) errors are reduced in magnitude and frequency; (ii) response capacities of different components are matched -- to prevent bottlenecks and reduce safety factors; (iii) resources are shared between systems to minimize reserve capacities; (iv) errors are remembered and used to reduce future errors. This regulatory strategy requires a dedicated organ, the brain.

        “The brain tracks multitudinous variables and integrates their values with prior knowledge to predict needs and set priorities. The brain coordinates effectors to mobilize resources from modest bodily stores and enforces a system of flexible trade-offs: from each organ according to its ability, to each organ according to its need. The brain also helps regulate the internal milieu by governing anticipatory behavior. Thus, an animal conserves energy by moving to a warmer place – before it cools, and it conserves salt and water by moving to a cooler one before it sweats.”

        The vital role of the brain, referred to above as the dedicated organ, is to encode, retrieve and produce learned behavior.  These learning-related traces guide the organism in multitudinous tasks needed to maintain biological integrity (equilibrium) and to ensure that it is not destroyed by predators so that it can ultimately reproduce and perpetuate the species.  These important tasks are accomplished by storing experiences in neuronal circuits within the organ of learning (brain) for later use (Martin 2019c, 2021b).  Accordingly, an animal learns to predict which behaviors may profitably be repeated and which might end in catastrophe and should be avoided.

        It is in this manner that an organism maps a course through life, influenced by prediction and anticipation of the consequences of a chosen path.  And if perchance a behavior delivers a result better than predicted, certain neurons reward the “choosing circuits” within the prefrontal cortex via secretion of a pulse of dopamine (Martin 2020). This highly salient neurotransmitter signal encourages the brain to store the memory flagged as a behavior for frequent repetition, termed reward learning (Glimcher 2014, Schultz 2015).  

        Such forms of learning have been documented in our evolutionary ancestors such as the fruit fly Drosopholia melanogaster but in H. sapiens reward learning has become particularly important because the pulse of dopamine is experienced as “a pulse of satisfaction – a brief uplift in mood” (Sterling 2018).  These learning-related responses to stress may actually damage the body through stress-related disease processes, referred to as allostatic load (McEwen 1998).  More important for this discussion, reward learning forms the basis of pathological behaviors as addiction that constitutes behaviors that may be so frequently repeated as to become out-of-control and self-destructive, thereby overwhelming the behavioral repertoire.

        Koob and Le Moal introduced the notion of allostasis into the field of addiction to conceptualize a striking characteristic of addictive disorders, namely “the persistent vulnerability to relapse long after drug-taking has ceased,” as if a memory trace remained that guides behavior (Koob and Moal 1997; Roberts, Heyser, Cole et al. 2000; Koob and Le Moal 2001).  They view addiction “as a cycle of spiraling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking.” Accordingly, they proposed that:

        “The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drugtaking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse.”

        According to this perspective, allostasis refers to the process by which the body actively adapts to stressors in order to maintain stability and function.  In the context of addiction, repeated exposure to drugs or addictive behaviors can lead to dysregulation of both stress responses and reward systems, ultimately leading to a state of chronic allostasis, facilitating drug-seeking behaviors that seem impossible to satisfy and often persist despite potentially very negative consequences.

        The neurobiological underpinnings of allostasis are complex and involve interactions of multiple brain regions, neurotransmitter systems and post-synaptic intracellular processes.  One important factor is the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which actuates stress responses. Chronic drug use can lead to long-lasting changes in the HPA axis, including increased cortisol production and altered sensitivity to stressors (Martin 2021a). 

        Other key brain regions include the prefrontal cortex, amygdala, ventral striatum, and various regions of the midbrain and brainstem, all of which are part of the brain's reward circuitry (Martin 2019b). These regions interact with each other in complex ways to regulate not only drug-seeking behavior, but also a range of other psychological and physiological processes such as mood and emotion.  Such interactions occur via neurotransmitter systems such as dopamine, glutamate, GABA and opioids which, of course, mediate both allostasis and addiction.  Repeated drug use can lead to alterations in these systems, which can promote drug-seeking behavior, and lead to withdrawal symptoms and negative affect when drug use is discontinued (Martin 2018, 2019a).  

        Gene expression and protein synthesis change considerably in the cells in the brain and the rest of the body in response to stressors and can vary depending on the specific type and duration of the stressor, as well as genetic and environmental factors.  One of the main changes that occurs in response to stressors is an increase in the expression of genes involved in the stress response, such as those that encode for stress hormones, inflammatory cytokines and other signaling molecules. These genes are typically regulated by transcription factors, which are proteins that bind to specific regions of DNA and control the expression of nearby genes. 

        For example, the transcription factor cAMP response element-binding protein (CREB) is involved in the regulation of the HPA axis and is activated by stress hormones such as cortisol.  CREB binds to specific DNA sequences and induces the expression of genes involved in the stress response, such as those that encode for neuropeptides and neurotransmitters.  Additionally, the transcription factor NF-κB, a key regulator of inflammation is activated in response to various stressors, such as infection, injury, or psychological stress and induces the expression of genes involved in inflammation, such as cytokines and chemokines.  

        At the protein level, stressors can induce changes in the synthesis and activity of enzymes, receptors and other signaling molecules that are involved in the stress response.  For example, stress hormones such as cortisol can activate various enzymes that regulate glucose metabolism and can also alter the activity of ion channels and neurotransmitter receptors in the brain.  Overall, the changes in gene expression and protein synthesis that occur in response to stressors are complex and interdependent and involve a wide range of molecular mechanisms and signaling pathways. The precise changes that determine allostasis depend on the specific type and duration of the stressor, as well as genetic and environmental factors.

        As to be expected, allostasis in addiction is closely related to learning and memory (Kalant, LeBlanc and Gibbins 1971).  Allostasis is the process by which the body adapts to stressors and maintains physiological stability and learning and memory are the origins of behaviors that facilitate allostatic processes. When the body is exposed to stress, it releases various hormones and neurotransmitters that help coordinate the stress response. These same hormones and neurotransmitters also play a role in learning and memory (Martin 2019c).  For example, stress hormones such as cortisol and epinephrine can enhance memory consolidation, which is the process by which new memories are transferred from short-term to long-term storage.  

        At the same time, stress can also impair cognitive performance, particularly when stress is prolonged and chronic, as the hippocampus is particularly sensitive to brain injury from hypercortisolemia.  In addition, various of the brain regions that are involved in allostasis and stress regulation, such as the hippocampus, amygdala and prefrontal cortex, are also critical for learning and memory. Disruptions to these brain regions, such as those that can occur during chronic stress or addiction, can impair learning and memory processes and associated allostatic disorders (McEwen 1998). 

        Ultimately, understanding the role of allostasis in addiction may provide insights into potential treatment strategies for this complex condition.  Most importantly, neurobiological adaptation based on allostatic processes allow us to explain why the nervous system never returns to the way it was when drug use first began.  This is reminiscent of the quotation attributed to the ancient Greek pre-Socratic philosopher Heraclitus (flourished c. 500 BC), who viewed the world as constantly in flux: “No man ever steps in the same river twice, for it’s not the same river and he's not the same man.”  The allostatic processes that occur with addiction may explain why the essence of recovery is not simply stopping to use the drug or engage in a pathological behavior; recovery requires changing reinforcement contingencies, usually with altered lifestyles and fulfilment of human relationships (Martin, Weinberg and Bealer 2007).



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March 7 , 2024