Addiction, Stress and Allostasis

March 5, 2003

The following information on the relationship betwen drug (and behavioural?)

addiction and the process of allostasis ( " achieving homeostsais through

change " ) may be of interest to some list members.

An interesting aspect of the following studies is that they relate directly

to attempts to link sports conditioning, training and overtraining to Hans

Selye's early work on adaptation, stress and stressors (see Siff MC,

" Supertraining " 2003, Ch 1). When the adaptive systems of the body are

turned up and turned down again efficiently and not too frequently, the body

is able to cope effectively with challenges that it might not otherwise

survive. However, there are a number of circumstances in which allostatic

systems may either be overstimulated or not perform normally, and this

condition has been termed " allostatic load " or the price of adaptation

(McEwen and Stellar, Arch. Int. Med. 1993; 153:2093.). Allostatic load can

lead to what Selye referred to as dis-ease over long periods.

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Nature Neuroscience online: 10 June 2002, July 2002 Vol 5 No 7 pp 625 - 626

<http://www.nature.com/cgi-taf/DynaPage.taf?file=/neuro/journal/v5/n7/abs/nn872.\

html>

Neurobiological evidence for hedonic allostasis associated with escalating

cocaine use

Serge H. Ahmed, J. Kenny, F Koob & Athina Markou

A paradoxical aspect of the transition to drug addiction is that drug users

spend progressively more time and effort to obtain drug hedonic effects that

continually decrease with repeated experience.

According to the hedonic allostasis hypothesis, increased craving for and

tolerance to the hedonic effects of drugs result from the same chronic

alteration in the regulation of brain reward function (allostasis). Here we

show in rats that repeated withdrawals from prolonged cocaine

self-administration produces a persistent decrease in brain reward function

that is highly correlated with escalation of cocaine intake and that reduces

the hedonic impact of cocaine.

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Allostasis

Sex, stress and the hippocampus: allostasis, allostatic load and the aging

process.

McEwen BS

Neurobiol Aging 2002 Sep;23(5):921.

The adaptive responses of the body that maintain homeostasis in response to

stressors can be called " allostasis " , meaning " achieving stability through

change " .

Mediators produced by the immune system, autonomic nervous system (ANS) and

hypothalamo-pituitary-adrenal(HPA) axis produce allostasis. The brain also

shows allostasis, involving the activation of nerve cell activity and the

release of neurotransmitters. When the individual is challenged repeatedly or

when the allostatic systems remain turned on when no longer needed, the

mediators of allostasis can produce a wear and tear on the body and brain

that has been termed " allostatic load " .

Examples of allostatic load include the accumulation of abdominal fat, the

loss of bone minerals and the atrophy of nerve cells in the hippocampus.

Studies of the hippocampus as a target of stress and sex hormones have

revealed a considerable degree of structural plasticity and remodeling in the

adult brain that differs between the sexes. Three forms of hippocampal

structural plasticity are affected by circulating hormones:

(1) repeated stress causes remodeling of dendrites in the CA3 region;

(2) different modalities of stress suppress neurogenesis of dentate gyrus

granule neurons;

(3) ovarian steroids regulate synapse formation during the estrous cycle of

female rats.

All three forms of structural remodeling of the hippocampus are mediated by

hormones working in concert with excitatory amino acids (EAA) and NMDA

receptors. EAA and NMDA receptors are also involved in neuronal death that is

caused in pyramidal neurons by seizures, by ischemia and by severe and

prolonged psychosocial stress. The aging brain seems to be more vulnerable to

such effects, although there are considerable individual differences in

vulnerability that can be developmentally determined. Moreover, the brain

retains considerable resilience in the face of stress, and estrogens appear

to play a role in this resilience. " Resilience is an example of successful

allostasis in which wear and tear is minimized, and estrogens exemplify the

type of agent that works against the allostatic load associated with aging. "

This review discusses the current status of work on underlying mechanisms for

protection and damage.

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From the Pages of Science Week & SW Neuroscience:

http://scienceweek.com/matrix9.htm

ON THE ADDICTED BRAIN

D. Goldman and C. Barr (National Institute on Alcohol Abuse and Alcoholism,

US) discuss addiction, the authors making the following points:

1) Addictions are relapsing, remitting lifelong illnesses that are

notoriously difficult to treat. One year after they have stopped drinking,

approximately one third of patients with alcoholism remain abstinent, one

third have resumed drinking but not at their former level of consumption, and

one third have relapsed completely. A defining problem with respect to the

treatment of addiction is that we do not know how to restore the addicted

brain to its former state, and many therapies -- for example, methadone

maintenance for opiate addiction -- do not even attempt to do so. Because of

the difficulty of treating addictions and a lack of understanding of the

benefits that partially successful therapy convey to patients, their

families, and the community, many addicts are never identified or treated.

2) Life is complex, but many events can be defined as stress if they are

viewed from the simplistic perspective of their effect on the brain.

Behavioral, physiological, and molecular mechanisms help the body adapt to

stress. Adaptations that return function to a previous set point may be

thought of as homeostatic.(1) However, adaptation may also result in new

physiological set points outside the normal range. This phenomenon, which is

referred to as " allostasis " , is defined as " homeostasis through change " (2)

3) The body functions through the coordinated activity of systems evolved

over millennia. Although humans are highly resilient and capable of

surviving in the most stressful environments, it is not surprising that

chronic or repeated stress increases the risk of a variety of diseases,

including psychiatric disorders. The addictions are among the more important

sources of stress at the individual, family, and community levels. Recently,

allostatic alteration of brain function through stress-related mechanisms

has been identified as one component of the pathway to addiction.(3)

The brain survives addiction, but in the absence of the drug, the brain does

not return to the base-line set point, and chronic dysphoria and anxiety are

present. The clinical goal is to relieve the patient's depression and

anxiety, but treatment of depression alone rather than in combination with

treatment of addiction is often ineffective. Patients with alcoholism who are

abstinent may nevertheless have extended periods of anxiety, depression, and

sleep disturbances, predisposing them to relapse.(4,5)

References:

1. Selye H. The stress of life. New York: McGraw-Hill, 1976.

2. McEwen BS. Stress, adaptation, and disease: allostasis and allostatic

load. Ann N Y Acad Sci 1998;840:33-44.

3. Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and

allostasis. Neuropsychopharmacology 2000;24:97-129.

4. Adinoff B, PR, Bone GH, et al. Hypothalamic-pituitary-adrenal axis

functioning and cerebrospinal fluid corticotropin releasing hormone and

corticotropin levels in alcoholics after recent and long-term abstinence.

Arch Gen Psychiatry 1990;47:325-330.

5.Sillaber I, Rammes G, Zimmermann S, et al. Enhanced and delayed

stress-induced alcohol drinking in mice lacking functional CRH1 receptors.

Science 2002;296:931-933.

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New Engl. J. Med. 2002 347:843

Related Background Brief:

STRESS, ADAPTATION, AND DISEASE: ALLOSTASIS AND ALLOSTATIC LOAD.

Adaptation in the face of potentially stressful challenges involves

activation of neural, neuroendocrine and neuroendocrine-immune mechanisms.

This has been called " allostasis " or " stability through change " by Sterling

and Eyer (Fisher S., Reason J. (eds): Handbook of Life Stress, Cognition and

Health. J. Wiley Ltd. 1988, p. 631), and allostasis is an essential component

of maintaining homeostasis.

When these adaptive systems are turned on and turned off again efficiently

and not too frequently, the body is able to cope effectively with challenges

that it might not otherwise survive. However, there are a number of

circumstances in which allostatic systems may either be overstimulated or

not perform normally, and this condition has been termed " allostatic load " or

the price of adaptation (McEwen and Stellar, Arch. Int. Med. 1993;

153:2093.). Allostatic load can lead to disease over long periods. Types of

allostatic load include

(1) frequent activation of allostatic systems;

(2) failure to shut off allostatic activity after stress;

(3) inadequate response of allostatic systems leading to elevated activity

of other, normally counter-regulated allostatic systems after stress.

The author provides examples for each type of allostatic load from research

pertaining to autonomic, CNS, neuroendocrine, and immune system activity.

The relationship of allostatic load to genetic and developmental

predispositions to disease is also considered.

B.S. McEwen: Ann New York Acad Sci 1998 840:33.

Related Background Brief:

DRUG ADDICTION, DYSREGULATION OF REWARD, AND ALLOSTASIS.

The authors review recent developments in the neurocircuitry and

neurobiology of addiction from a perspective of allostasis. A model is

proposed for brain changes that occur during the development of addiction

that explain the persistent vulnerability to relapse long after drug-taking

has ceased. Addiction is presented 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.

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 drug-taking 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 authors suggest that 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.

G.F. Koob and M. Le Moal: Neuropsychopharmacology 2001 24:97.

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Dr Mel C Siff

Denver, USA

http://groups.yahoo.com/group/Supertraining/

March 6, 2003

Dr Siff,

Given my interest in substance abuse, I found the posted articles most useful.

Thank you for the posting.

Whilst reading them I couldn't help but think if there was a relationship here

regarding weight/diet problems.

A common symptom presenting in treatment centres is high levels of stress in

mostly all clients, including

those with associated weight problems, Anorexia Nervosa, Bulimia and Obesity --

regularly,

treatment response is most favorable when stress reduction techniques are

incorporated in the treatment regime.

There are often quite remarkable results with positive weight changes when

treatment regimes have a dominance

of stress management and counselling focusing on non weight related issues.

Alan BROWN

MELBOURNE

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Mel Siff wrote: