The impact of stress on addiction

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Abstract

This article will review data obtained from both clinical and preclinical investigations demonstrating that exposure to stress has a significant impact on drug addiction. The preclinical literature suggests that stress increases reward associated with psychomotor stimulants, possibly through a process similar to sensitization. While it is not conclusive that a similar process occurs in humans, a growing clinical literature indicates that there is a link between substance abuse and stress. One explanation for the high concordance between stress-related disorders and drug addiction is the self-medication hypothesis, which suggests that a dually diagnosed person often uses the abused substance to cope with tension associated with life stressors or to relieve symptoms of anxiety and depression resulting from a traumatic event. However, another characteristic of self-administration is that drug delivery and its subsequent effects on the hypothalamo–pituitary–adrenal (HPA) axis are under the direct control of the individual. This controlled activation of the HPA axis may result in the production of an internal state of arousal or stimulation that is actually sought by the individual (i.e., the sensation-seeking hypothesis). During abstinence, exposure to stressors or drug-associated cues can stimulate the HPA axis to remind the individual about the effects of the abused substance, thus producing craving and promoting relapse. Continued investigations into how stress and the subsequent activation of the HPA axis impact addiction will result in the identification of more effective and efficient treatment for substance abuse in humans. Stress reduction, either alone or in combination with pharmacotherapies targeting the HPA axis may prove beneficial in reducing cravings and promoting abstinence in individuals seeking treatment for addiction.

Introduction

According to Dr. Hans Selye, stress can be defined as the nonspecific response of the body to any demand placed upon it to adapt, whether that demand produces pleasure or pain (Selye, 1975). Although stressors can elicit different responses in different individuals depending on “conditioning” or interactions with the environment, the sympathetic nervous system and the hypothalamo–pituitary–adrenal (HPA) axis are typically activated (Stratakis and Chrousos, 1995). This stress response or “stress cascade” is responsible for allowing the body to make the necessary physiological and metabolic changes required to cope with the demands of a homeostatic challenge (Miller and O'Callaghan, 2002). Sympathetic nervous system responses include an increase in heart rate, a rise in blood pressure, a shift in blood flow to skeletal muscles, an increase in blood glucose, dilation of the pupils and a stimulation of respiration. Thus, the activation of the sympathetic nervous system results in a variety of physiological processes which prepare the organism for flight or fight, whether to face the stressor or attempt to escape it, to maintain homeostasis.

The HPA axis is initially activated by the secretion of corticotropin-releasing hormone (CRH) from the hypothalamus Sarnyai et al., 2001, Turnbull and Rivier, 1997, Goeders, 2002. CRH-containing neurons projecting from the parvocellular division of the paraventricular nucleus to the external zone of the median eminence release the peptide into the adenohypophyseal portal circulation in response to stress. The binding of CRH to receptors located in the anterior pituitary results in the synthesis of proopiomelanocortin, a large precursor protein that is cleaved to produce several smaller biologically active peptides, including β-endorphin and adrenocorticotropin hormone (ACTH). ACTH diffuses through the general circulation until it reaches the adrenal glands, where it stimulates the biosynthesis and secretion of adrenocorticosteroids (i.e., cortisol in humans or corticosterone in rats). The Type I mineralocorticoid receptor has a high affinity for corticosterone and is usually fully occupied at basal concentrations of the hormone. This receptor also displays a high affinity for the mineralocorticoid, aldosterone. The Type II glucocorticoid receptor has a lower affinity for corticosterone and is more likely to be occupied when plasma corticosterone is elevated (e.g., during “stress”). This receptor also has a high affinity for the synthetic glucocorticoid, dexamethasone.

When one considers the impact of stress on drug addiction and how activation of the HPA axis augments the motivation and/or vulnerability for drug use, a number of questions come to mind. How can a stimulus (i.e., stress) that is generally regarded as something to avoid or escape actually increase the perception of drug reward? Furthermore, how can drugs (e.g., cocaine, amphetamine) that result in the activation of the HPA axis be among the most reinforcing drugs ever studied? This article will address these questions in the context of both clinical and preclinical data.

Section snippets

Stress and vulnerability to addiction

During the acquisition of drug self-administration, an animal comes into contact with a drug and its potentially rewarding effects for the first time (Goeders, 2002). This is also when the animal learns to make the response that leads to drug delivery, thereby producing reinforcement. Environmental events that decrease the lowest dose of a drug that is recognized by the animal as a reinforcer are considered to be events that increase vulnerability or the propensity for an animal to acquire

Stress and relapse to addiction

Reinstatement is a preclinical approach that is widely regarded as an animal model of the propensity to relapse to drug taking, involving mechanisms related to the development and expression of craving Gerber and Stretch, 1975, Stewart and de Wit, 1987. A number of excellent reviews on the reinstatement of extinguished drug seeking have recently been published Stewart, 2000, Weiss et al., 2001, See, 2002, Shaham et al., 2003, including specific reviews on the reinstatement of cocaine Spealman

Conclusions

Data obtained from clinical and preclinical investigations indicate that exposure to stress increases the vulnerability for addiction. The preclinical literature suggests that stress increases reward associated with psychomotor stimulants, possibly through a process similar to sensitization Piazza and Le Moal, 1998, Goeders, 2002. It is not conclusive that a similar process occurs in humans, but a growing clinical literature indicates that there is a link between substance abuse and stress.

Acknowledgments

This work was supported by USPHS Grants DA06013 and DA13463 from the National Institute on Drug Abuse.

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