Chronic stress, drug use, and vulnerability to addiction

Abstract

Stress is a well-known risk factor in the development of addiction and in addiction relapse vulnerability. A series of population-based and epidemiological studies have identified specific stressors and individual-level variables that are predictive of substance use and abuse. Preclinical research also shows that stress exposure enhances drug self-administration and reinstates drug seeking in drug-experienced animals. The deleterious effects of early life stress, child maltreatment, and accumulated adversity on alterations in the corticotropin releasing factor and hypothalamic-pituitary-adrenal axis (CRF/HPA), the extrahypothalamic CRF, the autonomic arousal, and the central noradrenergic systems are also presented. The effects of these alterations on the corticostriatal-limbic motivational, learning, and adaptation systems that include mesolimbic dopamine, glutamate, and gamma-amino-butyric acid (GABA) pathways are discussed as the underlying pathophysiology associated with stress-related risk of addiction. The effects of regular and chronic drug use on alterations in these stress and motivational systems are also reviewed, with specific attention to the impact of these adaptations on stress regulation, impulse control, and perpetuation of compulsive drug seeking and relapse susceptibility. Finally, research gaps in furthering our understanding of the association between stress and addiction are presented, with the hope that addressing these unanswered questions will significantly influence new prevention and treatment strategies to address vulnerability to addiction.

Figure 1

A schematic model of stress effects on addiction, representing the cross-sensitization of stress and drugs on behavioral and neurochemical responses, that are mediated by the stress and reward pathways. Column A lists three types of vulnerability factors: (1) developmental/individual-level factors such as frontal executive function development, negative emotionality, behavioral/self control, impulsivity or risk taking, and altered initial sensitivity to rewarding effects of drugs; (2) stress-related vulnerability factors such as early adverse life events, trauma and child maltreatment experiences, prolonged and chronic stress experiences; and (3) genetic influences and family history of psychopathology. Each of these factors influences each other to significantly affect alterations in neurobiological pathways involved in stress regulation and cognitive and behavioral control (Column B). Such changes at least partially mediate the mechanisms by which stress and individual and genetic factors in column A interact to increase risk of maladaptive behaviors represented in column C when an individual is faced with stress or challenge situations.

Figure 2

Mean and standard errors for peak craving and anxiety ratings during exposure to stress, drug cues, and neutral imagery conditions. (A) Peak craving is significantly higher in abstinent alcoholics and cocaine patients compared to social drinkers (P < 0.0001). (B) Peak anxiety ratings are significantly higher in abstinent alcoholics and cocaine patients compared to social drinkers (P < 0.001). (Detailed statistics provided in Fox et al. and Sinha et al.239)