There is a complex and bidirectional relationship between stress and drug use disorders. Accumulating evidence establishes a link between internal and external forms of stress and vulnerability to drug addiction. Conversely, drug addiction leads to altered hormonal and brain stress systems and an internal state of stress, which can enhance drug use. The generalizations described in this review oversimplify a field that requires further investigation. However, several salient points can be made.
Both stress and drugs of abuse activate the HPA axis and extended amygdala. Preclinical and human studies have generally shown that specific forms of stress are associated with vulnerability to drug use disorders and can precipitate relapse. The effects of stress on drug use depend in part on the type, context and severity of the stressor, the genetic background of the drug taker and the interplay between the positive and negative reinforcing influences of the drug and the stressor. Stress-related effects on dopaminergic activity may be one mechanism underlying increased risk for addiction. Early in the development of drug use, both stress- and drug-induced activation of the HPA axis allows glucocorticoids to sensitize the reward pathways, although the exact effects on mesolimbic dopamine are still to be determined. Altered HPA axis stress response, which is influenced by a multitude of genetic and environmental factors, may also be a mechanism involved in increased risk for addiction. Although most single genes and individual factors described in this review probably account for only a small proportion of the variability in cortisol responses to stress, even a small difference in cortisol responses could result in substantial divergence in lifetime cortisol exposure (McEwen 1998
) and therefore influence risk for drug addiction.
As a person transitions from social drug use to drug dependence, the balance between the positive and negative reinforcing effects of the drug shifts. Although multiple brain regions are involved in this transition, the mesolimbic dopamine system, modulated by various forms of stress and glucocorticoids and the extended amygdala, through alterations in CRF, GABA, NPY and CREB, are likely to alter the reinforcing properties of both drugs of abuse and stress. When drug dependence is manifest, along with episodes of withdrawal, the neurochemical environment in the amygdala produces anxiogenic states by increasing expression of CRF and further activating the HPA axis. This neurochemical milieu creates craving and drug-seeking behaviors, which increase vulnerability of relapse to addiction.
Although research has progressed to explore the role and characteristics of the stress response in the context of risk for addiction, more work is still needed to understand the specific nature of how stress and the subsequent activation of the HPA axis impact addiction. An improved understanding of what biological mechanisms underlie stress-related disorders may be helpful in elucidating their pathogenesis, a step crucial in developing their prevention and treatment. Eventually, a combination of pharmacotherapies targeting the stress response systems such as HPA axis and other cognitive behavioral stress management techniques may lead to improved outcomes of addiction treatments.