Michela Marinelli and Pier Yincenzo Piazza

INSERM U.588, Université de Bordeaux 2, Rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France

Abstract: In this review, we examine how differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis can influence vulnerability to drug addiction. Glucocorticoid hormones, the final step in the activation of the HPA axis, show a basal circadian secretion, and rise in response to stressful events. Studies manipulating levels of glucocorticoids show that these hormones facilitate the behavioral response to psychostimulant drugs. Thus, blockade of glucocorticoid secretion reduces drug-induced responses such as locomotor activity, self-administration and relapse, whereas an increase in glucocorticoids has opposite effects. We then describe how these behavioral effects of glucocorticoids involve an action on the dopamine system, one of the major systems mediating the addictive properties of drugs. Thus, decreasing glucocorticoid levels reduces the activity of the dopamine system, whereas an increase in the concentration of these hormones can increase dopamine transmission. The causal relationship between glucocorticoid hormones, dopamine, and behavioral response to addictive drugs suggests that inter-individual differences in glucocorticoid levels could explain inter-individual differences in drug vulnerabilities. In this review we expand this notion by suggesting that individuals with greater vulnerability to drugs may also differ in their sensitivity to glucocorticoid hormones. We propose that increased exposure to glucocorticoids, whether induced by repeated stress or increased sensitivity to these hormones, could result in the sensitization of the dopamine reward system; this would enhance reactivity to drugs and increase liability to develop addiction.

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