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Tobacco use is the leading cause of preventable mortality in the United States, and Food and Drug Administration (FDA) approved medications fail to maintain long-term abstinence for the majority of smokers. One of the principal mechanisms associated with the initiation, maintenance of, and relapse to smoking is stress. Targeting the brain stress systems as a potential treatment strategy for tobacco dependence may be of therapeutic benefit. This review explores brain stress systems in tobacco use and dependence. The corticotropin-releasing factor (CRF) system, the hypothalamic-pituitary-adrenal (HPA) axis, and the noradrenergic system are discussed in relation to tobacco use. Preclinical and clinical investigations targeting these stress systems as treatment strategies for stress-induced tobacco use are also discussed. Overall, nicotine-induced activation of the CRF system, and subsequent activation of the HPA axis and noradrenergic system may be related to stress-induced nicotine-motivated behaviors. Pharmacological agents that decrease stress-induced hyperactivation of these brain stress systems may improve smoking-related outcomes.

Targeting the Brain Stress Systems for the Treatment of Tobacco/Nicotine Dependence: Translating Preclinical and Clinical Findings