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

Abstract

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.

Consideration of sex and gender differences in addiction medication response

“…A substantial body of preclinical literature indicates that stress exposure induces relapse to drug seeking, including nicotine [ 69 ], a phenomenon mediated by brain stress circuits, including noradrenergic pathways [ 70 ]. Stress regulation plays an especially critical role in the maintenance of and relapse to smoking in women [ 71 , 72 ]. With a small sample, we demonstrated that guanfacine attenuates the effect of stress on smoking behavior and increases quitting behavior [ 73 ].…”