There are consistent findings across basic neurobiological and genetic studies that the gene encoding FK506 binding protein 5 (FKBP5) is among those that modulate the stress response and HPA-axis activity in humans. FKBP5 has been linked to stress hormone dysregulation,7-9 risk of PTSD, anxiety disorders, and depressive disorder,10-14 and recently, alcohol withdrawal.15 FKBP5 functions in a feedback loop that regulates HPA-axis activity. FKBP5 expression is induced by glucocorticoids16 and the encoded protein, FK506 binding protein 51, represses glucocorticoid receptor (GR) signaling.17 The HPA-axis and the nicotinic cholinergic system are closely linked. However, the function of this critical regulatory gene in the context of smoking-related behaviors and the effects of nicotine has not been thoroughly investigated. Nicotine activates the HPA-axis in a dose-dependent fashion, resulting in the release of adrenocorticotropic hormone (ACTH) and cortisol.18, 19 Glucocorticoids have been shown to inhibit or desensitize nicotinic acetylcholine receptors20, 21 and may enhance nicotine self-administration in rats possibly by increasing the dose needed to produce a particular level of reinforcement.22 Stress hormones also influence the severity of nicotine withdrawal in rats23 and potentially, relapse
