To further support the hypothesis that negative affective symptoms drive the escalation of nicotine self-administration, possible associations between anxiety-like behavior (among other negative affective symptoms) and the escalation of nicotine self-administration will need to be explored, and the possibility that manipulation of CRF and other stress and anti-stress systems can block the escalation of nicotine intake should be examined. The gene discussed is CRH; the disease is Anxiety.