Corticotropin releasing factor: A key role in the neurobiology of addiction

• CRF systems have emerged as mediators of the body’s response to stress and, relatedly, the pathophysiology of addiction.
• CRF systems have a prominent role in driving the addiction via actions in the central extended amygdala.
• Addiction-related actions are anxious behavior, brain reward deficits, excessive drug use and stress-induced drug-seeking.
• Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often with stress history.

Drug addiction is a chronically relapsing disorder characterized by loss of control over intake and dysregulation of stress-related brain emotional systems. Since the discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) and the structurally-related urocortins, CRF systems have emerged as mediators of the body’s response to stress. Relatedly, CRF systems have a prominent role in driving addiction via actions in the central extended amygdala, producing anxiety-like behavior, reward deficits, excessive, compulsive-like drug self-administration and stress-induced reinstatement of drug seeking. CRF neuron activation in the medial prefrontal cortex may also contribute to the loss of control. Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often in interaction with stress history. Drug discovery efforts have yielded brain-penetrant CRF1 antagonists with activity in preclinical models of addiction. The results support the hypothesis that brain CRF–CRF1 systems contribute to the etiology and maintenance of addiction.