The role of CRF and CRF-related peptides in the dark side of addiction

Abstract

Drug addiction is a chronically relapsing disorder characterized by a compulsion to seek and take drugs, the development of dependence, and the manifestation of a negative emotional state when the drug is removed. Activation of brain stress systems is hypothesized to be a key element of the negative emotional state produced by dependence that drives drug-seeking through negative reinforcement mechanisms, defined as the "dark side" of addiction. The focus of the present review is on the role of corticotropin-releasing factor (CRF) and CRF-related peptides in the dark side of addiction. CRF is a key mediator of the hormonal, autonomic, and behavior responses to stressors. Emphasis is placed on the role of CRF in extrahypothalamic systems in the extended amygdala, including the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition area in the shell of the nucleus accumbens, in the dark side of addiction. The urocortin/CRF(2) systems have been less explored, but results suggest their role in the neuroadaptation associated with chronic drug use, sometimes in opposition to the effects produced by the CRF(1) receptor. Compelling evidence argues that the CRF stress system, including its activation of the hypothalamic-pituitary-adrenal axis, plays a key role in engaging the transition to dependence and maintaining dependence once it is initiated. Understanding the role of the CRF systems in addiction not only provides insight into the neurobiology of the dark side of addiction, but also provides novel targets for identifying vulnerability to addiction and the treatment of addiction.

Figure 1

Diagram illustrating the multiple actions of CRF in mediating stress responses in the body. CRF drives the hypothalamic-pituitary adrenal axis by acting to release adrenocorticotropic hormone (ACTH) in the portal system of the pituitary. CRF activates the sympathetic system by actions in the brainstem and mediates arousal and behavioral responses to stressors by actions in the amygdala, other basal forebrain regions, and ventral midbrain such as the ventral tegmental area. Ach, acetylcholine; NE, norepinephrine.

Figure 2

Schematic of mammalian corticotropin-releasing factor (CRF) receptors (red polygons), their putative natural ligands (green ovals), and synthetic receptor antagonists (blue squares). Black arrows indicate receptor affinity. Grouped ligands are broadly ordered from top (earliest) to bottom in chronological order of reported discovery. oCRF, ovine CRF; r/hCRF, rat/human CRF. [Taken with permission from Zorrilla et al., 2003.]

Figure 3

Brain circuits hypothesized to be recruited at different stages of the addiction cycle as addiction moves from positive reinforcement to negative reinforcement. The top right circuit refers to the hypothalamic-pituitary-adrenal (HPA) axis which (i) feeds back to regulate itself, (ii) activates the brain reward neurocircuit, and (iii) facilitates the extrahypothalamic stress neurocircuit. The bottom right circuit refers to the extrahypothalamic brain stress circuits in feed-forward loops from the brain stem, some of which may be noradrenergic. The extrahypothalamic brain stress system outputs via the hypothalamus, brain stem, and ventral tegmental area to engage stress-like and fear-like behavioral responses. BNST, bed nucleus of the stria terminalis; NE, norepinephrine. [Adapted from Koob and Le Moal, 2004.]