Indeed, it is well established that chronic alcohol alters CRF activity independent from the HPA axis. CRF is a 41 amino acid neuropeptide that is widely distributed throughout mammalian brain. As noted above, CRF-containing neurons are found in high concentrations in the PVN of the hypothalamus where they play a primary role in regulating HPA axis activity, which is critical for orchestrating behavioral and physiological responses to stress. CRF-containing neurons are also found outside the neuroendocrine (HPA) axis. The extra-hypothalamic distribution of CRF includes an extensive network of interconnected neural structures (e.g., central amygdala (CeA), bed nucleus of the stria terminalis (BNST), prefrontal cortex) that are intimately associated with brain reward and stress pathways. The actions of CRF (and related peptides urocortin I, II, and III) are modulated by CRF-binding protein and mediated through interaction with two excitatory G-protein-coupled receptor subtypes (CRF1 and CRF2) (Bale and Vale, 2004). CRF1 and CRF2 receptors are distributed in overlapping yet distinct patterns within these brain reward and stress circuits. This anatomical distribution of CRF and its associated binding sites is congruent with the
