Activation of both the CRH1 and CRH2 receptors is linked to a G protein, and activates adenylate cyclase cascade and an increase in intracellular cyclic adenosine monophosphate (cAMP) and calcium levels; CRH appears to bind primarily to CRH1 receptors.60,61 The distribution of CRH1 receptor sites includes regions of the hippocampus, septum, and amygdala (medial and R428 lateral region) and neocortex, ventral thalamic, and medial hypothalamic sites; sparse receptors

are located in the PVN and the pituitary gland. The distribution is widespread in cerebellum in addition to brain stem sites such as major sensory nerves and the solitary nucleus.62,63 The distribution of CRH2 receptors is more limited Inhibitors,research,lifescience,medical than that of CRH1 receptors and Inhibitors,research,lifescience,medical is found primarily in subcortical regions including the amygdala, septum, BNST, and PVN and ventral medial nucleus of the hypothalamus.63,64 Differential regulation of CRH by glucocorticoids Glucocorticoids are importantly involved in the

restraint of CRH production in regions of the PVN.65,66 This negative feedback is a fundamental way in which the hypothalamic-pituitary-adrenal (HPA) axis is Inhibitors,research,lifescience,medical restrained during stress and activity67 Glucocorticoids directly control neuronal excitability68 Some of the glucocorticoid effects on the brain are quite rapid, suggesting that corticosterone has nongenomic membrane effects via γ-aminobutyric acid(GABA)-ergic mechanisms.69 Inhibitors,research,lifescience,medical Neurons within the lateral BNST and within the PVN may activate or inhibit PVN function via GABAergic mechanisms.70,71 While the profound effect of inhibition is indisputable, there are neuronal populations within the PVN that project to the brain stem that are not inhibited by glucocorticoids, Inhibitors,research,lifescience,medical and the activity of which is actually enhanced.66,72 That is, CRH neurons en route to the pituitary are restrained by glucocorticoids, but CRH en

route to other regions of the brain appears not to be restrained.66,73-75 Moreover, the activity of extrahypothalamic regions of the brain in which CRH is expressed (central nucleus of the amygdala or lateral BNST) is actually increased by glucocorticoid hormones.54,66,75,76 CRH, glucocorticoids, and fear-related behaviors Central CRH activation has many been consistently linked to the induction of fear, uncertainty, unfamiliarity, and uncontrollability in animal studies.9,52,53,77-79 Central infusions of CRH induce or potentiate a number of fearrelated behavioral responses,80 and infusion of CRH antagonists both within and outside the amygdala reduce fear-related responses.52,81 One study, for example, reported that injection of a CRH antagonist into the basolateral complex of the amygdala, one of the regions in the amygdala which contains glucocorticoid receptors,82 immediately following footshock diminished retention of aversive conditioning in an inhibitory avoidance task.