1 The significance of dysregulated basal glucocorticoid pulsatility in affective disorders. Conway-Campbell BL, Wiles CC, and Lightman SL Depressive illness is characterised by changes in the basal set-point of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in altered regulation of glucocorticoid secretory activity (Holsboer, 2000). The neuroendocrine HPA axis is under the control of neural circuits in the CNS and has actions on many peripheral systems throughout the body. The principle signal arises from activation of parvocellular neurones of the hypothalamic paraventricular nucleus (PVN), which synthesise and secrete corticotrophin-releasing factor (CRF), and/or arginine vasopressin (AVP). These peptides then act synergistically on corticotropes of the anterior pituitary gland, to release adrenocorticotrophic hormone (ACTH) which amplifies the neuroendocrine signal. ACTH acts directly at the adrenal cortex to increase the rate of synthesis and release of adrenal corticosteroids which function as effector hormones. Secretory activity can be modulated at both the pituitary and adrenal levels, but it is primarily the hypothalamic neuroendocrine signal which governs the pattern of HPA activity via a complex pattern of neural inputs, gene expression and feedback control. One of the classic identifying features of adrenal corticosteroids (cortisol in man and corticosterone in rodents) is the intrinsic rhythm of its secretion (Lightman et al., 2000, Young et al., 2004). Over the last decade, we have used an automated blood sampling system to define corticosterone pulsatility in free running rats in their home cages. These studies have revealed a complex ultradian rhythm of endogenous corticosterone, with discrete peaks occurring at approximately hourly intervals. Modulation of the amplitude of these pulses generates the well- characterised circadian profile. This pulsatility has also been reported in numerous species including rat (Jasper and Engeland, 1991, Jasper and Engeland, 1994, Windle et al., 1998a, Atkinson et al., 2006), rhesus monkey (Tapp et al., 1984, Sarnyai et al., 1995), Syrian hamster (Loudon et al., 1994, Lucas et al., 1999), horse (Cudd et al., 1995), sheep (Engler et al., 1989a, Engler