Functional subsets of serotonergic neurones: implications for control of the hypothalamic-pituitary-adrenal axis.

Serotonergic systems play an important role in the regulation of behavioural, autonomic and endocrine responses to stressful stimuli. This includes modulation of both the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-spinal-adrenal (HSA) axis, which converge at the level of the adrenal cortex to regulate glucocorticoid secretion. Paradoxically, serotonin can either facilitate or inhibit HPA axis activity and stress-related physiological or behavioural responses. A detailed analysis of the brainstem raphé complex and its ascending projections reveals that facilitatory and inhibitory effects of serotonergic systems on glucocorticoid secretion may be due to influences of topographically organized and functionally diverse serotonergic systems. (i) A serotonergic system arising from the middle and caudal dorsal raphé nucleus and projecting to a distributed central autonomic control system and a lateral 'emotional motor system'. Evidence suggests that serotonin can sensitize this subcortical circuit associated with autonomic arousal, anxiety and conditioned fear. (ii) A serotonergic system arising from the median raphé nucleus and projecting extensively and selectively to a ventral subiculum projection system. Evidence suggests that serotonin facilitates this limbic circuit associated with inhibition of ultradian, circadian and stress-induced activity of both the HPA axis and the HSA axis. These new perspectives, based on functional anatomical considerations, provide a hypothetical framework for investigating the role of serotonergic systems in the modulation of ultradian, circadian and stress-induced neuroendocrine function.