Impact of Psychoactive Drugs HPA Axis Regulation

Corticotrophin releasing hormone on factor (CRF) and its co-secretagogue vasopressin (AVP) organize the behavioral, sympathetic, and neuroendocrine response to daily-and sleep-related events and stressors (de Kloet et al. 2005). The neuroendocrine response proceeds via the hormones of the HPA axis, e.g., hypothalamic CRF and AVP, pituitary ACTH, and adrenal glucocorticoids. CRF, AVP, and POMC peptides also have elaborate ► neuropep-tide networks in the limbic-midbrain which modulate the processing of circadian and stressful information (Herman et al. 2003). Additionally, many neurotransmitter systems influence dynamically at several levels the activity of the HPA axis. These include among others ► GABA, ► glutamate, monoamines, neuropeptides, and gas-based messengers. More recently, the ► endocannabinoid system has been proposed to exert an inhibitory action on HPA axis activation.

Under basal conditions the hormones of the HPA axis are released in hourly pulses (Lightman et al. 2008). The magnitude of these pulses changes during day and night with the largest amplitude at the start of the activity period. Awakening triggers an additional distinct HPA response. The pulsatile HPA axis pattern shows gender differences. The frequency of the pulses alters during chronic stressful or inflammatory conditions. The ultra-dian rhythm becomes disordered during Cushing and Addison's disease and during the aging process. The pulse generator resides in the hypothalamus, but its nature is unknown and pulses are amplified on the adrenal level. Frequency encoding is a common mechanism in information processing by hormonal systems and evidence is accumulating that resilience in target tissues depends on pulsatile exposure to glucocorticoids.

Superimposed on the ultradian rhythm is the response to stressors. In fact, it has been shown in rats that the magnitude of the HPA axis response depends on the phase of the rhythm: corticosterone responses were larger when a stressor is experienced at the ascending rather at the descending phase. The onset, duration, and magnitude of the HPA axis response is affected by the previous experience, and, in particular, early life events are potent stimuli capable to program the reactivity of the axis to stressors in later life. The most profound psychological stressors are characterized by loss of control, no information, and no prediction of upcoming events combined with a sense of fear and uncertainty. This condition results in a profound and long-lasting activation of the HPA axis.

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