Review: Central non-glucocorticoid inhibitors of the hypothalamo-pituitary-adrenal axis.

The popular perception of stress is that of social or work tensions and pressures that have an overall negative influence often accompanied by increased frequency of illness. However, stress is not all bad. A healthy response to acute stress is crucial for our interaction with the environment and for our ability to deal with everyday challenges, either physical or psychological. The key is to be able to terminate a response to stress when the stressor is no longer present. Failure to terminate a response to acute stress can result in the syndrome of chronic stress which is associated with inappropriately elevated secretion of glucocorticoids, with consequent immunosuppression and predisposition to infection and illness. Responses of the hypothalamo–pituitary–adrenal (HPA) axis to stress are mediated principally through the neuropeptides corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) which are synthesised in the parvocellular subdivision of the hypothalamic paraventricular nucleus (PVN) (for review see Buckingham et al. 1997). CRH and AVP are transported down axonal projections to the median eminence (ME) where they are secreted into the hypophysial portal blood system to synergistically stimulate the release of adrenorticotrophin (ACTH) from corticotroph cells in the anterior pituitary, leading to increased secretion of glucocorticoids from the adrenal cortex (Fig. 1). Glucocorticoid feedback at the hippocampal and hypothalamic levels is a well-recognised mechanism for inhibiting basal and stress-induced HPA axis activity (for a review see De Kloet et al. 1998), but there is also considerable evidence for the existence of non-glucocortocoid mechanisms of inhibition. In adrenalectomised animal models, basal plasma ACTH concentrations are elevated but not maximally, since stressors such as ether (Rees et al. 1971), restraint (Chowdrey et al. 1991) and haemorrhage (Darlington et al. 1990) are capable of further stimulating ACTH release. In addition, a chronic osmotic stimulus inhibits ACTH release through a mechanism which, because it occurs in adrenalectomised rats, cannot be regulated by glucocorticoids ( Jessop et al. 1990). Thus the HPA axis is subject to mechanisms of tonic inhibition which operate independently of glucocorticoids. Inhibitory agents may act at any or all levels of the HPA axis. Lesioning of selective hypothalamic nuclei can enhance the HPA axis response to some stressors (Herman & Cullinan 1997), providing evidence for endogenous hypothalamic inhibitors acting on CRH and/or AVP expression within the PVN. Observations of pulsatile ACTH secretion after complete lesioning of the PVN (and elimination of CRH from the ME) have revealed a surprising degree of residual pituitary–adrenocortical activity (Boyle et al. 1997). Total PVN lesioning was still accompanied by an ACTH response to some cytokines (Kovacs & Elenkov 1995), and electrical lesions that destroyed the entire hypothalamus did not prevent a response to the stress of laparotomy (Witorsch & Brodish 1972). One explanation for these results is that the lesions eliminate not only hypothalamic corticotrophin-releasing factors but also inhibitory factors which may be acting to block the secretion of ACTH from the anterior pituitary. Further evidence for the release of ACTH inhibitors into hypophysial portal blood was supplied by the report that hypothalamo–pituitary disconnection in sheep was accompanied by increased ACTH and cortisol secretion (Engler et al. 1988). Although some of these results could be explained by the existence of novel extrahypothalamic ACTH-releasing factors, cumulative evidence is compelling for the existence of compounds acting on the hypothalamus and/or anterior pituitary that can inhibit the stress response. The purpose of this review is to distil the literature on non-glucocorticoid inhibitors of the HPA axis (briefly reviewed by Grossman & Tsagarakis 1989 and Engler et al. 1994) and to assess the extent to which this information has contributed to our understanding of the biochemical mechanisms of stress control. The emphasis throughout will be on inhibitory agents that have the potential to operate at the hypothalamus or the anterior pituitary, rather than at the adrenal cortex. Compounds directly affecting glucocorticogenesis have been the 169