Cuenta de Resultados

Whereas it is conceivable that a CRH/vasopressin hyperdrive contributes to behavioral, emotional, and hormonal symptoms of mood disorders, the ques-tion remains which mechanisms mediate this hyperactivity of CRH and vasopressin-secreting neurons. The gene expression of both neuropeptides is suppressed by ligand-activated glucocorticoid receptors. The efficiency of this negative feedback action of circulating corticosteroids depends on the number of corticosteroid receptors, their affinity, and the degree of interac-tion with other factors (e.g., heat shock protein) involved in the transcripinterac-tion machinery.

Corticosteroids act in the brain mainly through regulation of genes by binding to intracellular receptors, which then bind to specific response ele-ments at promoter regions of steroid-regulated genes. Two different recep-tors mediate corticosteroid effects at the nucleus as dimers, the high-affinity (K_D= 0.3 nM for corticosterone in the rat) mineralocorticoid receptor (MR) Figure 2–3. Corticotropin-releasing hormone (CRH) synthesized and re-leased from parvocellular neurons of the paraventricular nucleus binds to CRH₁ re-ceptors at the pituitary corticotrophs to elicit expression of the

pro-opiomelanocortin (POMC) gene via a G-protein–coupled signaling step enhanc-ing cyclic adenosine monophosphate (cAMP) formation. CRH has a much lower af-finity to CRH_2Areceptors, which are less widely distributed over the brain and mainly expressed in the lateral septal, ventromedial hypothalamic, and medial amygdaloid nuclei. Urocortin (UCN), which has a 63% sequence identity with urotensin and a 45% sequence identity with CRH, also binds at CRH1receptors to evoke POMC and subsequent adrenocorticotropic hormone (ACTH) release. In ad-dition, UCN is much more potent than CRH at binding and activating CRH2A re-ceptors, indicating that UCN is an endogenous ligand for the CRH_2Areceptors.

Both neuropeptides (CRH and UCN) bind to CRH-binding protein (UCN:

K_i= 0.1 nM; CRH: 0.21 nM).

Source. Adapted from Vaughan J, Donaldson C, Bittencourt J, et al: “Urocortin, a Mammalian Neuropeptide Related to Fish Urotensin I and to Corticotropin-Releasing Factor.” Nature 378:287–292, 1995. Copyright 1995, Macmillan Maga-zines Limited. Used with permission.

and the low-affinity (K_D= 3.0 nM) glucocorticoid receptor (GR) (DeKloet and Reul 1987). The highest expression of these receptors is in the hippo-campus, in which many neurons colocalize MR and GR to act as homodimers or heterodimers (Trapp et al. 1994). The occurrence of high- and low-affinity receptors that have distinct DNA-binding properties after homodimerization or heterodimerization keeps the cellular response to corticosteroids at a high level of flexibility, which is important if one considers the large circulating corticosteroid concentration range (Trapp and Holsboer 1996).

Defective negative feedback of the HPA system is the most common neuroendocrine symptom of mood disorders (Holsboer 1995). As docu-mented for the combined dexamethasone-CRH test in control subjects, in-creasing dosages of dexamethasone suppress the releasable amount of ACTH and cortisol in response to CRH (Heuser et al. 1994). Modell et al. (unpub-lished observations) estab(unpub-lished a dose-response curve and showed that pa-tients with depression needed higher dexamethasone dosages than control subjects to suppress CRH-induced ACTH and cortisol release. This finding and the observation that probands without depression but at genetic risk for it also have signs of negative feedback disturbance (Holsboer et al. 1995) led us to hypothesize that the pathogenesis of mood disorders involves impaired corticosteroid receptor function (Holsboer and Barden 1996).

Our view is supported by the actions of antidepressants that increase the capacity of corticosteroid receptors and subsequently reduce basal and stress-stimulated levels of ACTH and corticosterone when administered to rats (Reul et al. 1993, 1994a). This finding in rats would explain the gradual normalization of negative feedback disturbance in patients with depression during treatment with antidepressants and would also explain the findings by Checkley, who demonstrated in patients with depression that metyrapone (a drug that inhibits hydroxylation at the C-11 position of the steroid molecule and thus reduces cortisol synthesis) not only diminished cortisol hyper-secretion, but also ameliorated depressive symptomatology (O’Dwyer et al.

1995). Finally, transgenic mice that express antisense directed to GR mRNA proved to be severely impaired in their cognitive function as well as showed exaggerated HPA activity when stressed. After long-term treatment with an-tidepressants, both cognitive and neuroendocrine disturbances gradually dis-appeared (Montkowski et al. 1995). This transgenic mouse appears to be well suited as a test model for several signs and symptoms of depression and their response to drug treatment (Holsboer and Barden 1996).

Animal studies have also provided insights into the mechanisms underly-ing the preeminent role of stressors in early life. Plotsky and Meaney (1993) showed that daily handling and maternal separation of rat pups produces

in-creased hypothalamic CRH mRNA and CRH concentrations at baseline and increased CRH depletion and plasma corticosterone levels in response to re-straint stress. Ladd et al. (1996) studied the long-term effects of early stress on the development of CRH neural systems in the rat brain. They showed that early environmental stressors can lead to changes in CRH pathways that are manifested by enhanced basal and stress-induced plasma ACTH concen-trations, which—if extrapolated to humans traumatized early—can increase the vulnerability to stress-related mood disorders. Likewise, adverse early rearing of nonhuman primates may lead to long-term overactivity of CRH-producing neurons, as reflected by elevated cisternal CSF content (Coplan et al. 1996).

Given that disturbed regulation of CRH neuronal circuitries plays a caus-ative role in producing cardinal signs and symptoms of depression, these studies demonstrate that early trauma may increase the vulnerability to de-veloping a mood disorder in later life. Reul et al. (1994b) showed that an im-mune challenge with human red blood cells in pregnant rats changes fetal brain development in a way that results in decreased hippocampal MR and GR concentrations in adults. These long-term effects render the adult ani-mals more susceptible to stressors as they show higher stress-elicited ACTH and corticosterone levels throughout their lifetime than control animals.

In summary, these clinical and preclinical findings support the view that mood disorders can be seen as stress system disorders, in which impairment of GR and MR action plays a causal role. The impairments may be genetically determined or acquired through a variety of early stressors, or both. It is pos-sible that antidepressants exert their clinical efficacy through reinstatement of complete corticosteroid receptor function. Of course, other important ac-tions of these drugs also need careful consideration.