Long-term alterations in the corticotropin-releasing hormone system : effects on emotional function and attention

Abstract

Depression is one of the most common medical conditions worldwide. The most frequently observed neuroendocrine symptom among depressives is an enhanced secretion of the stress hormone cortisol. It has been hypothesised that corticotropin-releasing hormone (CRH) hypersecretion is, at least in part, responsible for these elevated cortisol levels. In addition, increased CRH levels in the CSF indicate that the hyperactivity of the CRH system is not limited to an augmented release of CRH into the portal vein, which indirectly enhances cortisol release, but possibly also in the brain. Therefore, it is possible that some of the symptoms, such as increased anxiety, altered endocrinological responses to 5-HT1A receptor challenge and reduced attentional performance observed in depression are due to a hyperactive central CRH system. In this work, the role of CRH on these phenomena was investigated in mice. In order to assess anxiety-related behaviour, a range of anxiety tests, based on different principles, were employed. Investigation of differences between four mouse strains and effects of long-term treatment with the selective serotonin reuptake inhibitor citalopram on anxiety-related behaviour revealed that the outcome of one test does not necessarily predict the outcome of another test based on different principles, suggesting that different aspects of anxiety can be taxed. Along similar lines, life-long overproduction of CRH increases anxiety-related behaviour in some paradigms, but not in all. Therefore, one might speculate that chronic CRH excess may increase some, but not all, aspects of anxiety. Treatment of CRH overexpressors revealed that chronic treatment with citalopram increased anxiety-related behaviour in wildtype mice, but induced opposite effects in CRH overexpressing mice, i.e., the effects of antidepressants depended on baseline performance. Citalopram has beneficial effects in both patients suffering from anxiety disorders as well as depressive patients. These findings open the possibility that the beneficial effects of citalopram in depressed patients may at least in part depend on the activity of the CRH system seen in these patients, and that the elevation of CRH activity may be the cause of the occurrence of increased anxiety in this illness. Furthermore, the results obtained with citalopram suggest important interactions between CRH and serotonin (5-HT). Related to this, a lack of increased HPA-axis activation after a 5-HT1A receptor challenge was demonstrated, a phenomenon also reported in depressed patients. This contrasts an unaltered hypothermic response after such pharmacological challenge in CRH transgenic mice, which has also been reported in depressed patients. Finally, the role of CRH in attentional processes, which are also impaired in depressed patients, were investigated. Lack of CRH did not affect visuospatial attention. In addition, lack of CRH receptor 2 or acute blockade of CRH receptor 1 did not affect attentional processes. Life-long loss of CRH receptor 1 resulted in a mild impairment. However, closer examination of performance of these animals suggest that this may not be a pure attentional deficit and opens the possibility that other factors contributed to these effects. In contrast, overproduction of CRH induced a more clear-cut impairment in visuospatial attention. Moreover, altered responsiveness to cholinergic drugs on visuospatial attentional performance observed in these mice point towards an interaction of the CRH system and the cholinergic neurotransmitter system in the modulation of these processes. Taken together, overproduction of CRH increases some aspects of anxiety-related behaviour, blocks 5-HT1A receptor mediated HPA-axis activation, and disrupts visuospatial attention, all symptoms that occur in depression. Therefore, inhibiting CRH activity may be a potential target for treatment of depression