Functional interaction between 5-HT6 receptors and hypothalamic–pituitary–adrenal axis: Cognitive implications

The serotonin 5-HT6 receptor has become a promising target for the treatment of neuropsychological diseases, such as affective disorders. Increasing evidence implicates stress and its effector system, the hypothalamic–pituitary–adrenal (HPA) axis, in the neurobiology of depression. In addition, there are important memory disturbances in stress-related psychiatric disorders that have been associated to an impairment of the HPA axis reactivity. The aim of the present work is to study the functional interactions between 5-HT6 receptors and HPA axis. In a situation of increased HPA axis responsiveness (maternal separation, MS) no differences were found in the expression of 5-HT6 gene in the hippocampus or frontal cortex, although serotonin levels were higher in the frontal cortex of MS rats. 5-HT6 receptor mRNA expression increased significantly in the hippocampus in a situation of decreased glucocorticoid levels, such as adrenalectomy. Cognitive deficits associated to HPA dysfunction, such those found in the MS model, were fully reversed by administration of SB271046, a selective 5-HT6 receptor antagonist. A chronic treatment with SB271046 did not modify CRF mRNA levels in the hypothalamus, but there was a higher glucocorticoid receptor density in the hippocampus compared to control. In contrast, in the frontal cortex, treatment with SB271046 induced a significant decrease in glucocorticoid receptor density. These data suggest that expression of 5-HT6 receptors might be differentially regulated depending on levels of circulating adrenal corticoids. These results are discussed in terms of therapeutical approaches to the treatment of behavioral (depressive-like) and cognitive disturbances associated to an altered response to stress.