Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: cognitive implications

The serotonin 5-HT(6) 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, th...

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Bibliographic Details
Published in:Neuropharmacology 2008-03, Vol.54 (4), p.708
Main Authors: Marcos, B, Aisa, B, Ramírez, M J
Format: Article
Language:English
Subjects:
Acetates - pharmacology
Adrenalectomy - methods
Animals
Behavior, Animal - drug effects
Cognition - drug effects
Corticosterone - metabolism
Corticotropin-Releasing Hormone - genetics
Corticotropin-Releasing Hormone - metabolism
Drug Interactions
Frontal Lobe - drug effects
Frontal Lobe - metabolism
Hippocampus - drug effects
Hippocampus - metabolism
Hypothalamo-Hypophyseal System - drug effects
Hypothalamo-Hypophyseal System - physiology
Male
Maternal Deprivation
Morpholines - pharmacology
Neuropsychological Tests
Pituitary-Adrenal System - drug effects
Pituitary-Adrenal System - physiology
Rats
Rats, Wistar
Receptors, Serotonin - genetics
Receptors, Serotonin - physiology
Serotonin - administration & dosage
Serotonin Antagonists - pharmacology
Sulfonamides - pharmacology
Thiophenes - pharmacology
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Summary:The serotonin 5-HT(6) 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-HT(6) receptors and HPA axis. In a situation of increased HPA axis responsiveness (maternal separation, MS) no differences were found in the expression of 5-HT(6) gene in the hippocampus or frontal cortex, although serotonin levels were higher in the frontal cortex of MS rats. 5-HT(6) 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-HT(6) 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-HT(6) 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.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2007.11.019