Magnesium deficiency induces anxiety and HPA axis dysregulation: Modulation by therapeutic drug treatment

Preclinical and some clinical studies suggest a relationship between perturbation in magnesium (Mg2+) homeostasis and pathological anxiety, although the underlying mechanisms remain largely unknown. Since there is evidence that Mg2+ modulates the hypothalamic-pituitary adrenal (HPA) axis, we tested...

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Bibliographic Details
Published in:Neuropharmacology 2012-01, Vol.62 (1), p.304-312
Main Authors: Sartori, S.B., Whittle, N., Hetzenauer, A., Singewald, N.
Format: Article
Language:English
Subjects:
ACTH
Adrenocorticotropic Hormone - blood
Analysis of Variance
Animals
Anxiety
Anxiety - blood
Anxiety - drug therapy
Anxiety - etiology
Anxiety - pathology
Corticosterone
Corticotropin releasing hormone
Corticotropin-Releasing Hormone - genetics
Corticotropin-Releasing Hormone - metabolism
Dark Adaptation
Desipramine
Desipramine - pharmacology
Desipramine - therapeutic use
Diazepam
Disease Models, Animal
Exploratory Behavior
Fever
Food Deprivation
Hypothalamo-Hypophyseal System - drug effects
Hypothalamo-Hypophyseal System - metabolism
Hypothalamo-Hypophyseal System - physiopathology
Magnesium
Magnesium Deficiency - complications
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Paroxetine - pharmacology
Paroxetine - therapeutic use
Pituitary-Adrenal System - drug effects
Pituitary-Adrenal System - metabolism
Pituitary-Adrenal System - physiopathology
Protein Precursors - genetics
Protein Precursors - metabolism
Proto-Oncogene Proteins c-fos - metabolism
Radioimmunoassay
Reaction Time - drug effects
Reaction Time - physiology
RNA, Messenger - metabolism
Selective serotonin re-uptake inhibitor
Stress axis
Stress, Psychological - drug therapy
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Summary:Preclinical and some clinical studies suggest a relationship between perturbation in magnesium (Mg2+) homeostasis and pathological anxiety, although the underlying mechanisms remain largely unknown. Since there is evidence that Mg2+ modulates the hypothalamic-pituitary adrenal (HPA) axis, we tested whether enhanced anxiety-like behaviour can be reliably elicited by dietary Mg2+ deficiency and whether Mg2+ deficiency is associated with altered HPA axis function. Compared with controls, Mg2+ deficient mice did indeed display enhanced anxiety-related behaviour in a battery of established anxiety tests. The enhanced anxiety-related behaviour of Mg2+ deficient mice was sensitive to chronic desipramine treatment in the hyponeophagia test and to acute diazepam treatment in the open arm exposure test. Mg2+ deficiency caused an increase in the transcription of the corticotropin releasing hormone in the paraventricular hypothalamic nucleus (PVN), and elevated ACTH plasma levels, pointing to an enhanced set-point of the HPA axis. Chronic treatment with desipramine reversed the identified abnormalities of the stress axis. Functional mapping of neuronal activity using c-Fos revealed hyper-excitability in the PVN of anxious Mg2+ deficient mice and its normalisation through diazepam treatment. Overall, the present findings demonstrate the robustness and validity of the Mg2+ deficiency model as a mouse model of enhanced anxiety, showing sensitivity to treatment with anxiolytics and antidepressants. It is further suggested that dysregulations in the HPA axis may contribute to the hyper-emotionality in response to dietary induced hypomagnesaemia. This article is part of a Special Issue entitled ‘Anxiety and Depression’. ► Robustness and validity of the Mg2+ deficiency model of enhanced anxiety is shown. ► The Mg2+ deficiency model is sensitive to anxiolytic/antidepressant treatments. ► We suggest an inverse relationship between Mg2+ and anxiety. ► An aberrant HPA axis may contribute to the hyper-emotionality of Mg2+ deficiency.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2011.07.027