title: Magnesium deficiency induces anxiety and HPA axis dysregulation: modulation by therapeutic drug treatment.
abstract: Preclinical and some clinical studies suggest a relationship between perturbation in magnesium (Mg(2+)) homeostasis and pathological anxiety, although the underlying mechanisms remain largely unknown. Since there is evidence that Mg(2+) modulates the hypothalamic-pituitary adrenal (HPA) axis, we tested whether enhanced anxiety-like behaviour can be reliably elicited by dietary Mg(2+) deficiency and whether Mg(2+) deficiency is associated with altered HPA axis function. Compared with controls, Mg(2+) deficient mice did indeed display enhanced anxiety-related behaviour in a battery of established anxiety tests. The enhanced anxiety-related behaviour of Mg(2+) deficient mice was sensitive to chronic desipramine treatment in the hyponeophagia test and to acute diazepam treatment in the open arm exposure test. Mg(2+) 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 Mg(2+) deficient mice and its normalisation through diazepam treatment. Overall, the present findings demonstrate the robustness and validity of the Mg(2+) 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'.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, and Centre for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Peter-Mayr-Strasse 1, A-6020 Innsbruck, Austria. simone.sartori@uibk.ac.at
authors.forename: S B
authors.initials: SB
authors.lastname: Sartori
authors.forename: N
authors.initials: N
authors.lastname: Whittle
authors.forename: A
authors.initials: A
authors.lastname: Hetzenauer
authors.forename: N
authors.initials: N
authors.lastname: Singewald
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000097:blood / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D003345:Corticosterone; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D003623:Dark Adaptation; D003891:Desipramine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005106:Exploratory Behavior; D005334:Fever; D005508:Food Deprivation; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008274:Magnesium; D008275:Magnesium Deficiency / Q000150:complications*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017374:Paroxetine / Q000494:pharmacology / Q000627:therapeutic use; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000188:drug therapy
chemical_list: D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C041645:pro-corticotropin releasing hormone; D017374:Paroxetine; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D008274:Magnesium; D003891:Desipramine; D003345:Corticosterone