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 (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'.

Increased novelty-induced motor activity and reduced depression-like behavior in neuropeptide Y (NPY)-Y4 receptor knockout mice.

There is growing evidence that neuropeptide Y (NPY) acting through Y1 and Y2 receptors has a prominent role in modulating anxiety- and depression-like behavior in rodents. However, a role of other Y-receptors like that of Y4 receptors in this process is poorly understood. We now investigated male Y2, Y4 single and Y2/Y4 double knockout mice in behavioral paradigms for changes in motor activity, anxiety and depression-like behavior. Motor activity was increased in Y2, Y4 and Y2/Y4 knockout mice under changing and stressful conditions, but not altered in a familiar environment. Y4 and Y2 knockout mice revealed an anxiolytic phenotype in the light/dark test, marble burying test and in stress-induced hyperthermia, and reduced depression-like behavior in the forced swim and tail suspension tests. In Y2/Y4 double knockout mice, the response in the light/dark test and in the forced swim test was further enhanced compared with Y4 and Y2 knockout mice, respectively. High levels of Y4 binding sites were observed in brain stem nuclei including nucleus of solitary tract and area postrema. Lower levels were found in the medial amygdala and hypothalamus. Peripheral administration of pancreatic polypeptide (PP) induced Y4 receptor-dependent c-Fos expression in brain stem, hypothalamus and amygdala. PP released peripherally from the pancreas in response to food intake, may act not only as a satiety signal but also modulate anxiety-related locomotion.

Role of voltage-gated L-type Ca2+ channel isoforms for brain function.

Voltage-gated LTCCs (L-type Ca2+ channels) are established drug targets for the treatment of cardiovascular diseases. LTCCs are also expressed outside the cardiovascular system. In the brain, LTCCs control synaptic plasticity in neurons, and DHP (dihydropyridine) LTCC blockers such as nifedipine modulate brain function (such as fear memory extinction and depression-like behaviour). Voltage-sensitive Ca2+ channels Cav1 .2 and Cav1.3 are the predominant brain LTCCs. As DHPs and other classes of organic LTCC blockers inhibit both isoforms, their pharmacological distinction is impossible and their individual contributions to defined brain functions remain largely unknown. Here, we summarize our recent experiments with two genetically modified mouse strains, which we generated to explore the individual biophysical features of Cav1.2 and Cav1.3 LTCCs and to determine their relative contributions to various physiological peripheral and neuronal functions. The results described here also allow predictions about the pharmacotherapeutic potential of isoform-selective LTCC modulators.

The anxiety-like phenotype of 5-HT receptor null mice is associated with genetic background-specific perturbations in the prefrontal cortex GABA-glutamate system.

A deficit in the serotonin 5-HT(1A) receptor has been found in panic and post-traumatic stress disorders, and genetic inactivation of the receptor results in an anxiety-like phenotype in mice on both the C57Bl6 and Swiss-Webster genetic backgrounds. Anxiety is associated with increased neuronal activity in the prefrontal cortex and here we describe changes in glutamate and GABA uptake of C57Bl6 receptor null mice. Although these alterations were not present in Swiss-Webster null mice, we have previously reported reductions in GABA(A) receptor expression in these but not in C57Bl6 null mice. This demonstrates that inactivation of the 5-HT(1A) receptor elicits different and genetic background-dependent perturbations in the prefrontal cortex GABA/glutamate system. These perturbations can result in a change in the balance between excitation and inhibition, and indeed both C57Bl6 and Swiss-Webster null mice show signs of increased neuronal excitability. Because neuronal activity in the prefrontal cortex controls the extent of response to anxiogenic stimuli, the genetic background-specific perturbations in glutamate and GABA neurotransmission in C57Bl6 and Swiss-Webster 5-HT(1A) receptor null mice may contribute to their shared anxiety phenotype. Our study shows that multiple strains of genetically altered mice could help us to understand the common and individual features of anxiety.

Brain activation pattern induced by stimulation of L-type Ca2+-channels: contribution of Ca(V)1.3 and Ca(V)1.2 isoforms.

Ca(V)1.2 and Ca(V)1.3, are the main dihydropyridine-sensitive L-type calcium channel isoforms in the brain. To reveal the contribution of each isoform to the neuronal activation pattern elicited by the dihydropyridine L-type calcium channel activator BayK 8644, we utilized Fos expression as a marker of neuronal activation in mutant mice (Ca(V)1.2(DHP-/-) mice) expressing dihydropyridine-insensitive Ca(V)1.2 L-type calcium channels. BayK 8644-treated wildtype mice displayed intense and widespread Fos expression throughout the neuroaxis in 77 of 80 brain regions quantified. The Fos response in Ca(V)1.2(DHP-/-) mice was greatly attenuated or absent in most of these areas, suggesting that a major part of the widespread Fos induction including most cortical areas was mediated by Ca(V)1.2 L-type calcium channels. BayK 8644-induced Fos expression in Ca(V)1.2(DHP-/-) mice indicating predominantly Ca(V)1.3 L-type calcium channel-mediated activation was noted in more restricted neuronal populations (20 of 80), in particular in the central amygdala, the bed nucleus of the stria terminalis, paraventricular hypothalamic nucleus, lateral preoptic area, locus coeruleus, lateral parabrachial nucleus, central nucleus of the inferior colliculus, and nucleus of the solitary tract. Our data indicate that selective stimulation of other than Ca(V)1.2 L-type calcium channels, mostly Ca(V)1.3, causes neuronal activation in a specific set of mainly limbic, hypothalamic and brainstem areas, which are associated with functions including integration of emotion-related behavior. Hence, selective modulation of Ca(V)1.3 L-type calcium channels could represent a novel (pharmacotherapeutic) tool to influence these CNS functions.

[Urodynamic parameters before and following a vaginal incontinence operation]. / Urodynamische Parameter vor und nach vaginaler Inkontinenzoperation.

We compared two groups of patients 14 months after vaginal hysterectomy and pelvic floor repair, group I (n = 20) postoperatively continent versus group II (n = 27) postoperatively incontinent. Preoperative urodynamic findings were of no prognostic value with regard to continence. There was no statistical difference in maximum resting urethral closure pressure (UCP), urethral functional length and dynamic and reflectoric vesico-urethral transmission factor, in spite of group I having a slightly higher resting UCP than group II. Group II showed a significant decrease of resting UCP postoperatively.

[Pregnancy complications caused by choledochus cyst]. / Schwangerschafts-komplikationen durch Choledochuszyste.

A 27 year old primipara up to the 22nd gestational week without serious complaints developed a huge choledochal cyst with classical signs of tumour in the right upper abdomen, pain, and icterus. Diagnosis, monitoring, and therapy, as well as causal relationship to pregnancy, are discussed.