Minocycline does not evoke anxiolytic and antidepressant-like effects in C57BL/6 mice.

Minocycline is a broad-spectrum tetracycline antibiotic with multiple actions, including anti-inflammatory and neuroprotective effects, that was proposed as novel treatment for several psychiatric disorders including schizophrenia and depression. However, there are contradictory results regarding antidepressant effects of minocycline in rodent models. Additionally, the possible anxiolytic effect of minocycline is still poorly investigated. Therefore, we aimed to clarify in the present study the influence of minocycline on behavioral correlates of mood disorders in standard tests for depression and anxiety, the Porsolt Forced Swim Test (FST), Elevated O-Maze, Dark-Light Box Test and Openfield Test in adult C57BL/6 mice. We found, unexpectedly, that mice treated with minocycline (20-40mg/kg, i.p.) did not display antidepressant- or anxiolytic-like behavioral changes in contrast to mice treated with diazepam (0.5mg/kg, anxiety tests) or imipramine (20mg/kg, depressive-like behavior). These results are relevant for future studies, considering that C57BL/6 mice, the most widely used strain in pharmacological and genetic animal models, did not react as expected to the treatment regime applied.

Immobilization stress sensitizes rat dorsal horn neurons having input from the low back.

BACKGROUND: Stress is known to promote several forms of muscle pain including non-specific low back pain. However, the question if stress alone activates nociceptive central neurons has not been studied systematically. Here, we investigated the influence of repeated immobilization stress on dorsal horn neurons and behaviour in the rat. METHODS: The stress consisted of immobilization in a narrow tube for 1 h on 12 days. Single dorsal horn neurons were recorded with microelectrodes introduced into the spinal segment L2. In this segment, about 14% of the neurons responded to mechanical stimulation of the subcutaneous soft tissues of the low back in naïve rats. The neurons often behaved like wide dynamic range cells in that they had a low mechanical threshold and showed graded responses to noxious stimuli. RESULTS: The stress-induced changes in neuronal response behaviour were (1) appearance of new receptive fields in the deep tissues of the hindlimb, (2) increased input from deep soft tissues, but unchanged input from the skin and (3) significant increase in resting activity. Surprisingly, the pressure-pain threshold of the low back remained unchanged, although dorsal horn neurons were sensitized. In the open field test, the rats showed signs of increased anxiety. CONCLUSIONS: This study shows that stress alone is sufficient to sensitize dorsal horn neurons. The data may explain the enhanced pain low back patients report when they are under stress. The increased resting discharge may lead to spontaneous pain.

Implications of p75NTR for dentate gyrus morphology and hippocampus-related behavior revisited.

The pan-neurotrophin receptor p75NTR is expressed in the adult brain in a discrete pattern. Although numerous studies have addressed its implications for hippocampal functions, the generated sets of data are surprisingly conflicting. We have therefore set out to re-investigate the impact of a deletion of the full-length p75NTR receptor on several parameters of the dentate gyrus (DG), including neurogenesis and hippocampus-related behavior by using p75NTR(ExIII) knockout mice. Moreover, we investigated further parameters of the DG (cholinergic innervation, dendritic spines). In addition, we analyzed on the morphological level the impact of aging by comparing adult and aged p75NTR(ExIII) mice and their age-matched littermates. Adult (4-6 months old), but not aged (20 months old), p75NTR(ExIII) knockout mice display an enhanced volume of the DG. However, adult neurogenesis within the adult DG was unaffected in both adult and aged p75NTR(ExIII) knockout mice. We could further demonstrate that the change in the volume of the DG was accompanied by an increased cholinergic innervation and increased spine densities of granule cells in adult, but not aged p75NTR deficient mice. These morphological changes in the adult p75NTR deficient mice were accompanied by specific alterations in their behavior, including altered behavior in the Morris water maze test, indicating impairments in spatial memory retention.

Significant increase in anxiety during aging in mGlu5 receptor knockout mice.

Glutamatergic mechanisms regulate neuronal circuits implicated in mood and anxiety. Emotional disorders as anxiety and depression are particularly difficult to treat during aging and mechanisms underlying emotional disturbances in the brain of the elderly are poorly understood. This may result from the small number of studies investigating these disorders in aged animals. Among glutamate receptors, metabotropic mGlu5 receptors are thought to play an important role, since their pharmacological blockade induces strong anxiolytic effects. However, the implication of mGlu5 in regulating anxiety is not yet completely understood. Here we analyzed both young adult and aged mice lacking mGlu5 receptors, to clarify, if genetic deletion of the receptor induces similar to pharmacological blockade anxiolytic effects. Unexpectedly, mGlu5 receptor knockout (KO) mice showed increased anxiety accentuating with aging. In contrast, young adult mice displayed an anti-depressive-like phenotype that was no longer detectable in aged animals. Our data support important distinct roles of mGlu5 receptors in modulating anxiety and depression during aging.

Finasteride treatment inhibits adult hippocampal neurogenesis in male mice.

INTRODUCTION: The 5-alpha-reductase inhibitor finasteride is used for the treatment of androgenic alopecia, benign prostate hyperplasia and prostate cancer. Besides inhibiting the conversion of testosterone to the biologically more active 5alpha-dihydrotestosterone, it also inhibits the production of neurosteroids. Decreased neurosteroid levels are postulated to be involved in the pathophysiology of psychiatric disorders such as depression. As neurosteroids metabolized by 5-alpha-reductase influence neural plasticity, we investigated whether finasteride treatment alters adult hippocampal neurogenesis, implicated in the pathophysiology of depression. METHODS: Male C57BL/6N mice were treated subchronically (7 days) with finasteride or vehicle. Adult neurogenesis was assessed at two different time points after treatment (day 1; day 35) using immunohistochemistry. RESULTS: Finasteride treatment led to a significant decrease in brain 5alpha-dihydrotestosterone levels and induced a reversible reduction in the number of newborn cells and young neurons in the hippocampus. 35 days after the last finasteride injection, neurogenesis had returned to normal. DISCUSSION: These data indicate that inhibition of 5-alpha-reductase activity by finasteride treatment influences neuronal plasticity on a structural level. These changes might contribute to the pathophysiology of depressive episodes observed after finasteride treatment.

Dopamine receptor 3 (D3) knockout mice show regular emotional behaviour.

The "Dopamine Deficiency Hypothesis" and a considerable number of recent pharmacological studies propose to thoroughly verify and improve the standard of knowledge regarding a possible role of dopamine in the pathogenesis and treatment of depression. To elucidate the potential role of D3 receptors in the development of a depressive-like phenotype, we subjected D3 receptor knockout mice to a series of selected behavioural paradigms particularly focussing on depressive-like traits. In our experimental design we exposed animals with a deficiency of the D3 receptor (D3-/-) to a standardised behavioural test battery, in which general changes of locomotion, exploration, anxiety and depressive-like characteristics (i.e. Learned Helplessness, Sucrose Consumption and Forced Swim test) can be detected. Thorough behavioural phenotyping, however, neither revealed behavioural consequences on the basal level (locomotion, exploration) nor depressive- or anxiety-like alterations. Hence, these results do not indicate an evident involvement of the D3 receptor in the development of a depression-like syndrome in mice for now. This does, however, not exclude the D3 receptor as a potential target for pharmacotherapy.

AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression.

Recent evidence indicates that glutamate homeostasis and neurotransmission are altered in major depressive disorder, but the nature of the disruption and the mechanisms by which it contributes to the syndrome are unclear. Glutamate can act via AMPA, NMDA, or metabotropic receptors. Using targeted mutagenesis, we demonstrate here that mice with deletion of the main AMPA receptor subunit GluR-A represent a depression model with good face and construct validity, showing behavioral and neurochemical features of depression also postulated for human patients. GluR-A(-/-) mice display increased learned helplessness, decreased serotonin and norepinephrine levels, and disturbed glutamate homeostasis with increased glutamate levels and increased NMDA receptor expression. These results correspond well with current concepts regarding the role of AMPA and NMDA receptors in depression, postulating that compounds that augment AMPA receptor signaling or decrease NMDA receptor functions have antidepressant effects. GluR-A(-/-) mice represent a model to investigate the pathophysiology underlying the depressive phenotype and to identify changes in neural plasticity and resilience evoked by the genetic alterations in glutamatergic function. Furthermore, GluR-A(-/-) mice may be a valuable tool to study biological mechanisms of AMPA receptor modulators and the efficacy of NMDA antagonists in reducing behavioral or biochemical changes that correlate with increased helplessness.

Suitability of tamoxifen-induced mutagenesis for behavioral phenotyping.

Tamoxifen-induced mutagenesis via the so-called CreER(T2) fusion enzyme is a key technology for the inducible gene knockout in the adult murine brain. However, it requires a subchronic transient treatment with high doses of the non-selective estrogen receptor antagonist tamoxifen. It has been shown earlier that acute tamoxifen treatment causes behavioral alterations, while the long-term behavioral effects of tamoxifen in mice are so far unknown. Therefore C57BL/6 male mice, a common strain used for targeted mutagenesis and behavioral analyses, were subjected to a tamoxifen treatment protocol as used for inducible mutagenesis in vivo, and analyzed for effects on general behavior (locomotion, exploration), emotional behavior (anxiety, depression) and on learning and memory after a drug-free interval period of 4 weeks. The results demonstrate that a test for depression-like behavior, i.e. the Forced Swim Test, is affected even more than 4 weeks after tamoxifen treatment. In contrast, in all other tests, tamoxifen treated mice showed unaltered behaviors, indicating that the currently established 5-day protocol of tamoxifen treatment (40 mg/kg bid) for inducible mutagenesis has no or little effects on the behavior of C57BL/6 male mice after a latency period of 4 weeks. These results are important for all studies using tamoxifen-induced mutagenesis since this protocol obviously does not evoke alterations in general behaviors such as locomotion, exploration or anxiety-like behaviors, which might confound more complex behavioral analyses, nor does it affect standard tests for learning and memory, such as Morris Water Maze, contextual and cued Fear Conditioning and T-Maze learning.