Neonatal bilateral whisker trimming in male mice age-dependently alters brain neurotransmitter levels and causes adolescent onsets of social behavior abnormalities.

Tactile perception via whiskers is important in rodent behavior. Whisker trimming during the neonatal period affects mouse behaviors related to both whisker-based tactile cognition and social performance. However, the molecular basis of these phenomena is not completely understood. To solve this issue, we investigated developmental changes in transmitters and metabolites in various brain regions of male mice subjected to bilateral whisker trimming during the neonatal period (10 days after birth [BWT10 mice]). We discovered significantly lower levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), the major noradrenaline metabolite, in various brain regions of male BWT10 mice at both early/late adolescent stages (at P4W and P8W). However, reduced levels of dopamine (DA) and their metabolites were more significantly identified at P8W in the nuclear origins of monoamine (midbrain and medulla oblongata) and the limbic system (frontal cortex, amygdala, and hippocampus) than at P4W. Furthermore, the onset of social behavior deficits (P6W) was observed later to the impairment of whisker-based tactile cognitive behaviors (P4W). Taken together, these findings suggest that whisker-mediated tactile cognition may contribute toprogressive abnormalities in social behaviors in BWT10 mice accompanied by impaired development of dopaminergic systems.

Substantial acetylcholine reduction in multiple brain regions of Mecp2-deficient female rats and associated behavioral abnormalities.

Rett syndrome (RTT) is a neurodevelopmental disorder with X-linked dominant inheritance caused mainly by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The effects of various Mecp2 mutations have been extensively assessed in mouse models, but none adequately mimic the symptoms and pathological changes of RTT. In this study, we assessed the effects of Mecp2 gene deletion on female rats (Mecp2+/-) and found severe impairments in social behavior [at 8 weeks (w), 12 w, and 23 w of age], motor function [at 16 w and 26 w], and spatial cognition [at 29 w] as well as lower plasma insulin-like growth factor (but not brain-derived neurotrophic factor) and markedly reduced acetylcholine (30%-50%) in multiple brain regions compared to female Mecp2+/+ rats [at 29 w]. Alternatively, changes in brain monoamine levels were relatively small, in contrast to reports on mouse Mecp2 mutants. Female Mecp2-deficient rats express phenotypes resembling RTT and so may provide a robust model for future research on RTT pathobiology and treatment.

Mirogabalin, a novel ligand for α2δ subunit of voltage-gated calcium channels, improves cognitive impairments in repeated intramuscular acidic saline injection model rats, an experimental model of fibromyalgia.

Mirogabalin is a novel potent and selective ligand for the α2δ subunit of voltage-gated calcium channels, and shows potent and sustained analgesic effects in neuropathic pain and fibromyalgia models. Fibromyalgia is often associated with multiple comorbid symptoms, such as anxiety, depression and cognitive impairment. In the present study, we investigated the effects of mirogabalin on cognitive impairments in an experimental animal model for fibromyalgia, repeated intramuscular acidic saline injection model (Sluka model) rats. Male rats received two repeated intramuscular injections of pH 4 acidic saline into their gastrocnemius muscle. After developing mechanical hypersensitivity as identified in the von Frey test, the animals received the test substance orally once daily for 13 days and were subjected to four cognitive function tests, (Y-maze, novel object recognition, Morris water maze and step-through passive avoidance). Sluka model rats showed cognitive impairments in all four tests. Oral administration of mirogabalin (3 and 10 mg/kg) improved the cognitive impairments in these rats. In conclusion, mirogabalin improved the impaired cognitive function in Sluka model rats. It may thus also alleviate cognitive impairments as well as painful symptoms in fibromyalgia patients.

Tyr-Trp administration facilitates brain norepinephrine metabolism and ameliorates a short-term memory deficit in a mouse model of Alzheimer's disease.

The physiological actions of orally ingested peptides on the brain remain poorly understood. This study examined the effects of 39 orally administered synthetic Tyr-containing dipeptides on the enhancement of brain norepinephrine metabolism in mice by comparing the concentration of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Although Tyr-Tyr administration increased blood and cerebral cortex (Cx) Tyr concentrations the most, Tyr-Trp increased Cx MHPG concentration the most. The oral administration of Tyr-Trp ameliorated a short-term memory deficit of a mouse model of cognitive dysfunction induced by amyloid beta peptide 25-35. Gene expression profiling of mouse brain using a microarray indicated that Tyr-Trp administration led to a wide variety of changes in mRNA levels, including the upregulation of genes encoding molecules involved in catecholamine metabolism. A comparative metabolome analysis of the Cx of mice given Tyr-Trp or Tyr-Tyr demonstrated that Tyr-Trp administration yielded higher concentrations of Trp and kynurenine pathway metabolites than Tyr-Tyr administration, as well as higher L-dopa levels, which is the initial product of catecholamine metabolism. Catecholamines were not significantly increased in the Cx of the Tyr-Tyr group compared with the Tyr-Trp group, despite a marked increase in Tyr. Presumably, Tyr-Trp administration enhances catecholamine synthesis and metabolism via the upregulation of genes involved in Tyr and Trp metabolism as well as metabolites of Tyr and Trp. These findings strongly suggest that orally ingested Tyr-Trp modulates the brain metabolome involved in catecholamine metabolism and contributes to higher brain function.

Dehydroeffusol Rescues Amyloid ß25-35-Induced Spatial Working Memory Deficit.

Amyloid ß (Aß) peptides produced from the amyloid precursor protein, a transmembrane protein, are neurotoxic and blocking the neurotoxicity may lead to prevention of Alzheimer's disease (AD). Here we tested whether Aß25-35-induced cognitive decline is rescued by treatment with dehydroeffusol, a phenanthrene isolated from Chinese medicine Juncus effusus. Dehydroeffusol (5 ~ 15 mg/kg body weight) was orally administered to mice for 6 days and Aß25-35 (2 mM) was injected at the rate of 1 µl/min for 3 min into the lateral ventricle. Y-maze test was performed after dehydroeffusol administration for 12 days. Aß25-35 impaired learning and memory in the test, while the impairment was dose-dependently rescued by dehydroeffusol administration. The present study indicates that treatment with dehydroeffusol is effective for rescuing Aß25-35-induced cognitive decline.

Anxiolytic-like effects of mirogabalin, a novel ligand for α2δ ligand of voltage-gated calcium channels, in rats repeatedly injected with acidic saline intramuscularly, as an experimental model of fibromyalgia.

BACKGROUND: Mental disorders including anxiety and depression are common comorbidities in fibromyalgia patients, and exert a profound impact on their quality of life. Mirogabalin, a novel ligand for the α2δ-subunit of voltage-gated calcium channels, shows analgesic effects in fibromyalgia and neuropathic pain models. To provide additional information regarding its potential utility for treating chronic pain, we examined its anxiolytic-like effects in rats repeatedly injected with acidic saline intramuscularly (Sluka model), as an experimental fibromyalgia model. METHODS: Male Sprague-Dawley rats received two intramuscular injections of acidic saline (pH 4.0) into the gastrocnemius muscle. After the development of tactile allodynia demonstrated by decreased paw withdrawal threshold to von Frey filaments, anxiety-like behaviours were evaluated using the open field test and the elevated plus maze test. RESULTS: Sluka model rats exhibited anxiety-like behaviours in the open field test (significant decreases in distance travelled and time spent in the central area, and significant increases in time spent in the wall area) and the elevated plus maze test (significant decreases in time spent in the open arms and significant increases in time spent in the closed arms). A single oral dose of mirogabalin (3 or 10 mg/kg) significantly alleviated and normalised these anxiety-like behaviours. CONCLUSIONS: Sluka model rats exhibited anxiety-like behaviours in the open field test and the elevated plus maze test, but mirogabalin alleviated these behaviours. Mirogabalin might thus have the potential to relieve anxiety in fibromyalgia patients.

Anxiolytic effects of the novel α2δ ligand mirogabalin in a rat model of chronic constriction injury, an experimental model of neuropathic pain.

RATIONALE: Psychiatric disorders such as anxiety and depression are frequently observed in neuropathic pain patients, and negatively impact their quality of life. Mirogabalin is a novel ligand for the α2δ subunit of voltage-gated calcium channels and has unique binding characteristics to α2δ subunits and potent and long-lasting analgesic effects in neuropathic pain models. OBJECTIVES: To provide further information on the pharmacological profile of mirogabalin and its utility for chronic pain therapy, we investigated its anxiolytic effects in an experimental animal model for neuropathic pain. METHODS: In chronic constriction injury (CCI) model rats, mechanical hypersensitivity was determined by the von Frey test. Anxiety- and depression-related behaviours were evaluated using the elevated plus maze test and forced swimming test, respectively. RESULTS: CCI model rats showed sustained tactile allodynia followed by anxiety-related behaviours, not depression-related behaviours. The tactile allodynia (significant decreases in paw withdrawal threshold) developed within 2 weeks after model preparation, whereas the anxiety-related behaviours (significant decreases in the number of entries and time spent in open arms and significant increases in time spent in closed arms) were observed at 5 weeks but not 4 weeks after model preparation. Single oral administration of mirogabalin (3 or 10 mg/kg) dose-dependently alleviated the above-mentioned anxiety-related behaviours and tactile allodynia. CONCLUSIONS: CCI model rats showed anxiety-related behaviours in a time-dependent manner in the elevated plus maze test. Mirogabalin alleviated both the anxiety-related behaviours and tactile allodynia in CCI model rats. Mirogabalin may provide effective anxiety relief as well as pain relief in patients with neuropathic pain.

Memantine ameliorates learning and memory disturbance and the behavioral and psychological symptoms of dementia in thiamine-deficient mice.

Several studies have reported on the beneficial effects of memantine on behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease. However, the effects of memantine on BPSD-like behaviors in animals have not been well addressed. Here, the effects of memantine on memory disturbance and BPSD-like behaviors were evaluated in thiamine-deficient (TD) mice. Memantine (3 and 10 mg/kg, b.i.d.) was orally administered to ddY mice fed a TD diet for 22 days. During the treatment period, the forced swimming test, elevated plus-maze test, passive avoidance test, and locomotor activity test were performed. Neurotransmitter levels in the brain were analyzed after the treatment period. Daily oral administration of memantine ameliorated the memory disturbances, anxiety-like behavior, and depression-like behavior observed in TD mice. Memantine did not have a significant effect on monoamine levels, but increased glutamate levels in the hippocampus in TD mice. These results suggest that memantine prevents or suppresses the progression of BPSD-like behaviors that develop due to TD. This effect may be mediated in part by the enhancement of glutamatergic neuron activity in the hippocampus.

Novel oestrogen receptor ß-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice.

Hormonal changes due to menopause can cause various health problems including weight gain and depressive symptoms. Multiple lines of evidence indicate that oestrogen receptors (ERs) play a major role in postmenopausal obesity and depression. However, little is known regarding the ER subtype-specific effects on obesity and depressive symptoms. To delineate potential effects of ERß activation in postmenopausal women, we investigated the effects of a novel oestrogen receptor ß-selective ligand (C-1) in ovariectomized mice. Uterine weight, depressive behaviour, and weight gain were examined in sham-operated control mice and ovariectomized mice administered placebo, C-1, or 17ß-oestradiol (E2). Administration of C-1 or E2 reduced body weight gain and depressive-like behaviour in ovariectomized mice, as assessed by the forced swim test. In addition, administration of E2 to ovariectomized mice increased uterine weight, but administration of C-1 did not result in a significant increase in uterine weight. These results suggest that the selective activation of ERß in ovariectomized mice may have protective effects against obesity and depressive-like behaviour without causing an increase in uterine weight. The present findings raise the possibility of the application of ERß-ligands such as C-1 as a novel treatment for obesity and depression in postmenopausal women.

Riluzole rapidly attenuates hyperemotional responses in olfactory bulbectomized rats, an animal model of depression.

Growing evidence indicates that the glutamatergic neurotransmitter system is central to the neurobiology and treatment of depression. Riluzole, a drug currently used to slow the progression of amyotrophic lateral sclerosis (ALS), directly affects the glutamatergic system. In this study, we investigated the effects of riluzole in olfactory bulbectomy (OBX) rats, an animal model of depression. The olfactory bulbs in rats were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed significant increases in emotionality responses. Single (1st day administration) and subchronic (7th day administration) riluzole treatment (1-10 mg/kg, po) significantly and dose-dependently reduced hyperemotional responses in OBX rats. Both single and subchronic riluzole treatment (10 mg/kg, po) had no significant effects on the emotional responses in sham operated rats. In addition, we demonstrated that single riluzole treatment (10 mg/kg, po) significantly decreased extracellular glutamate levels in medial prefrontal cortex of OBX rats by in vivo microdialysis. We provide the first experimental evidence that riluzole rapidly attenuated hyperemotional responses in OBX rats, an animal model of depression.

Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model.

The responses of olfactory bulbectomized (OBX) rats to antidepressant treatment are similar to those of depressed patients since chronic administration of an antidepressant reverses OBX-induced behavioral and physiological changes. Previously, using several animal models, it was demonstrated that single treatment with delta-opioid receptor agonists produced an antidepressant-like effect. This study examined the antidepressant effects resulting from subchronic exposure for 8 days to the delta-opioid receptor agonist SNC80 in an OBX rat model of depression. The olfactory bulbs were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed a significant increase in emotionality score and a decrease in the time spent and entries in the open arm of a plus-maze. In the case of OBX rats, these changes were dose- and time-dependently reversed by chronic SNC80 treatment (1-10 mg/kg, s.c.) for 7 days, as same as desipramine (10 mg/kg, i.p.). Moreover, the concentration of 5-HT and its metabolite 5-HIAA in the frontal cortex, hippocampus, and amygdala were decreased in OBX rats, and these changes were also normalized by SNC80 treatment, rather than desipramine treatment. In addition, SNC80 also significantly reversed the loss of TH-positive cells produced by OBX in the dorsal raphe. In conclusion, we demonstrated that subchronic SNC80 treatment could completely reverse OBX-induced behavioral abnormalities and defects in serotonergic function.

Effects of milnacipran and fluvoxamine on hyperemotional behaviors and the loss of tryptophan hydroxylase-positive cells in olfactory bulbectomized rats.

RATIONALE: It has been reported that many of the behavioral and serotonergic neuronal changes observed in olfactory bulbectomy (OBX) were improved by subchronic administration of a variety of antidepressants. OBJECTIVE: We examined the effects of subchronic treatment with milnacipran, a dual serotonin and noradrenaline reuptake inhibitors (SNRIs) and fluvoxamine, selective serotonin reuptake inhibitors (SSRI) in the OBX-induced hyperemotional behaviors and tryptophan hydroxylase (TPH), rate-limiting enzyme of 5-HT. MATERIALS AND METHODS: The olfactory bulbs were removed by suction. Drugs were administered p.o. once daily for 8 days beginning 14 days post-surgery. The hyperemotionality behaviors of OBX rats were measured by rating scale and in the elevated plus-maze test. RESULTS: OBX rats, after milnacipran or fluvoxamine treatment, showed significant decrease in the score of hyperemotional responses on 7th day as compared with vehicle-treated OBX rats. In addition, milnacipran and fluvoxamine in OBX rats respectively produced a significant increase in the percentage of time spent in and number of entries into open arms in the elevated plus maze test. Furthermore, when 5-HTnergic neuronal function was examined using antibodies against tryptophan hydroxylase (TPH) following the behavioral tests, fluvoxamine significantly reversed the loss of TPH-positive cells produced by OBX in the dorsal raphe. CONCLUSION: We demonstrated that chronic treatment with milnacipran or fluvoxamine was effective to improve both the hyperemotional behavior and the loss of TPH-positive cells seen in OBX rats.

[The approaches in the discovery of antidepressants using affective disorder models].

With the recent appearance of SSRI and SNRI, medication options with respect to depression have broadened. However, patients displaying clear improvement with existing antidepressants still do not exceed about 60 percent of total patients. New types of therapeutic agent development are currently required. Conditions for the determination of new antidepressants are: 1) instantaneous medications displaying a high level of antidepressant action in the early stages of treatment and 2) medications displaying efficacy with respect to patients that are therapy-resistant. However, drug discovery using new animal models is critical as part of drug development of these types of antidepressants in addition to models used in the past such as the forced swim test. We adopted two animal models (olfactory bulbectomy model and conditioned fear stress (CFS) model) developed for pharmacological evaluation of antidepressants. It has been well known that olfactory bulbectomied rats display extreme emotional response (aggressiveness and anxiety). However the improvement of this response occurs following chronic but not acute antidepressant treatment. Thus, we used this model to evaluate the period of the manifestation of antidepressant action. Mice exhibited a marked suppression of motility when they were returned to the same environment in which they had previously received an electric foot shock. Thus, it is suggested that the CFS stress model may be a useful model for therapy-resistant depression due to the fact that motor suppression is not readily attenuated by antidepressant treatment. In this report, we provide an overview of the approaches in the discovery of new antidepressants using these affective disorder models.