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Effects of pre-germinated brown rice on depression-like behavior in mice

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Effects of pre-germinated brown rice on depression-like behavior in mice

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We investigated the antidepressant-like effects of pre-germinated brown rice (PGBR) and polished rice (PR) pellets, respectively, in comparison with control (AIN-93G) pellets in the forced swimming test and the learned helplessness paradigm in mice. Mice were fed respective pellets for 30 days. The immobility time on the 2nd day of the forced swimming test was shorter in mice fed with PR or PGBR pellets than in mice fed with control pellets. In the learned helplessness paradigm, the number of escape failures in mice fed with PGBR pellets was significantly smaller than that in mice fed with control pellets. Compared to the control group, an increase in serotonin (5-HT) levels, but not in 5-hydroxyindoleacetic acid (5-HIAA) levels, and a decrease in the 5-HIAA/5-HT ratio were observed in the frontal cortex of the PGBR group. There were no differences among the three groups in terms of 5-HT and 5-HIAA levels and their ratios in the hippocampus and striatum. The levels of noradrenaline and 3-methoxy-4-hydroxyphenylglycol were not affected by the food pellets in all the brain regions tested. Additionally, we could not detect any differences in the expression of the 5-HT1A receptor and the 5-HT transporter in the frontal cortex of the three groups. These results suggest that the increase of 5-HT levels in the mouse frontal cortex contributes to the antidepressant-like effects of PGBR pellets.

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... In addition, the protease activity of GBR increased 1.5 times after germination (Yamada et al. 2005;Patil and Khan 2011). Recently, GBR and pre-GBR have been reported to possess high neuroprotective activity such as suppression of cell death induced by H 2 O 2 in SH-SY5Y cells by blocking the cell cycle reentry and apoptotic mechanisms (Ismail et al. 2012), and the antidepressant-like effect by increasing 5-HT levels in the mouse frontal cortex (Mamiya et al. 2007). ...
... Rats gained weight more than twice at 4 weeks and gradually increased till the end of the experiment. This agreed with the report by Mamiya et al. (2007) that pre-GBR and polished rice gained more weight twice than cornstarch significantly at 4 weeks. On the other Fig. 3 Flow cytometric analysis of apoptosis by annexin V and propidium iodide staining on brain tissue of rats in control (CT) pretreated with GBR or 4-PBA and/or rotenone (RT) injection groups was shown and expressed as four quadrants: viable cells (lower left), the percentage of early apoptotic (lower right), early necrotic (upper left) and dead (upper right) ...
... This may suggest that the altered GABA function in PD is secondary to changes in the DA system. As it has been previously reported that pre-GBR and GBR contain a large amount of GABA, and GABA can be carried into the brain through the BBB (Mamiya et al. 2007), therefore, GBR may attenuate the decrease in GABA level in PD condition. ...
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The effects of germinated brown rice (GBR) on the motor deficits and the dopaminergic (DA) cell death were investigated in Parkinson’s-like disease (PD) rats. Reactive oxidative species generated by chronic subcutaneous injection of rotenone (RT) lead to neuronal apoptosis particularly in the nigrostriatal DA system and produce many features of PD, bradykinesis, postural instability and rigidity. In this study, 4-phenylbutyric acid (4-PBA), previously reported to inhibit RT-induced DA cell death, was used as the positive control. Results show that pretreatment with GBR as well as 4-PBA significantly enhanced the motor activity after RT injection, and GBR affected significantly in open field test, only in the ambulation but not the mobility duration, and ameliorated the time to orient down (t-turn) and total time to descend the pole (t-total) in pole test as compared to RT group, but significantly lowered both t-turn and t-total only in 4-PBA group. The percentage of apoptotic cells in brain measured by flow cytometry and the inflammatory effect measured by ELISA of TNF-α showed significant increase in RT group as compared to the control (CT) group at P < 0.05. Apoptotic cells in RT group (85.98 %) showed a significant (P < 0.05) increase versus CT group (17.50 %), and this effect was attenuated in GBR+RT group by decreasing apoptotic cells (79.32 %), whereas, increased viable cells (17.94 %) versus RT group (10.79 %). GBR in GBR + RT group could decrease TNF-α both in the serum and in brain. In summary, GBR showed a neuroprotective effect in RT-induced PD rats, and it may be useful as a value-added functional food to prevent neurodegenerative disease or PD.
... (i) Control group (AC): eight animals received distilled water for 31 days. (ii) Acute stress group (AS): seven animals received distilled water for 31 days and animals underwent the forced swimming test (FST) (Mamiya et al., 2007) at day 30 and 31. (iii) Fluoxetine + FST group (AF): seven animals received distilled water for 28 days and on days 29 to 31 received fluoxetine (Fulox 20 â , Fluoxetine HCl equivalent, Reg. ...
... The FST was performed by modification of the previous studies (Mamiya et al., 2007). Briefly, rats were dropped individually into a transparent acrylic cylinder (diameter 21 cm 9 height 50 cm) filled with water to a depth of approximately 30 cm. ...
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Depression and antidepressant drugs induce adverse effects in male reproduction. Therefore, it is important to investigate alternative treatment for depression without adverse effects on the male reproductive system. The aim of this study was to determine the effect of pre-germinated brown rice (PGBR) on sperm quality, testicular structure and androgen receptor (AR) expression in rat model of depression. Male Sprague Dawley rats were divided into five groups including control (distilled water only), depression induced by forced swimming test (FST), FST + fluoxetine (antidepressant drug), FST + GABA (gamma-aminobutyric acid) (standard) and FST + PGBR. When compared with the control, sperm motility showed a significant decrease in FST + fluoxetine group. Sperm morphology also decreased significantly in depression and FST + fluoxetine groups. The morphological changes of seminiferous tubules showed significant increases in depression and FST + fluoxetine groups, while AR expression showed significant decreases in depression, FST + fluoxetine and FST + GABA groups. Interestingly, there were no significant differences in all sperm quality parameters, testicular structure and AR expression in FST + PGBR group. These findings reflect the recovery effects of PGBR treatment on sperm quality, morphological changes of seminiferous tubules and AR expression in stress-induced rats. Therefore, PGBR may potentially develop for the treatment for depression without adverse effect on male reproduction.
... japonica (Hoshino-yume)). PGBR was prepared at 25-30% water content to induce germination and dried to 15% according to a patented procedure ( nutrients in the PGBR pellets were the same as those in AIN-93G, except that cornstarch was replaced with PGBR, as reported previously [9,10]. All experiments were approved with the Guidelines for Animal Experiments of Meijo University (Approved number: Yaku-Jitsu-12) and the Guiding Principles for the Care and Use of Laboratory Animals approved by the Japanese Pharmacological Society (2007). ...
... Whereas we have already clarified that PGBR increases serotonin contents in the frontal cortex [10], the relationship between increased serotonin in the frontal cortex and PGBR on cognitive impairment is unclear, so that we aim to clarify the correlations between PGBR and neurotransmitters in the brain in a future study. In conclusion, we surmise that the reversal effects of PGBR on Ab 25-35 -induced cognitive dysfunction are at least partially due to the radical scavenging activity of FA in the PGBR. ...
Article
In this study, we investigated whether the food pellets containing pre-germinated brown rice (PGBR; hatsuga genmai in Japanese) were effective on the impairments of cognitive function induced by ß-amyloid peptide25-35 (Aß25-35) in mice. To evaluate the effects of PGBR, mice were received AIN-93G (as control pellets) or PGBR-added food pellets (PGBR pellets) during this study. Aß25-35 (3 nmol/3 ßmol i.c.v.) was injected to mice on the day 22. On the days 30 and 31, we assessed the tasks related to visible cognition using novel object recognition tests. By the injection of Aß25-35 in the control pellets-fed mice impairments were observed, but the mice fed PGBR-added food pellets did not show the deficits. After the behavioral tests, we found Aß25-35 increased lipid peroxidation in the hippocampus of control pellets-fed mice but not PGBR pellets-fed mice. Taken together, these results suggest that continuous feeding of food pellets containing PGBR (i) attenuates the Aß25-35-induced impairments of cognitive function, and (ii) inhibited increases in lipid peroxidation in the hippocampus.
... Germination-induced GABA and other elevated nutrients (e.g., phenolics) have several health-promoting effects, such as regulation of blood pressure and heart rate, alleviation of pain, anxiety and sleeplessness, stimulating immune cells, inhibits cancer cell proliferation and may prevent diabetes (Adamu et al. 2017;Azmi et al. 2013;Chen et al. 2012;Chung, Ryu, and Kang 2016;Esa et al. 2011;Esa et al. 2013;Hsu et al. 2008;Imam et al. 2012a;Lee et al. 2019;Lee et al. 2007a;Oh and Oh 2004;Oh and Oh 2003;Oo et al. 2020;Owolabi, Chakree, and Yupanqui 2019;Owolabi et al. 2020;Wu et al. 2013a). GBR has also been reported to modulate neurological depression-like behavior in mice using a forced swimming test and learned helplessness paradigm (Mamiya et al. 2007) and to improve psychological parameters of stress in lactating human mothers (Sakamoto et al. 2007). There are (Beaulieu, Boue, and Goufo 2022b). ...
Article
Over the last 30 years, thousands of articles have appeared examining the effects of soaking and germinating brown rice (BR). Variable germination conditions and methods have been employed to measure different health-beneficial parameters in a diverse germplasm of BR. Research results may therefore appear inconsistent with occasional anomalies, and it may be difficult to reach consensus concerning expected trends. Herein, we amassed a comprehensive review on germinated brown rice (GBR), attempting to codify 133 peer-reviewed articles regarding the effects on 164 chemical parameters related to health and nutrition in BR and in value-added food products. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-2020) approach was used to direct the flow of the literature search. A pair-wise comparison t-test was performed to deliver an overall approach indicating when a given compound has been found to significantly increase or decrease through germination, which was grouped into GABA and polyamines, γ-Oryzanol and phytosterols, phenolic compounds, vitamins, proteins and amino acids, starchy carbohydrates, free sugars, lipids, minerals and phytic acid. This resource will stimulate interest in germinating rice and optimistically help increase both production and consumption of highly nutritious, health-beneficial rice with pigmented bran. FULL TEXT LINK: https://www.tandfonline.com/eprint/IV4E8UGZBT6J45MCEYWW/full?target=10.1080/10408398.2022.2094887
... On the other hand, it is shown that feeding on GBR diet decreased the accumulation of lead and hence improved learning and memory deficits in developing rats after Pb exposure that may be due to the antioxidative effects of phenolic compounds and high content of GABA [15]. GBR has also been shown to possess antidepressant effects in mice [16]. Another report has shown that GBR was able to improve learning ability in Aβ-induced learning and memory deficits in mice, likely as a result of high amounts of GABA in GBR, through modulation of glutamatergic system resulting in memory enhancement [17]. ...
Article
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The neuroprotective and antioxidative effects of germinated brown rice (GBR), brown rice (BR) and commercially available γ-aminobutyric acid (GABA) against cell death induced by hydrogen peroxide (H 2 O 2) in human neuroblastoma SH-SY5Y cells have been investigated. Results show that GBR suppressed H 2 O 2 -mediated cytotoxicity and induced G0/G1 phase cell cycle arrest in SH-SY5Y cells. Moreover, GBR reduced mitochondrial membrane potential (MMP) and prevented phosphatidylserine (PS) translocation in SH-SY5Y cells, key features of apoptosis, and subsequent cell death. GBR exhibited better neuroprotective and antioxidative activities as compared to BR and GABA. These results indicate that GBR possesses high antioxidative activities and suppressed cell death in SH-SY5Y cells by blocking the cell cycle re-entry and apoptotic mechanisms. Therefore, GBR could be developed as a value added functional food to prevent neurodegenerative diseases caused by oxidative stress and apoptosis.
... The GABA content of 20.97 mg/100 g was obtained from this process.The benefits of GABA have been illustrated in several research works. GABA has an ability to reduce the transmittal of stress, anxiety and grief (Mamiya et al., 2006;Sahley, 1997). A high level of GABA may have a role in the recovery from chronic alcohol-related diseases . ...
Article
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Gamma-aminobutyric acid (GABA), commonly produced by germination of brown rice grain, is a free amino acid which could help relieving or preventing non-communicable diseases in human. Several research works have been conducted on GABA production from germinated brown rice. However, the yielded GABA (10.1-69.2 mg/100 g germinated brown rice) was comparatively low; thus the amount was insufficient to be used as active ingredients in functional foods. The objective of this study was to explore alternative methods in order to gain higher yield of GABA. A new process of repeated soaking (in tap water at 35 °C, 3 h) and incubation (at 37 °C, 21 h) during germination was developed. The amount of GABA produced was highest at 116.88 ± 9.24 mg/100 g germinated brown rice (dry basis). However, an unpleasant odour was generated by some microorganisms during long germination. Lactic acid was applied at soaking step to overcome this problem; whereby 0.5% lactic acid solution (vol./vol.) could effectively control the microorganisms without impairing GABA producing ability and sensory qualities.
... To label bread as having GBR, it must have at least 30% GBR, but that much rice interferes with the gluten and carbon dioxide escapes, causing bread to shrink. Mamiya et al. (2006) investigated the antidepressant-like effects of GBR and polished rice pellets in comparison with control (AIN-93G) pellets in the forced swimming test and they learned helplessness paradigm in mice. The immo- bility time on the second day of the forced swimming test was shorter in mice fed with polished rice or GBR pellets than in mice fed with control pellets. ...
Article
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Rice is a staple food for over half of the world's population. Germinated brown rice (GBR) is considered whole food because only the outermost layer i.e. the hull of the rice kernel is removed which causes least damage to its nutritional value. Brown rice can be soaked in water at 30 °C for specified hours for germination to get GBR. Soaking for 3 h and sprouting for 21 h has been found to be optimum for getting the highest gamma-aminobutyric acid (GABA) content in GBR, which is the main reason behind the popularity of GBR. The intake of GBR instead of white rice ameliorates the hyperglycemia, boosts the immune system, lowers blood pressure, inhibits development of cancer cells and assists the treatment of anxiety disorders. Germination process could be used as enzymatic modification of starch that affects pasting properties of GBR flour. GBR would improve the bread quality when substituted for wheat flour. It is concluded that GBR has potential to become innovative rice by preserving all nutrients in the rice grain for human consumption in order to create the highest value from rice.
... These indices helped us to evaluate the behavioral changes of mice in response to stress. Although the mechanism of behavior changing in OF test is not clear, researchers suggest that the reason is the dysfunction of frontal brain and hippocampus during stress 21,22 . Many studies had indicated that forced swimming, a mild physiological stress could induce less exploratory behavior, but there are less studies reporting the behavior changing in hypoxia stress. ...
Article
This study examined heat shock protein 70 expression in the CA3 subfield of hippocampus and exploratory behaviors of different aged mice using gradual hypoxia preconditioning stress and forced swimming stress models. Serum corticosterone and lactic dehydrogenase indicated stress level. The exploratory behaviors in an open field test were observed. The HSP70 expression in the CA3 subfield of hippocampus was measured by immunohistochemical method. The results showed that gradual hypoxia and forced swimming stresses have different effects on behaviors in different aged mice. The forced swimming mice had a longer time of staying in centre square, less square crossing, less vertical movement, and fewer number of stools. The aged gradual hypoxia group displayed less vertical movement and fewer number of stools compared with the aged control group. The result is consistent with the conclusion that forced swimming could induce less exploratory behaviors and a depression state of mice. Gradual hypoxia induced higher level of serum corticosterone than the forced swimming in the young group animals. Both gradual hypoxia and forced swimming induced significant higher level of corticosterone in the aged groups, but there is no significant difference of the concertration of serum corticosterone between the aged stressed groups. The young stressed groups had lower serum LDH than the control group, and the forced swimming induced much lower serum LDH level in both the young and the aged mice. The young control group had significant higher level of serum LDH than that of the aged control group. B oth gradual hypoxia and forced swimming induce higher HSP70 expression in the CA3 subfield of hippocampus; the aged animals had more obvious HSP70 expression after stressed period. The study indicated that the two stress modes had different effects on behaviors and peripheral response to stress, but had the same effect on HSP70 expression in the CA3 subfield of hippocampus in different aged mice. The preconditioning stress could induce higher HSP70 expression to protect body from stress consequence.
... Many studies have demonstrated the health advantages of consuming PBR. For instance, the intake of PBR boosts the immune system, ameliorates the hyperglycemia, and assists treating anxiety disorders [3,4,5]. Nowadays, PBR and related products, such as yogurts, drinks and cosmetics, are becoming more popular in many countries such as Japan, Korea, Thailand and some European countries. ...
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This is the first study to apply plasma technology for improving nutrition value of cereal products. Cold plasma, a mixture of oxygen and argon plasma, was applied to rice seeds before pre-germination process. Plasma condition of 10 watts, 5 seconds, and 5 millimeters distance and 10 watts, 5 seconds, and 8 millimeters distance created high germination rates of pre-germinated brown rice. The latter conditions gave the grains with longer roots and bodies. Plasma treatment could result in increasing contents of total phenolics and γ-aminobutyric acid. Gas chromatography-mass spectrometry revealed 13 identifiable compounds: simple phenolic compounds; pyrans; furan; quinone; and fatty acids, in which biosyntheses of these 13 compounds were likely to be promoted by the plasma processing. These findings suggest that plasma technology could provide better quality pre-germinated brown rice.
... Germinated brown rice (GBR) has been reported to possess important biological activities including antioxidative and neuroprotective properties [16,17]. Additionally, it was reported to protect neuronal cells from oxidative stress-induced cytotoxicity, alleviate depressionlike behaviors as well as enhance learning ability, and improve memory impairment resulting from A administration [18][19][20][21]. These properties of GBR are thought to be mediated by its bioactive-rich constituents [22]. ...
Article
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The pathogenesis of Alzheimer’s disease involves complex etiological factors, of which the deposition of beta-amyloid (A β ) protein and oxidative stress have been strongly implicated. We explored the effects of H 2 O 2 , which is a precursor for highly reactive hydroxyl radicals, on neurotoxicity and genes related to AD on neuronal cells. Candidate bioactive compounds responsible for the effects were quantified using HPLC-DAD. Additionally, the effects of germinated brown rice (GBR) on the morphology of A β (1-42) were assessed by Transmission Electron Microscopy and its regulatory effects on gene expressions were explored. The results showed that GBR extract had several phenolic compounds and γ -oryzanol and altered the structure of A β (1-42) suggesting an antiamyloidogenic effect. GBR was also able to attenuate the oxidative effects of H 2 O 2 as implied by reduced LDH release and intracellular ROS generation. Furthermore, gene expression analyses showed that the neuroprotective effects of GBR were partly mediated through transcriptional regulation of multiple genes including Presenilins, APP, BACE1, BACE2, ADAM10, Neprilysin, and LRP1. Our findings showed that GBR exhibited neuroprotective properties via transcriptional regulation of APP metabolism with potential impact on A β aggregation. These findings can have important implications for the management of neurodegenerative diseases like AD and are worth exploring further.
... These issues necessitate search for newer alternatives, and germinated brown rice has shown promise in this regard. In the past, germinated brown rice was reported to improve memory and cognition, possibly because of its rich GABA content (Mamiya et al., 2004; Mamiya et al., 2007; Zhang et al., 2010). GABA is an inhibitory neurotransmitter that may elicit anti‐depressant and anti‐anxiolytic effects (Kalueff and Nutt, 2007), and may produce similar properties due germinated brown rice, although it is likely that other bioactive compounds play a role in these effects. ...
Chapter
White rice is a major staple food for people in low to middle income countries and it can increase the risk of cardiometabolic disease. Brown rice, especially when germinated, is a healthier alternative. Various functional properties have been documented for the bioactive-rich germinated brown rice. Nutrigenomic studies, dwelling on interactions at diet-genome interface, have expanded our understanding of the role of diets on health. The nutrigenomic basis for the functional properties of GBR have also been reported; its antihyperglycemic, hypocholesterolemic, and antioxidative effects are mediated by its bioactives, partly via transcriptional regulation of genes involved in gluconeogenesis, cholesterol metabolism, and oxidative stress, respectively. Additionally, GBR's ability to improve menopausal symptoms is reported to be due to its ability to upregulate bone metabolism and uterine estrogen related genes, and downregulate inflammatory genes. Food synergy plays a role in the overall functional effects of GBR. Further studies on proteomics, metabolomics, nutrikinetics, and nutridynamics are indicated.
... Previously, we reported that continuous intake of PGBR also increases the serotonin content in the learned helplessness paradigm [18]. It has been reviewed that one of main energy sources in PGBR, glucose, modifies the brain function [19]. ...
Article
We previously reported that the continuous feeding of mice with pellets of pregerminated brown rice (PGBR; Hatsuga genmai in Japanese) enhances their spatial learning. Here, we show the possible relationships of the enhancement of learning and memory with the glutamatergic system in the brain of PGBR-pellet-fed mice. The enhancement of learning and memory in the novel object recognition and Y-maze tests after 28-day-feeding of PGBR pellets was inhibited by dizocilpine (10 μg/kg s.c.), an N-methyl-D-aspartate (NMDA) receptor antagonist, whereas the extracellular glutamate level and the glutamate content were not affected in the frontal cortex and hippocampus. In the frontal cortex of mice fed PGBR pellets, the phosphorylation of calcium calmodulin kinase IIα (CaMKIIα), one of the important events after NMDA receptor activation, was facilitated compared with that of mice fed control pellets. This facilitation was inhibited by dizocilpine (10 μg/kg s.c.), whereas the phosphorylation of extracellular signal-regulated protein kinases (ERKs), another index of memory formation was not affected by PGBR pellets. On the other hand, in the hippocampus, there was no significant difference in the phosphorylation of CaMKIIα and ERKs between the control and PGBR pellets-fed mice. Taken together, these results suggest that PGBR enhances the NMDA receptor/CaMKIIα signaling in the frontal cortex, leading to enhanced learning and memory in mice.
... [23,[89][90][91] Taurine and beta-alanine Increased BDNF and hippocampal phosphorylation levels of ERK1/2, Akt, GSK3b, CREB and decreased metabolite of serotonin (5HTIAA) [92,93] Perilla. frutescens seed oil-rich Increased BDNF and serotonin levels [19] Whole egg Increased the Trp/LNAA ratio [2] Inulin-type oligosaccharides Not fully elucidated [94] Pre-germinated brown rice Decreased in frontal cortex 5-HIAA/5-HT ratio [95] Curcumin Normalized levels of BDNF, synapsin I, and CREB and is an antioxidant. [96,97] High-fat diets (HFD) Not fully elucidated when given during development may inoculate an individual against depression [78] while 4% creatine supplementation displayed an antidepressant-like response in female but not male rats [79,80]. ...
Article
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Recently, most of evidence shows that caloric restriction could induce antidepressant-like effects in animal model of depression. Based on studies of the brain–gut axis, some signal pathways were common between the control of caloric restriction and depression. However, the specific mechanism of the antidepressant-like effects induced by caloric restriction remains unclear. Therefore, in this article, we summarized clinical and experimental studies of caloric restriction on depression. This review may provide a new therapeutic strategy for depression.
... Germination or water-soaking has positive effects on amino acid composition and protein availability, and also increases the contents of total sugars and bioactive components, while antinutrients concentrations diminish (Caceres et al. 2014;Liang et al. 2008;Xia et al. 2017). Researches have confirmed that GBR intake has many beneficial effects on human health including antihyperlipidemic, antihypertensive, and antidepressant-like actions, and reduces the risk of some chronic diseases, such as diabetes and cancer (Cho and Lim 2016;Mamiya et al. 2007;Roohinejad et al. 2010;Wu et al. 2013). ...
Article
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Key message This review surveys rice nutritional value, mainly focusing on breeding achievements via adoption of both genetic engineering and non-transgenic strategies to improve key nutrients associated with human health. Abstract Rice (Oryza sativa) is an essential component of the diets and livelihoods of over 3.5 billion people. Polished rice is mostly consumed as staple food, fulfilling daily energy demands and part of the protein requirement. Brown rice is comparatively more nutritious, containing more lipids, minerals, vitamins, dietary fiber, micronutrients, and bioactive compounds. In this article, we review the nutritional facts about rice including the level of γ-aminobutyric acid, resistant starch, lysine, iron, zinc, β-carotene, folate, anthocyanin, various carotenoids, and flavonoids, focusing on their synthesis and metabolism and the advances in their biofortification via adoption of both conventional and genetic engineering strategies. We conclude that besides representing a staple food, rice has the potential to become a source of various essential nutrients or bioactive compounds through appropriate genetic improvements to benefit human health and prevent certain chronic diseases. Finally, we discuss the available, non-genetically engineering strategies for the nutritional improvement of rice, including their main strengths and constraints.
... In animal studies, the consumption of GABAenriched foods including pre-germinated brown rice has been shown to improve memory and learning abilities in rats (Mamiya et al., 2007) adding evidence to the crucial role played by GABA in memory process owing to GABA's major inhibitory role as a neurotransmitter (Mody et al., 1994). In another study conducted in mice, the polyphenol ferulic acid was reported to protect against b-induced neurotoxicity and memory disturbance (Kim et al., 2007). ...
Article
Aging reduces the absorption of nutrients. Literature related to functional bread processing techniques including sprouting of grains and the application of encapsulation technology and the bioavailability of bioactives was reviewed. Functional ingredients including sprouted/germinated grain particularly brown rice and wheat flours enhance the bioactive properties of functional bread. Ingredients with high polyphenol content such as lavender and melissa by‐products, tea‐extracts and aronia powder enhance the bioactive content and appear to have a favourable effect on the shelf‐life of bread and antioxidant status of consumers. Incorporation of encapsulated bioactive compounds into bread have a huge potential to improve the bread quality and increase the bioavailability and bioaccessibility of bioactive compounds including polyphenols. More investigations and new areas of research should focus on sprouted grain flours and the application of encapsulation technologies especially nanoencapsulation to optimize the bioactivity, storage, bioavailability and nutritional profile of bread to improve nutrition and health with aging.
... The column temperature was maintained at 25 C and the detector potential was set at 750 mV. The mobile phase consists of 0.1 mol/L citric acid and 0.1 mol/L sodium acetate, pH 3.9, containing 17% methanol, 180 mg/ L sodium-1-octanesulfonate and 5 mg/L EDTA; the flow rate was 0.5 mL/min (Mamiya et al., 1998(Mamiya et al., , 2007. The levels were expressed as mg/mg protein. ...
Article
Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant emotional behaviors in mice. Identification of affected brain systems and its molecular basis will lead to new insights into relations between protein acetylation events and psychiatric disorders. Here we report the dopaminergic abnormalities in Hdac6 KO mice. The dopamine transmission mediated by D1-like and D2-like G protein-coupled dopamine receptors is known to play roles in controlling movement, cognition, and motivational processes, and its dysfunction causes psychiatric disorders. We found that Hdac6 KO mice showed significantly increased locomotor response to novel, but not to habituated environment. In addition, Hdac6 KO mice showed a long-lasting sensitivity to psychostimulants, increased locomotor response to D2-like, but not D1 dopamine receptor agonists, and rapid locomotor response to apomorphine, a direct dopamine agonist, in dopamine-depleted condition. Hdac6 protein was expressed in dopaminergic neurons and their terminals in adult mice brain, and Hdac6-depletion augmented acetylation levels of dopamine-enriched synaptosomal proteins. In Hdac6 KO mice, the striatal content of dopamine and its metabolites was normal in basal condition, but mRNA level of D2 dopamine receptor in the striatum was decreased by 30%. Taken together, our results provide evidence that Hdac6 deficiency leads to aberrant dopamine-dependent behaviors by enhancing postsynaptic dopamine D2 receptor response. This study points out the possibility that Hdac6 and reversible-acetylation events play a regulatory role in D2 dopamine receptor signaling, and thus participate in the pathology of the dopamine-related psychiatric disorders such as schizophrenia.
... In animal studies, the benefits of PGR have been reported as decreasing accumulation of lead (Pb), reducing cognition deficits, and protecting against neuronal cell loss from Aβ. 12 Previous studies demonstrated that PGR improves learning and memory in several rodent models. [13][14][15] Furthermore, PGR has shown high anti-oxidative activities and suppression of cell death in SH-SY5Y cells by blocking apoptotic mechanisms and reducing lipid peroxidation (in hypercholesterolemia rabbits). 11,16,17 However, there has been no the research study of the effect of GBGR on learning and memory. ...
Article
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Germinated black glutinous rice (GBGR) is a black glutinous rice (BGR) that has been soaked in water to initiate pre-germination. It is also known as pre-germinated brown rice (PGR). Important nutrients in GBGR are γ-aminobutyric acid (GABA), γ-oryzanol, and other bioactive lipids. GABA concentrations in GBGR are more than 15 times greater than in non-germinated rice. PGR has been reported to have neuroprotective effects in developing rats against the accumulation of lead and protects against neuronal cell loss and memory deficits, but there has been no such report regarding GBGR. We therefore investigated the effects and protective mechanisms of GBGR against Aβ25-35 peptide induced neurotoxicity in rats. In our in vivo studies, rats were fed with control, BGR, and GBGR diets throughout the experiment and were injected intraventricularly of 15 μL aggregated Aβ25-35 peptide on day 22. The effects on locomotor activities were evaluated by open field test, spatial navigation and recognition memory by Morris water maze and novel object recognition tests, respectively. Glutamate and GABA concentrations were analyzed by high performance liquid chromatography with electrochemical detection. Finally, the neuronal viability was counted by histological techniques. The results showed that rats given GBGR significantly increased spatial and recognition memory and increased GABA concentration in the hippocampus. Moreover, GBGR also improved neuronal viability. It can be concluded that GBGR has a potential role to protect against memory deficits in an Alzheimer's rat model.
... According to previous studies, rice and corn, our fundamental foods, are beneficial, not only as our main carbohydrate source, but also preventive and therapeutic effect with respect to neurodegenerative effects (Torre et al. 2008;Ismail et al. 2012). This might be due to the chemical known as melatonin (N-acetyl-5methoxytryptamine) found in rice and corn since melatonin can function as an antioxidant (Mamiya et al. 2007). Melatonin was also shown to help reducing sleeplessness in depressive patients (Lewy et al. 1998;Trotti & Karroum 2016). ...
Article
The purpose of this study was to investigate the effect of extruded polished rice (PR), brown rice (BR), and germinated brown rice (GBR) on the behavior of ICR mice in a repeated open field test, as well as their concentrations of plasma lipids, glucose, and minerals. After 4 weeks in the open field test, the locomotion distance was significantly lower in mice fed GBR than those fed PR, but showed no difference in mice fed a diet with the same gamma-aminobutyric acid (GABA) content as GBR. The different rice diets had little influence on plasma lipids and glucose but the plasma calcium content was significantly higher in mice fed BR than those fed PR. These results suggest that the influence of GBR on mice behavior may be related to other components of GBR in addition to GABA and that BR and GBR may have no negative influence on mineral levels.
Article
In this study we investigated whether κ-opioid receptor stimulation by dynorphin A (1-13), a potent fragment of endogenous peptide, attenuated repeated stress-induced behavioral impairments in mice. In order to reduce the motivation to escape, mice were preexposed to inescapable electric footshock (day 0), and then dynorphin A (1-13) was administered to mice prior to the stress from the next day for 4 d (days 1-4). Dynorphin A (1-13) (1500 pmol/5 µL intracerebroventricular (i.c.v.)) attenuated the repeated stress-induced escape failures from the shock, and this improvement was inhibited by the pretreatment of nor-binaltorphimine (4.9 nmol/kg subcutaneously (s.c.)), a κ-opioid receptor antagonist. In the neurochemical experiments, we detected an increase in 5-hydroxyindoleacetic acid (5-HIAA) content, but not in serotonin (5-HT) content, and an increase in the 5-HIAA/5-HT ratio was observed in the amygdala of the group with footshock compared with the group without shock. Additionally, the changes in 5-HIAA content and the ratio were reversed by dynorphin A (1-13). However, there were no differences in 5-HT or 5-HIAA content or their ratios in the hippocampus among the three groups. These results suggest that dynorphin might alleviate the stress-induced behavioral impairments accompanied by regulation of the 5-HTergic system in the brain.
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Rice bran contains a great amount of functional lipids and phytochemicals including γ-oryzanols, tocotrienols, and tocopherols. However, utilization of those compounds is limited and needs some proven guidelines for better implementation. We introduce some effective strategies for the utilization of rice functional lipids, including an introduction of pigmented rice varieties for better bioactive compounds, biofortification of rice tocotrienols, plasma technology for improving rice phytochemicals, supercritical CO2 extraction of high quality rice bran oil, and an example on the development of tocotrienol-fortified foods.
Article
Although brown rice (BR) contains significantly higher levels of nutrients than the traditionally used polished white rice (WR), its consumption among the population is still not noteworthy. WR and BR are essentially same grain. The only difference between the two is the application of an exhaustive milling procedure during the processing of WR that removes all other layers of the grain except the portion of its white endosperm. BR, on the other hand, is prepared by removing only the outer hull of the rice seed. Thus, in addition to its inner endosperm, the bran and germ are also left on the BR. Hence, BR retains all its nutrients, including proteins, lipids, carbohydrates, fibers, vitamins, minerals, tocopherols, tocotrienols, γ-oryzanol, and γ-aminobutyric acid (GABA) packed into the bran and germ of the seed. Since BR tastes nutty and takes longer to cook than WR, it is not appreciated by the consumers. However, these problems have been circumvented using non-thermal ultra-high hydrostatic pressure (UHHP)-processing for the treatment of BR. A superior modification in the physicochemical and functional qualities of UHHPBR, along with its ability to curb human diseases may make it a more palatable and nutritious choice of rice over WR or the untreated-BR. Here, we have reviewed the mechanism by which UHHP treatment leads to the modification of nutrients such as proteins, lipids, carbohydrates, and fibers. We have focused on the effects of rice on cell and animal models of different conditions such as hyperlipidemia, diabetes, and hypertension and the possible mechanisms. Finally, we have emphasized the effects of UHHPBR in human cases with rare conditions such as osteoporosis and brain cognition − two age-related degenerative diseases of the elderly population.
Article
Brown rice, unmilled or partly milled, contains more nutritional components than ordinary white rice. Despite its elevated content of bioactive components, brown rice is rarely consumed as a staple food for its dark appearance and hard texture. The germination of brown rice can be used to improve its taste and further enhance its nutritional value and health functions. Germinated brown rice is considered healthier than white rice, as it is not only richer in the basic nutritional components such as vitamins, minerals, dietary fibers, and essential amino acids, but also contains more bioactive components, such as ferulic acid, γ-oryzanol, and gamma aminobutyric acid. Moreover, germinated brown rice has been reported to exhibit many physiological effects, including antihyperlipidemia, antihypertension, and the reduction in the risk of some chronic diseases, such as cancer, diabetes, cardiovascular disease, and Alzheimer's disease. Therefore, it is likely that germinated brown rice will become a popular health food.
Article
Brown rice (BR) contains bran layers and embryo, where a variety of nutritional and biofunctional components, such as dietary fibers, γ-oryzanol, vitamins, and minerals, exist. However, BR is consumed less than white rice because it has an inferior eating texture when cooked. Germination is one of the techniques used to improve the texture of the cooked BR. In addition, it induces numerous changes in the composition and chemical structure of the bioactive components. Moreover, many studies reported that the germination could induce the formation of new bioactive compounds, such as gamma-aminobutyric acid (GABA). The consumption of germinated brown rice (GBR) is increasing in many Asian countries because of its improved eating quality and potential health-promoting functions. However, there is still a lack of studies on the compositional and functional changes of the bioactive components during germination. This review contains recent research findings, especially on the bioactive components in GBR.
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Physicochemical properties of white rice (WR), brown rice (BR) and germinated brown rice (GBR) starches from a mixed variety of MR219 and MR220, commonly consumed Malaysian varieties, were compared in this study. The granular size of the starch particles, measured using scanning electron microscope (SEM), varied from 2 to 8 µm for all starches and appeared in polyhyedral shapes. Amylose content in WR, BR and GBR as analysed using colorimetric method was found to be 25.77, 23.83 and 21.78%, respectively. The amylose content of GBR was significantly lower than that of WR or BR. Results also show that germination affected gelatinization and pasting properties. This study has profound implications for future studies on functional properties of GBR and may help us understand what role changes in physicochemical properties, brought about by germination, play in determining functional effects.
Article
Brown rice is unpolished rice with immeasurable benefits for human health. Brown rice (BR) and pre-germinated brown rice (PGBR) are known to contain various functional compounds such as gamma-oryzanol, dietary fibre and gamma-aminobutyric acid (GABA). In the present study, the experimental diets containing BR and PGBR (24, 48 h pre-germination) were used to investigate the influence of pre-germination time of brown rice on blood cholesterol in Sprague-Dawley male rats. Hypercholesterolaemia and elevation of LDL-cholesterol were successfully ameliorated by the experimental diets containing BR and PGBR (24 and 48 h pre-germination). As compared to the control sample, the pre-germination time had a significant (P < 0.05) effect on blood cholesterol of Sprague-Dawley male rats. It was also found that the significantly (P < 0.05) better effect on lipid profile of hypercholesterolaemic rats was observed by prolonging the pre-germination time. As compared to non-germinated brown rice, the germinated brown rice showed the higher cardio-protective effect on hypercholesterolaemic Sprague-Dawley male rats. The present study suggests that the changes of blood cholesterol can be mainly modulated by using the PGBR rather than BR. The prolonging of pre-germination time led to an increase in the bioactive components, thereby providing a more efficient functional diet affecting the high blood cholesterol. This study suggests that PGBR can be used instead of BR and polished rice in the human diet.
Article
We fed mice food granules containing fermented soybean (natto in Japanese) powder (hereafter "natto granules") for 14 d to investigate whether natto granules had any effects on mouse behavior. We noted an enhancement of locomotor activity in natto-granule-fed mice compared to control and soybean-pellet-fed mice. This enhanced locomotor activity was blocked by a low dose of haloperidol (1 microg/kg i.p.), a dopamine receptor antagonist, but not by methysergide, a serotonin 5-HT(1/2) receptor antagonist. The results suggest that the enhanced locomotor activity induced by continuous intake of natto granules in mice is sensitive to haloperidol.
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beta-Amyloid peptide (Abeta), the major constituent of the senile plaques observed in the brains of Alzheimer's disease patients, is cytotoxic to neurons and plays a central role in the pathogenesis of this disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of Abeta-induced neurotoxicity in vivo. Here, we used a mouse model of brain dysfunction induced by dl-buthionine-(S,R)-sulfoximine (BSO: 3micromol/3microL/mouse, i.c.v.), an inhibitor of glutathione synthesis. In the novel object recognition test, we found impairments of exploratory preference in the retention trial but not the training trial 24h after BSO treatment, suggesting that BSO produces cognitive dysfunction in mice. In the forebrain of this model, we observed increase in carbonyl protein levels, an index of biochemical oxidative damage of proteins, compared to vehicle-treated mice. Pretreatment with ferulic acid (5mg/kg, s.c.) once a day for 6 days inhibited the induction of deficits in memory and increase in carbonyl protein levels by BSO. These findings suggest that pretreatment with FA may attenuate the memory deficits and increase the carbonyl protein levels induced by BSO in mice.
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Previous studies from our laboratory indicated that pre-germinated brown rice (PR) contained certain unknown bioactive lipids that activated two enzymes related to diabetes: Na+/K+ATPase and homocysteine-thiolactonase. In this paper, we report on the isolation and structural characterization of the activator lipids from PR bran as acylated steryl glucosides (ASGs). The activator lipid was isolated by silica gel column chromatography, and its chemical structure was determined by NMR, GC-MS, and tandem mass spectrometry. We demonstrated that the bioactive component consists of a mixture of acylated steryl beta-glucosides. Delta8-cholesterol and 2-hydroxyl stearic acid were identified as constituents of ASGs. The steryl glucosides (SGs) subsequent to alkaline hydrolysis lost this enzyme activator activity. Soybean-derived ASGs were not active. This activity may be quite peculiar to PR-derived ASGs. Our findings suggest that the molecular species of ASG may play an important contributing role in the anti-diabetic properties of a PR diet.
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The existence of a number of classes of antidepressant drugs with diverse pharmacological effects would lead one to expect that antidepressant drugs acting through different pharmacological mechanisms should produce different behavioral effects. Animal behavioral tests used to screen antidepressant drugs do not, however, discriminate between drugs that selectively enhance serotonin or norepinephrine transmission. Several components of human depression are differently affected by drugs selectively interacting with either serotonin or norepinephrine transmission. The ideal animal model for detecting antidepressant drug effects should thus be sensitive to all antidepressant drugs and should also display multiple components that are sensitive to specific drug classes. The revised scoring of the forced swimming test corresponds to a behavioral test for antidepressant drugs that meet these criteria.
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Nociceptin (also called orphanin FQ) is an endogenous heptadecapeptide that activates the opioid receptor-like 1 (ORL1) receptor. Nociceptin system not only affects the nociception and locomotor activity, but also regulates learning and memory in rodents. We have previously reported that long-term potentiation and memory of ORL1 receptor knockout mice are enhanced compared with those in wild-type mice. Here, we show the neuronal mechanism of nociceptin-induced modulation of learning and memory. Retention of fear-conditioned contextual memory was significantly enhanced in the ORL1 receptor knockout mice without any changes in cued conditioned freezing. Inversely, in the wild-type mice retention of contextual, but not cued, conditioning freezing behavior was suppressed by exogenous nociceptin when it was administered into the cerebroventricle immediately after the training. ORL1 receptor knockout mice exhibited a hyperfunction of N-methyl-D-aspartate (NMDA) receptor, as evidenced by an increase in [3H]MK-801 binding, NMDA-evoked 45Ca2+ uptake and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity and its phosphorylation as compared with those in wild-type mice. The NMDA-induced CaMKII activation in the hippocampal slices of wild-type mice was significantly inhibited by exogenous nociceptin via a pertussis toxin-sensitive pathway. However, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor GluR1 subunit at Ser831 and Ser845, and NMDA receptor subunit NR2B at Thr286 were phosphorylated similarly after NMDA receptor stimulation in both type of mice. The expressions of GluR1 and GluR2 also did not change, but the levels of polysialylated form of neuronal cell adhesion molecule (N-CAM) were reduced in the ORL1 receptor knockout as compared with wild-type mice. These results suggest that nociceptin system negatively modulates learning and memory through the regulation of NMDA receptor function and the expression of N-CAM.
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The ability to modify mice genetically has been one of the major breakthroughs in modern medical science affecting every discipline including psychiatry. It is hoped that the application of such technologies will result in the identification of novel targets for the treatment of diseases such as depression and to gain a better understanding of the molecular pathophysiological mechanisms that are regulated by current clinically effective antidepressant medications. The advent of these tools has resulted in the need to adopt, refine and develop mouse-specific models for analyses of depression-like behavior or behavioral patterns modulated by antidepressants. In this review, we will focus on the utility of current models (eg forced swim test, tail suspension test, olfactory bulbectomy, learned helplessness, chronic mild stress, drug-withdrawal-induced anhedonia) and research strategies aimed at investigating novel targets relevant to depression in the mouse. We will focus on key questions that are considered relevant for examining the utility of such models. Further, we describe other avenues of research that may give clues as to whether indeed a genetically modified animal has alterations relevant to clinical depression. We suggest that it is prudent and most appropriate to use convergent tests that draw on different antidepressant-related endophenotypes, and complimentary physiological analyses in order to provide a program of information concerning whether a given phenotype is functionally relevant to depression-related pathology.
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We evaluated the effects of pre-germinated brown rice (hatsuga genmai, PGR) on learning and memory and compared them with those of polished rice or cornstarch. In mice that were fed pellets of polished rice or PGR for two weeks, the learning ability in the Morris water maze test was significantly enhanced compared with mice that were fed cornstarch pellets. In the Y-maze test, the intake of food pellets for two weeks failed to affect spontaneous alternation behavior. Beta-amyloid(25-35) (Abeta(25-35): 3 nmol/mouse, i.c.v.) protein impaired spontaneous alternation behavior in mice that were fed pellets of cornstarch or polished rice. In contrast, PGR pellets prevented the Abeta(25-35)-induced impairment of spontaneous alternation behavior. These results suggest that polished rice and PGR have facilitating effects on spatial learning. In particular, it is surmised that PGR may prevent Alzheimer's disease associated with Abeta.
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Among all animal models, the forced swimming test (FST) remains one of the most used tools for screening antidepressants. This paper reviews some of the main aspects of the FST in mice. Most of the sensitivity and variability factors that were assessed on the FST are summarized. MECHANISMS: We have summarized data found in the literature of antidepressant effects on the FST in mice. From this data set, we have extrapolated information on baseline levels of strain, and sensitivity against antidepressants. We have shown that many parameters have to be considered in this test to gain good reliability. Moreover, there was a fundamental inter-strain difference of response in the FST. The FST is a good screening tool with good reliability and predictive validity. Strain is one of the most important parameters to consider. Swiss and NMRI mice can be used to discriminate the mechanisms of action of drugs. CD-1 seems to be the most useful strain for screening purposes, but this needs to be confirmed with some spontaneous locomotor activity studies.
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The intake of pre-germinated brown rice (PR) instead of white rice (WR) ameliorates the hyperglycemia. To clarify the mechanism(s) to decrease the post-prandial blood glucose concentration, the effect of water-soluble/oil-soluble fraction-depleted PR bran (termed as "DB"; which is destarched and defatted PR bran) on post-prandial blood glucose was compared with that of full-fat PR bran (PB) or WR. The test diets, WR diet, PB diet and DB diet which are containing identical amount of available carbohydrate (1.5 g) were fed to Wistar strain rats. Post-prandial blood glucose concentration and incremental area under the curve (IAUC) for DB diet were lower than those for WR diet, and there was no difference between the DB diet and PB diet. Changes in plasma insulin concentration and the IAUC obtained also revealed the same tendency as those observed in blood glucose concentration. These results indicate that the blood glucose-lowering effect of PB diet may be derived from the properties of PB involving substantially higher content of dietary fiber than WR, and that the potential benefit of intake of PR instead of WR in the prevention of diabetic vascular complications.
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Cholecystokinin (CCK), one of the most abundant neuropeptides in the brain, plays an important role in anxiogenesis through the activation of CCK receptor-2 (CCKR-2). Accumulating evidence, however, has suggested this role depends on endogenous CCKergic “tone,” which is largely determined by the expression level of the CCKR-2. Using the tTA/tetO-inducible transgenic (tg) approach, we show here that overexpression of the CCKR-2 in neurons of the forebrain significantly increases CCKR-2 binding capacity in tg mice compared with their littermate controls. Interestingly, these tg mice consistently exhibit increased fear responses, which are generally interpreted as anxiety-like behaviors in the rodent, in a battery of behavioral tests, which represented conflict situations or delivered stress to the subjects. The inhibition of transgene expression with doxycycline treatment completely diminished both increased receptor-binding activity and all behavioral phenotypes. Furthermore, treatment of tg mice with diazepam significantly attenuated these anxiety-like behaviors. Our results directly demonstrate that the elevated CCKergic tone via overexpression of the CCKR-2 in the brain may constitute an underlying molecular/neuronal mechanism for the expression of anxiety. In addition, our study has validated a robust genetic anxiety model in the mouse in terms of their face, constructive, and predictive validity. • behaviors • transgenic mouse
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It is argued that exposure to stressors cansensitize the neural machinery that mediates fear for aperiod of time, and that during this time period fearconditioning is potentiated and responses to ambiguous or mildly fearful stimuli are exaggerated. Thecontrollability of the stressor is a key characteristicof the stressor which determines whether thissensitization occurs. That is, sensitization follows exposure to uncontrollable, but not tocontrollable, stressors. It is argued that thissensitization of the neural structures that mediate fearmay be similar to what is meant by anxiety, and thatbrain serotonin systems are a key component of thissensitization process. The implications of this point ofview for a variety of phenomena including learnedhelplessness and reactivity to drugs of abuse are discussed.
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Moclobemide [Ro 11–1163, p-chloro-N-(2-morpholinoethyl)benzamide, AURORIX] is known as an antidepressant and a reversible inhibitor of type A monoamine oxidase. In the present study, a forced swimming test was applied to mice to evaluate behavioral and neurochemical effects of this drug. During forced swimming posture of immobility, a typical behavioral change, was observed, and biochemical analysis of the brain revealed significant changes in the monoamine levels. The norepinephrine concentration was reduced, while that of its product was increased, indicating increase in norepinephrine turnover. The stress increased the levels of dopamine, serotonin, and their metabolites. Moclobemide significantly improved the immobility elicited by the test, and it could prevent the changes in the turnover of norepinephrine, dopamine, and serotonin induced by the stress. These results suggest that moclobemide may improve the behavioral changes induced by the forced swimming through its effects on monoamine metabolism.
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This paper presents two experiments that continue efforts to determine the neurochemical changes responsible for stress-induced behavioral depression. These expriments measured active motor behavior in a swim tank as well as levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in various brain regions of rats after the animals had (a) been exposed to electric shocks they could control (Avoidance-escape condition), or (b) received the same shocks with no control over them (Yoked condition), or (c) received no shock (No-shock condition). In the first experiment, measures were taken 90 min after the shock session ended. In the swim test, Yoked animals showed a depression of active behavior relative to the other groups. From measures of monoamine levels, the change found to be most closely related to this post-stress behavioral depression was in NE in the locus coeruleus (LC), where Yoked animals showed a considerable depletion of NE. In the second study, the same measures were taken 48 h and 72–96 h after the stress session. Yoked animals tested at 48 h post-stress showed motor depression, but those tested after 72–96 h did not. NE in the LC was significantly depleted in Yoked animals tested at 48 h post-stress but showed only slight (and non-significant) depletion in those tested 72–96 h post-stress. These results, together with others, suggest that large stress-induced depletion of NE in the LC is involved in mediating behavioral depression brought about by severe stress. It is further suggested that the time course for behavioral recovery and for the disappearance of NE depletion in the LC that was seen in Yoked animals after stress parallels the time course previously reported by other investigators for induction of catecholamine-synthesizing enzymes — tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) — in the LC, so that induction of TH and DBH activity may be a neurochemical mechanism to bring about recovery from poststress behavioral depression.
Article
We isolated genes for the opioid receptor homologue MOR-C, namely nociceptin receptor (designated alternatively as orphanin FQ receptor) and generated nociceptin receptor-knockout mice. Previously, we have reported that the nociceptin system appears to participate in the regulation of the auditory system. However, the behavior of the nociceptin receptor-knockout mice has yet to be fully characterized. In the present study, we investigated changes in several behavioral performances in mice which lack nociceptin receptor. Nociceptive thresholds of nociceptin receptor-knockout mice were unchanged in the hot-plate and electric foot-shock tests as well as tail-flick and acetic acid-induced writhing tests compared to those of wild-type mice. The nociceptin receptor-knockout mice did not show any behavioral changes in the elevated plus-maze task. Surprisingly, in the water-finding test, the nociceptin receptor-knockout mice showed an enhanced retention of spatial attention (latent learning) compared to wild-type mice. In a biochemical study, dopamine content in the frontal cortex was lower in nociceptin receptor-knockout mice than wild-type mice. These results suggest that nociceptin receptor plays an important role in spatial attention by regulating the dopaminergic system in the brain.
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Animal behavioural models of psychiatric disorders cannot exactly simulate human psychopathology, but they can be used to evaluate the behavioural changes induced by drugs and to suggest hypotheses about the functions of the CNS and its involvement in psychiatric disorders. This should lead to a more heuristic classification of psychotropic drugs and to clarification of their therapeutic possibilities. The following animal models simulate aspects of depressive disorders and are sensitive to the antidepressant effects of drugs. (i) The forced swimming test: described as 'behavioural despair' on the assumption that the animal has given up hope of escaping. (ii) The 'restraint stress' test: this may indicate a failure to adapt to stress. (iii) The learned-helplessness model: exposed to uncontrollable events, animals exhibit learning performance deficit and behavioural changes, including decreased locomotor activity and loss of appetite. (iv) Waiting behaviour: improvement in the ability to wait for and/or postpone an active response; this could be related to the reported beneficial effects of antidepressants on impulsive behaviour.
Article
Learned helplessness (LH) is prevented by pretreatment with acute benzodiazepines (BDZs), subchronic tricyclic antidepressants (TCAs), or escapable stress (ES). We have investigated the role of serotonin (5-HT) in LH prevention by these three prevention paradigms, using microdialysis to measure in vivo 5-HT release in frontal cortex (FC) after LH testing. Rats receiving pretreatment before inescapable stress with any of the three methods of prevention--BDZs, TCAs, or ES--showed escape behavior in the shuttle-box test for LH comparable to naive unstressed controls. K(+)-stimulated 5-HT release in all three groups receiving pretreatment was also similar to naive unstressed controls. Rats receiving saline before inescapable stress showed significantly more LH behavior in the shuttle-box task and had significantly lower 5-HT release as well. This suggests that LH correlates with a significant decrease in intracellular releasable 5-HT in FC, and that three different techniques for LH prevention, acute BDZs, subchronic TCAs, and ES all similarly prevent this 5-HT depletion.
Article
Exposure of animals to learned helplessness training produced a decrease in the calcium-specific release of serotonin from slices of neocortex, of GABA from hippocampal slices, and of serotonin from septal slices when measured 1 or 4 days later. Chronic, but not acute, administration of imipramine produced opposing changes in control rats and reversed the decreased release measured in helpless animals. These neurochemical changes characteristic of learned helplessness required 30 min of training to develop.
Article
The effect of manipulations aimed at modifying the function of the 5-HT system has been reviewed. 5-HT uptake inhibitors are devoid of any activity in rats and induce an anti-immobility effect in mice. The so-called 5-HT1A agonists reduce the immobility time with some differences in mice and rats, mice being less sensitive. None of the procedure aimed at reducing 5-HT function reduced immobility time. Therefore, the 5-HT system does not play a tonic role in animals performing the forced swimming test. The involvement of possible brain regions mediating the anti-immobility effects of 5-HT mimetic drugs has been discussed.
Article
The immobility time in the mouse forced swimming test was dose-dependently reduced by sigma 1 receptor agonists, such as 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) and (+)-pentazocine, and non-specific sigma receptor agonists, such as 1,3-di(2-tolyl)guanidine (DTG) and (+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylamin e hydrochloride (JO-1784). On the other hand, pre-treatment with N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma 1 receptor antagonist, completely antagonized the SA4503-, (+)-pentazocine- and DTG-induced reductions in immobility time. Such phenomena indicate that sigma receptor agonists alleviate behavioral despair. In addition, these antidepressive effects involve mainly the sigma 1 receptor subtype.
Article
We have previously found that repeated phencyclidine (PCP) treatment enhances the immobility induced by forced swimming and suggested that this behavioral change could be used as a model of the negative symptoms, particularly depression, of schizophrenia. The present study attempted to examine the effects of antidepressants on the depressive states (immobility) induced by forced swimming in mice repeatedly treated with PCP, compared with those in mice repeatedly treated with saline. In mice repeatedly treated with saline, desipramine (5 and 10 mg/kg) and imipramine (5 and 10 mg/kg) significantly attenuated immobility, whereas mianserin (5-20 mg/kg) and clomipramine (10 and 50 mg/kg) had no affect. In mice repeatedly treated with PCP, the enhancing effect of PCP on immobility was attenuated by mianserin (5-20 mg/kg) at doses which did not have any effect in saline-treated mice, and by desipramine at higher doses (20 and 50 mg/kg). However, imipramine (5-20 mg/kg) and clomipramine (10-50 mg/kg) did not affect PCP-induced enhancement of immobility. In the biochemical study, the content of 5-hydroxyindoleacetic acid (5-HIAA) and the 5-HIAA/5-hydroxytryptamine (5-HT) ratio in the prefrontal cortex in mice repeatedly treated with PCP, but not with saline, following the forced swimming test were significantly increased, compared with those in the corresponding control mice (which did not perform the test). The present findings suggest that the depressive states induced by the forced swimming in mice repeatedly treated with PCP are less sensitive to acute treatment with tricyclic antidepressants, and this may be due to increase in 5-HT turnover. Antidepressants such as mianserin, which have the 5-HT2 receptor antagonist properties, may be useful for the treatment of negative symptoms of schizophrenia.
Article
Chronic treatment with antidepressants renders serotonergic neuronal firing less sensitive to the inhibitory effect of serotonin (5-HT) reuptake blockers in the rat, and this has been considered as a major correlate of the therapeutic action of these drugs. We investigated whether the same mechanisms could be evidenced in an experimental model of depression, the learned helplessness paradigm. Rats rendered helpless by a single session of inescapable electrical footshocks exhibit, for several days, depression-like behavioural deficits which can be reversed by sub-chronic, but not acute, treatment with antidepressants. Recording of serotonergic neurons in the dorsal raphe nucleus revealed that, under baseline conditions, the spontaneous firing was similar in helpless rats and in non-helpless controls. However, neurons in the former group exhibited an enhanced sensitivity to the inhibitory action of the 5-HT reuptake blocker, citalopram (ED50 = 0.18 +/- 0.02 mg/kg IV in helpless rats versus 0.27 +/- 0.03 mg/kg IV in controls, P < 0.05). Treatment with zimeldine during 3 consecutive days induced in both helpless and control rats, a decrease in the inhibitory response of serotonergic neurons to the citalopram challenge, which resulted in a normalization of the neuronal reactivity in the helpless group (ED50 = 0.31 +/- 0.03 mg/kg IV). Since this adaptive phenomenon parallels the behavioural improvement induced by the repeated administration of zimeldine and other antidepressants in helpless rats, it might be considered as a crucial event in the mechanism of therapeutic action of these drugs.
Article
Benzodiazepines are routinely administered in combination with antidepressant drugs. Such combination can induce pharmacodynamic or pharmacokinetic interactions resulting in either a potentiation or a reduction of the effects of one of the drugs. The present study was undertaken to determine the effects of benzodiazepines alone and in combination with two classes of antidepressant drugs: "specific" norepinephrine uptake blockers (desipramine, maprotiline) and specific serotonin uptake blockers (indalpine, fluvoxamine) in the learned helplessness paradigm in rats. The present results show that daily injection of diazepam (0.2-2 mg/kg) and lorazepam (0.06-0.25 mg/kg) did not reverse the helpless behavior. The reversal of helpless behavior induced by indalpine (1 mg/kg/day) or fluvoxamine (4 mg/kg/day) was antagonized dose-dependently by daily coadministration of benzodiazepines. In contrast, the effects of desipramine (24 mg/kg/day) or maprotiline (48 mg/kg/day) were not modified.
Article
The roles of dopaminergic and opioid neurotransmissions in the activity of three tricyclic antidepressants endowed with different monoamine-reuptake properties [desipramine (DESI), imipramine (IMI), amineptine (AMN)] were examined using a behavioral model of depression in rats; the learned helplessness paradigm. In this model, exposure of rats to inescapable shocks (day 1) produced a subsequent escape deficit in a shuttle box test (days 3, 4, and 5). The escape deficit was reversed by AMN, DESI, and IMI administered twice daily for 5 days (16 and 32 mg/kg/day, p < 0.05, days 3, 4, and 5). In addition, AMN tended to enhance the motor activity of rats during the intertrial intervals, but on the first shuttle-box test only (day 3: p < 0.05, control vs AMN). Haloperidol, a preferential D2 dopamine receptor antagonist, acutely injected IP (37.5 microg/kg), suppressed the behavioral activity of DESI and IMI but not that of AMN. Naloxone, a preferential mu-opioid receptor antagonist, acutely injected IP (0.5 mg/kg), suppressed the behavioral activity of IMI but not that of DESI and AMN. It is concluded that an increased dopaminergic activity is a neurochemical effect common to the different tricyclic antidepressants (via a presynaptic mechanism for AMN and a postsynaptic mechanism for DESI and IMI), whereas an increased mu-opioid neurotransmission does not appear to be essential.
Article
To investigate functional changes in the brain serotonin transporter (SERT) after chronic antidepressant treatment, several techniques were used to assess SERT activity, density, or its mRNA content. Rats were treated by osmotic minipump for 21 d with the selective serotonin reuptake inhibitors (SSRIs) paroxetine or sertraline, the selective norepinephrine reuptake inhibitor desipramine (DMI), or the monoamine oxidase inhibitor phenelzine. High-speed in vivo electrochemical recordings were used to assess the ability of the SSRI fluvoxamine to modulate the clearance of locally applied serotonin in the CA3 region of hippocampus in drug- or vehicle-treated rats. Fluvoxamine decreased the clearance of serotonin in rats treated with vehicle, DMI, or phenelzine but had no effect on the clearance of serotonin in SSRI-treated rats. SERT density in the CA3 region of the hippocampus of the same rats, assessed by quantitative autoradiography with tritiated cyanoimipramine ([(3)H]CN-IMI), was decreased by 80-90% in SSRI-treated rats but not in those treated with phenelzine or DMI. The serotonin content of the hippocampus was unaffected by paroxetine or sertraline treatment, ruling out neurotoxicity as a possible explanation for the SSRI-induced decrease in SERT binding and alteration in 5-HT clearance. Levels of mRNA for the SERT in the raphe nucleus were also unaltered by chronic paroxetine treatment. Based on these results, it appears that the SERT is downregulated by chronic administration of SSRIs but not other types of antidepressants; furthermore, the downregulation is not caused by decreases in SERT gene expression.
Article
The modulation of [3H]-5-hydroxytryptamine ([3H]-5-HT) efflux from superfused rat cortical synaptosomes by delta, kappa, mu and ORL1 opioid receptor agonists and antagonists was studied. Spontaneous [3H]-5-HT efflux was reduced (20% inhibition) by either 0.5 μM tetrodotoxin or Ca2+-omission. Ten mM K+-evoked [3H]-5-HT overflow was largely Ca2+-dependent (90%) and tetrodotoxin-sensitive (50%). The delta receptor agonist, deltorphin-I, failed to modulate the K+-evoked neurotransmitter efflux up to 0.3 μM. The kappa and the mu receptor agonists, U-50,488 and endomorphin-1, inhibited K+-evoked [3H]-5-HT overflow (EC50=112 and 7 nM, respectively; Emax=28 and 29% inhibition, respectively) in a norBinaltorphimine- (0.3 μM) and naloxone- (1 μM) sensitive manner, respectively. None of these agonists significantly affected spontaneous [3H]-5-HT efflux. The ORL1 receptor agonist nociceptin inhibited both spontaneous (EC50=67 nM) and K+-evoked (EC50=13 nM; Emax=52% inhibition) [3H]-5-HT efflux. The effect of NC was insensitive to naloxone (up to 10 μM), but was antagonized by [Nphe1]nociceptin(1-13)NH2 (a novel selective ORL1 receptor antagonist; pA2=6.7) and by naloxone benzoylhydrazone (pA2=6.3). The ORL1 ligand [Phe1ψ(CH2-NH)Gly2]nociceptin(1-13)NH2 also inhibited K+ stimulated [3H]-5-HT overflow (EC50=64 nM; Emax=31% inhibition), but its effect was partially antagonized by 10 μM naloxone. It is concluded that the ORL1 receptor is the most important presynaptic modulator of neocortical 5-HT release within the opioid receptor family. This suggests that the ORL1/nociceptin system may have a powerful role in the control of cerebral 5-HT-mediated biological functions. British Journal of Pharmacology (2000) 130, 425–433; doi:10.1038/sj.bjp.0703321
Article
Depression is a major cause of disability worldwide, but we know little about the underlying fundamental biology. Research is hindered by the difficulties of modelling a disorder of higher cognitive functions in animals. Depression can be understood as the interaction of genetic susceptibility and environmental factors; however, current classifications are purely descriptive. The complexity of this field is best approached by rigorous explorations of known candidate systems in conjunction with the use of genomic tools to discover new targets for antidepressants and to predict therapeutic outcomes.
Article
We investigated the effects of U-50,488H, a kappa-opioid receptor agonist, on the learned helplessness model of depression in mice. Mice pre-exposed to inescapable electric footshock were treated with U-50,488H. Stimulation of the kappa-opioid receptor by U-50,488H (10 mg/kg/day, i.p.) attenuated the escape failure induced by pre-exposure to shock. This attenuation by U-50,488H was blocked by MR2266 (10 mg/kg/day, s.c.), an opioid receptor antagonist. These results suggest that the kappa-opioid system plays an important role in the learned helplessness depression in mice.
Article
The monoamine hypothesis has dominated our understanding of depression and of pharmacological approaches to its management and it has produced several generations of antidepressant agents, ranging from the monoamine oxidase inhibitors (MAOIs), through tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs), to the recently introduced selective noradrenaline reuptake inhibitor (NARI), reboxetine. Greater receptor selectivity has improved tolerability, but not efficacy, when newer compounds are compared with the original tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Essentially, the newer antidepressants have the same distinguishing feature as older ones, i.e. acute enhancement of monoaminergic neurotransmission. The monoamine hypothesis cannot conclusively link the acute biochemical action of antidepressants on monoamine levels with their delayed clinical effect of 10-14 days, nor can it explain the mode of action of antidepressants that are effective despite being very weak inhibitors of monoaminergic transmission (e.g. iprindole) or, incongruously, enhancing monoamine uptake (e.g. tianeptine). Compared with other fields of medicine, there has been a lack of progress in understanding the pathophysiology of depression and producing truly novel antidepressant agents. Other biological approaches to depression, such as overactivity of the hypothalamic-pituitary-adrenal axis, hippocampal neural plasticity in response to stress, and the link between the inflammatory response and depression, offer new approaches to finding pharmacological agents, aided by improved techniques for visualising the human brain, better animal models, and increased knowledge of human markers of depression. Copyright 2001 John Wiley & Sons, Ltd.
Article
Adaptive changes in the serotonergic system are generally believed to underlie the therapeutic effectiveness of the azapirone anxiolytics and a variety of antidepressant drugs. The serotonin-1A (5-HT(1A)) receptor has been implicated in affective disorders. Thus, studies of the regulation of 5-HT(1A) receptor function may have important implications for our understanding the role of this receptor in the mechanism of action of these therapeutic agents. This review focuses on the regulation of central 5-HT(1A) receptor function following administration of 5-HT(1A) receptor agonists or antidepressant drugs expected to increase the synaptic concentration of the neurotransmitter 5-HT. The majority of evidence supports regional differences in the regulation of central 5-HT(1A) receptor function following repeated agonist or antidepressant administration, which may be due to differences in processes involved in desensitization of the receptor at the cellular level. Region-specific differences in the regulation of 5-HT(1A) receptor function may be based on compensatory changes distal to the receptor, such as regulatory changes at the level of effector (e.g. adenylyl cyclase or ion channel), or at the level of the G protein such as changes in G protein expression, or phosphorylation of the G protein. It may be that the increase in serotonin neurotransmission, due to somatodendritic autoreceptor desensitization following agonist or antidepressant treatment, to normo-sensitive 5-HT(1A) receptors in certain brain regions (e.g. hippocampus or cortex) and to sub-sensitive 5-HT(1A) receptors in other brain regions (e.g. amygdala or hypothalamus) underlies the therapeutic efficacy of these drugs.
Article
Effects of pre-germinated brown rice (PGBR) on streptozotocin-induced diabetic rats were studied. The feeding of a PGBR diet to diabetic rats ameliorated the elevation of blood glucose and PAI-1 concentrations significantly, and tended to decrease the plasma lipid peroxide concentrations in comparison with rats fed a white rice diet. These results suggest that intake of PGBR instead of white rice is effective for the prevention of diabetic vascular complications.
Article
Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their antidepressant-like effects by increasing synaptic concentrations of serotonin (5-HT). The rat forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Procedural modifications recently introduced by our laboratory have enabled SSRI-induced behavioral responses to be measured in the modified FST. The use of this model to understand the pharmacological and physiological mechanisms underlying the role of 5-HT in the behavioral effects of antidepressant drugs is reviewed. Although all antidepressants reduced behavioral immobility, those antidepressants that increase serotonergic neurotransmission predominantly increase swimming behavior whereas those that increase catacholaminergic neurotransmission increase climbing behavior. The 5-HT(1A), 5-HT(1B/1D) and 5-HT(2C) receptors are the 5-HT receptors most important to the therapeutic effects of SSRIs, based on extensive evaluation of agonists and antagonists of individual 5-HT receptor subtypes. Studies involving chronic administration have shown that the effects of antidepressants are augmented following chronic treatment. Other studies have demonstrated strain differences in the response to serotonergic compounds. Finally, a physiological model of performance in the rat FST has been proposed involving the regulation of 5-HT transmission by corticotropin releasing factor (CRF).
Article
The term 'learned helplessness' refers to a constellation of behavioral changes that follow exposure to stressors that are not controllable by means of behavioral responses, but that fail to occur if the stressor is controllable. This paper discusses the nature of learned helplessness, as well as the role of the dorsal raphe nucleus, serotonin, and corticotropin-releasing hormone in mediating the behavioral effects of uncontrollable stressors. Recent research indicates that (a) uncontrollable stressors sensitize serotonergic neurons in the dorsal raphe, and that a corticotropin-releasing factor-related ligand, acting at the Type II receptor, is essential to this sensitization process, and (b) the consequent exaggerated release of serotonin in response to subsequent input is at least in part responsible for the behavioral changes that occur. Finally, implications for the general role of corticotropin-releasing hormone in stress-related phenomena and for the learned helplessness paradigm as an animal model of either depression or anxiety are discussed.