Role of nociceptin/orphanin FQ and nociceptin opioid peptide receptor in depression and antidepressant effects of nociceptin opioid peptide receptor antagonists

Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying K⁺ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.

The Relationship between Rainfall and Traffic Accident Patients in Busan

PURPOSE: Traffic accidents are increasing due to the development and increment of transportation. Previous studies on analysis of the correlation between environmental factors and traffic accidents have rarely been reported. The purpose of this study is to analyze the correlation between rainfall and traffic accidents including accident mechanism, incidence, and trauma severity of patients. METHODS: A retrospective review was conducted in 851 trauma patients who visited the emergency department (ED) after a traffic accident from January 2013 to December 2013; 248 patients due to a traffic accident when it was raining, and 603 patients when it was not raining. Demographic data, clinical data, and meteorological data (rainfall, daily mean air temperature, daily mean wind speed) in Busan were investigated. RESULTS: The incidence of traffic accidents was one-second and the injury severity score of patients was two points higher on rainy days. In addition, the length of hospital stay was three days longer (p=0.037), and the prognosis was poor in the rain group. Comparison of severe injury sustained over rain, injury time, and accident mechanism showed approximately a 3-fold odds increased rate of severe injury on rainy days (OR 2.55, 95% CI: 1.11-5.83, p=0.004) and a seven-fold odds increased rate of pedestrian traffic accidents (OR 7.26, 95% CI: 3.52-9.26, p<0.001) compared with car traffic accidents. In addition, a four-fold increased odds of night time (OR 3.79, 95% CI: 1.98-7.25, p<0.001) compared with day time accidents on rainy days. CONCLUSION: The incidence of traffic accidents and injury severity of patients increased on rainy days. Therefore, we suggest expansion of the scope of the emergency and trauma team activation for proper treatment on rainy days.

Effect of Acute and Chronic Electroconvulsive Shock on 5-Hydroxytrypamine 6 Receptor Immunoreactivity in Rat Hippocampus

Electroconvulsive shock (ECS) induces not only an antidepressant effect but also adverse effects such as amnesia. One potential mechanism underlying both the antidepressant and amnesia effect of ECS may involve the regulation of serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor, but less is known about the effects of acute ECS on the changes in 5-HT6 receptor expression in the hippocampus. In addition, as regulation of 5-HT receptor expression is influenced by the number of ECS treatment and by interval between ECS treatment and sacrifice, it is probable that magnitude and time-dependent changes in 5-HT6 receptor expression could be influenced by repeated ECS exposure. To explore this possibility, we observed and compared the changes of 5-HT6 receptor immunoreactivity (5-HT6 IR) in rat hippocampus at 1, 8, 24, or 72 h after the treatment with either a single ECS (acute ECS) or daily ECS for 10 days (chronic ECS). We found that acute ECS increased 5-HT6 IR in the CA1, CA3, and granule cell layer of hippocampus, reaching peak levels at 8 h and returning to basal levels 72 h later. The magnitude and time-dependent changes in 5-HT6 IR observed after acute ECS were not affected by chronic ECS. These results demonstrate that both acute and chronic ECS transiently increase the 5-HT6 IR in rat hippocampus, and suggest that the magnitude and time-dependent changes in 5-HT6 IR in the hippocampus appear not to be influenced by repeated ECS treatment.

Changes in c-Fos Expression in the Forced Swimming Test: Common and Distinct Modulation in Rat Brain by Desipramine and Citalopram

Rodents exposed to a 15-min pretest swim in the forced swimming test (FST) exhibit prolonged immobility in a subsequent 5-min test swim, and antidepressant treatment before the test swim reduces immobility. At present, neuronal circuits recruited by antidepressant before the test swim remain unclear, and also less is known about whether antidepressants with different mechanisms of action could influence neural circuits differentially. To reveal the neural circuits associated with antidepressant effect in the FST, we injected desipramine or citalopram 0.5 h, 19 h, and 23 h after the pretest swim and observed changes in c-Fos expression in rats before the test swim, namely 24 h after the pretest swim. Desipramine treatment alone in the absence of pretest swim was without effect, whereas citalopram treatment alone significantly increased the number of c-Fos-like immunoreactive cells in the central nucleus of the amygdala and bed nucleus of the stria terminalis, where this pattern of increase appears to be maintained after the pretest swim. Both desipramine and citalopram treatment after the pretest swim significantly increased the number of c-Fos-like immunoreactive cells in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim. These results suggest that citalopram may affect c-Fos expression in the central nucleus of the amygdala and bed nucleus of the stria terminalis distinctively and raise the possibility that upregulation of c-Fos in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim may be one of the probable common mechanisms underlying antidepressant effect in the FST.

Sex Differences in Hippocampal Neuronal Sensitization by Nicotine in M. gerbils

We studied the sex different nicotine effect on evoked population spike amplitudes (ePSA) and connexin (Cx) expression in the hippocampus CA1 area of gerbils. Acute doses of nicotine bitartrate (0.5 mg/kg: NT-0.5) slightly reduced ePSA in males but markedly augmented that in females. Acute NT (5.0 mg/kg) markedly increased the ePSA in all gerbils. Unlike acute NT-0.5, repeated NT-0.5 injection (twice a day for 7 days) significantly increased the ePSA in males and slightly affected the NT-0.5 effect in females. The Cx36 and Cx43 expression levels as well as Cx expressing neuronal populations were significantly increased by repeated NT-0.5 in in both male and female gerbils, and particularly, Cx43 expression was somewhat prominent in females. These results demonstrated a sex difference with respect to the nicotine effect on hippocampal bisynaptic excitability, irrelevant to connexin expression.

The Role of SIRT1 in Central Nervous System / 대한정신약물학회지

Silent mating type information regulation 2 homolog 1 (SIRT1) is a nicotinamide adenosine dinucleotide (NAD+)-dependent class III histone deacetylase and is distributed in central nervous system and peripheral tissue. SIRT1 interacts with various transcription factors and cofactors by histone deacetylation and is involved in the modulation of food intake, energy metabolism, circadian rhythms, learning and memory, neurogenesis and neuroprotection. Increased or decreased SIRT1 activity or levels by pharmacological treatment or in genetic animal models have demonstrated its function and role in Central Nervous System and peripheral tissue. Recent study suggests that dysregulation of SIRT1 may be involved in anxiety or depression, but relatively little is known about the involvement of SIRT1 in anxiety or depression. Therefore, through unraveling the functional role of SIRT1 in food intake, energy metabolism, learning and memory as well as neuropsychiatric disease, studies on SIRT1 can shed light on the new drug development in treating neurodegenerative disease, metabolic disorder and neuropsychiatric disorder.

Effects of Repeated Citalopram Treatments on Chronic Mild Stress- Induced Growth Associated Protein-43 mRNA Expression in Rat Hippocampus

Although growth associated protein-43 (GAP-43) is known to play a significant role in the regulation of axonal growth and the formation of new neuronal connections in the hippocampus, there is only a few studies on the effects of acute stress on GAP-43 mRNA expression in the hippocampus. Moreover, the effects of repeated citalopram treatment on chronic mild stress (CMS)-induced changes in GAP-43 mRNA expression in the hippocampus have not been explored before. To explore this question, male rats were exposed to acute immobilization stress or CMS. Also, citalopram was given prior to stress everyday during CMS procedures. Acute immobilization stress significantly increased GAP-43 mRNA expression in all subfields of the hippocampus, while CMS significantly decreased GAP-43 mRNA expression in the dentate granule cell layer (GCL). Repeated citalopram treatment decreased GAP-43 mRNA expression in the GCL compared with unstressed controls, but this decrease was not further potentiated by CMS exposure. Similar decreases in GAP-43 mRNA expression were observed in CA1, CA3 and CA4 areas of the hippocampus only after repeated citalopram treatment in CMS-exposed rats. This result indicates that GAP-43 mRNA expression in the hippocampus may differently respond to acute and chronic stress, and that repeated citalopram treatment does not change CMS-induced decreases in GAP-43 mRNA expression in the GCL.

Effects of Repeated Nicotine Treatment on the Changes in Glutamate Receptor Subunits Levels in Mesocorticolimbic Dopamine Areas

Recent studies suggest that alterations in glutamate receptor subunit levels in mesocorticolimbic dopamine areas could account for neural adaptations in response to psychostimulant drugs. Although many drugs of abuse induce changes in ionotropic glutamate receptor subunits in mesocorticolimbic dopamine areas, the changes of ionotropic glutamate receptor subunits by repeated nicotine treatment in these areas are not known. To answer this question, we injected male Sprague-Dawley rats twice daily with nicotine (0.4 mg/kg) or saline (1 ml/kg) for 10 days. The immunoreactivity of NR1, GluR1, and GluR2 glutamate receptor subunits was examined 16~18 h after the last injection of saline or nicotine. Repeated nicotine treatment significantly increased NR1 levels in the ventral tegmental area (VTA). In addition, repeated nicotine treatment showed a tendency towards an increase in GluR1 levels in the VTA as well as in striatum. However, there was no significant change in glutamate receptor subunits in other areas including nucleus accumbens (NAc). These results demonstrate that repeated nicotine treatment increases NR1 levels in VTA similarly to other drugs of abuse, suggesting that elevated glutamate receptor subunits in the VTA, but not NAc may be involved in the excitation of mesocorticolimbic dopamine neurons by nicotine.

Chronic mild stress decreases survival, but not proliferation, of new-born cells in adult rat hippocampus

New-born cells continue to proliferate and survive to become mature granule cells in adult rat hippocampus. Although this process, known as neurogenesis, is inhibited by acute stress, it is not clear whether chronic stress affects neurogenesis. To determine whether chronic mild stress (CMS) influences neurogenesis in the adult rat hippocampus, male Sprague-Dawley rats were exposed to CMS and administered bromodeoxyuridine (BrdU) before or after CMS to observe the survival/differentiation or proliferation of new-born cells, respectively. In addition, we measured brain-derived neurotrophic factor (BDNF) mRNA in the granule cell layer (GCL) of the hippocampus, because BDNF is known to play an important role in the survival of new-born cells. CMS significantly decreased the survival of newborn cells in the GCL, but did not influence the proliferation or differentiation of new-born cells. CMS did not affect the proliferation and survival of new-born cells in the hilus. In addition, CMS did not change BDNF mRNA levels in the GCL. These results demonstrate that CMS reduces the survival of new-born cells but not of their proliferation, suggesting that repeated mild stress could influence a part of neurogenesis, but not the whole part of neurogenesis. These results raise the possibility that the survival of new-born cells may be suppressed in the presence of normal BDNF mRNA levels in GCL.

Changes of Corticotropin-Releasing Factor(CRF) and Neuropeptide Y(NPY) of Rats in Response to Footshock or Reexposure to Conditions Previously Paired with Footshock

Corticotropin-releasing factor(CRF) and neuropeptide Y(NPY) are known to play important roles in mediating stress responses and stress-related behavior. To elucidate the role of neuropeptides in response to the condition that had paired with traumatic event, we observed the changes of CRF and NPY by immunohistochemistry using a conditioned footshock paradigm. Male Sprague-Dawley rats were placed in a shuttle box and exposed to 20 pairings of a tone(< 70dB, 5sec) followed by a footshock(FS, 0.8mA, 1sec) over 60min. A second group was exposed to the tone-footshock pairings, returned to the homecage for 2days, and then reexposed to the test chamber and 20tones alone for 60min, prior to sacrifice. Control groups were : a) sacrificed without exposure to FS ; b) exposed to the tone-footshock pairings and then sacrificed two days later ; or c) exposed to the chamber and tones alone, returned to the homecage for 2days and then reexposed to the chamber and 20tones over 60min prior to sacrifice. CRF was increased in animals exposed to FS or the aversive condition(context and tone) that had paired to FS in bed nucleus of the stria terminalis (BNST) compared to the control. NPY was increased by FS in amygdala and PVN, but the condition previously associated with FS results in slight increase only in amygdala area. These results suggest that the BNST appears to be the mostly involved neural circuit in response to explicit cues previously paired with footshock. Moreover, this study raise the possibility that increased CRF peptide in the BNST in response to re-exposure to the aversive condition may underlie, in part, the experience of conditioned fear-related anxiety behavior.

Radioactive cDNA microarray in Neurospsychiatry / 대한핵의학회잡지

Microarray technology allows the simultaneous analysis of gene expression patterns of thousands of genes, in a systematic fashion, under a similar set of experimental conditions, thus making the data highly comparable. In some cases arrays are used simply as a primary screen leading to downstream molecular characterization of individual gene candidates. In other cases, the goal of expression profiling is to begin to identify complex regulatory networks underlying developmental processes and disease states. Microarrays were originally used with cell lines or other simple model systems. More recently, microarrays have been used in the analysis of more complex biological tissues including neural systems and the brain. The application of cDNA arrays in neuropsychiatry has lagged behind other fields for a number of reasons. These include a requirement for a large amount of input probe RNA in fluorescent-glass based array systems and the cellular complexity introduced by multicellular brain and neural tissues. An additional factor that impacts the general use of microarrays in neuropsychiatry is the lack of availability of sequenced clone sets from model systems. While human cDNA clones have been widely available, high quality rat, mouse, and drosophilae, among others are just becoming widely available. A final factor in the application of cDNA microarrays in neuropsychiatry is cost of commercial arrays. As academic microarray facilitates become more commonplace custom made arrays will become more widely available at a lower cost allowing more widespread applications. In summary, microarray technology is rapidly having an impact on many areas of biomedical research. Radioisotope-nylon based microarrays offer alternatives that may in some cases be more sensitive, flexible, inexpensive, and universal as compared to other array formats, such as fluorescent-glass arrays. In some situations of limited RNA or exotic species, radioactive membrane microarrays may be the most practical experimental approach in studying psychiatric and neurodegenerative disorders, and other complex questions in the brain.

Effects of Repeated Stress on Expression of Corticotropin Releasing Factor Type I and II Receptors / 신경정신의학

OBJECTIVES: Corticotropin releasing factor (CRF) plays a primary role in coordinating the neuroendocrine, autonomic, immune and behavioral responses to stress. CRF exerts its action through two major receptors, corticotropin-releasing factor 1 Receptor (CRF-R1) and corticotropin-releasing factor 2 receptor (CRF-R2). Using two types of chronic stress models, we investigated the changes of CRF-R1 mRNA and CRF-R2A mRNA expressions and CRF mRNA in the stress related brain circuit areas. METHODS: Male Sprague-Dawley rats were exposed to either immobilization stress or variable intermittent unpredictable stress for 10 days and then in situ hybridization histochemistry was used to quantify CRF expression in the brain. RESULTS: 1) CRF1 receptor mRNA expressions were decreased in bed nucleus stria terminalis (BNST) following stressors. 2) CRF2A receptor mRNA expressions were increased in lateral septum following stressors. 3) CRF mRNA expressions were increased in central nucleus of amygdala (CeA) and BNST. CONCLUSION: The increased CRF mRNA of CeA and BNST may be related with anxiety response in the repeated stress. Down-regulation of CRF-R1 mRNA expression in BNST may represent a compensatory adaptation to chronic stress and may be involved in the anxiety response, whereas up-regulation of CRF-R2A mRNA expression in lateral septum may represent an anxiety response or impaired learning but the functional meaning is uncertain.

The Effect of Long Chain N-3 Polyunsaturated Fatty Acids on Development of Collagen-induced Arthritis in Rats / 영남의대학술지

BACKGROUND: The treatment of rheumatoid arthritis still depend on conserve therapy in major. Recent studies report that n-3 polyunsaturated fatty acids(PUFA) could modulate the incidence and progress of arthritis. The purpose of this study was to investigate the effects of n-3 PUFA on the development of collagen-induced arthritis in rats. MATERIALS AND METHODS: Female Louvain rats were used for this experiment. Rats were randomly assigned into either normal(n=8) or collagen-immunized groups, and collagen immunized groups were divided into control(n=8, normal diet) and n-3 PUFA(n=8, 5% n-3 PUFA in diet) groups. One week after feeding n-3 PUFA to rats, they were immunized with type II collagen emulsified in incomplete Freund's adjuvant into tail and back. Development of arthritis was confirmed by x-ray and microscopic examination. RESULTS: Incidence of arthritis at the 5th week after immunization was 38% in control and 0% in n-3 PUFA. Rats with arthritis showed edema in hind paws and inflammation in synovial membrane of the knee joint. Plasma glucose and insulin were not changed by both of immunization and diet. Plasma triglycerides and cholesterol concentrations were decreased by n-3 PUFA. CONCLUSION: n-3 PUFA may prevent or treat collagen-induced arthritis in rats. Further studies are needed for action mechanism of it.

The Effect of Long Chain N-3 Polyunsaturated Fatty Acids on Development of Collagen-induced Arthritis in Rats / 영남의대학술지

BACKGROUND: The treatment of rheumatoid arthritis still depend on conserve therapy in major. Recent studies report that n-3 polyunsaturated fatty acids(PUFA) could modulate the incidence and progress of arthritis. The purpose of this study was to investigate the effects of n-3 PUFA on the development of collagen-induced arthritis in rats. MATERIALS AND METHODS: Female Louvain rats were used for this experiment. Rats were randomly assigned into either normal(n=8) or collagen-immunized groups, and collagen immunized groups were divided into control(n=8, normal diet) and n-3 PUFA(n=8, 5% n-3 PUFA in diet) groups. One week after feeding n-3 PUFA to rats, they were immunized with type II collagen emulsified in incomplete Freund's adjuvant into tail and back. Development of arthritis was confirmed by x-ray and microscopic examination. RESULTS: Incidence of arthritis at the 5th week after immunization was 38% in control and 0% in n-3 PUFA. Rats with arthritis showed edema in hind paws and inflammation in synovial membrane of the knee joint. Plasma glucose and insulin were not changed by both of immunization and diet. Plasma triglycerides and cholesterol concentrations were decreased by n-3 PUFA. CONCLUSION: n-3 PUFA may prevent or treat collagen-induced arthritis in rats. Further studies are needed for action mechanism of it.

Neurobiology of Age-Associated Memory Impairment

The diagnostic concept of age-associated memory impairment (AAMI) suggests that clinically recognized memory dysfunction could be a feature of normal aging. Although the memory impairment associated with aging is well recognized, underlying neurobiological mechanisms of cognitive decline remain unclear. There are a number of age-related structural and physiological changes in the brain that could have implications for cognitive decline in the elderly. The impact of these age-related changes in the brain on cognition has been studied using postmortem neurochemical, neuropathological findings or neuroimaging techniques. The available evidence from studies in aged and demented humans suggested that cognitive deficits related to aging might involve concomitant alterations of various neurochemical systems in several brain regions such as the striatum, the hippocampus or the cortex. It also seems that these alterations occur in a complex way which affects dopaminergic, glutamaterigc and serotonergic neurotnasmission in addition to the loss of cholinergic neurons in the basal forebrain, However, data collected to explain the mechanism of AAMI are still limited, the definite interpretation of these findings must await futher studies.

Animal Models of Depresstion and Screening of Antidepressants / 대한정신약물학회지

Depression is one of the most common disease, but the pathophysiologic mechanism of depression remains elusive. To elucidate the cellular and molecular mechanisms of depression, animal models of depression have been developed, and these models were used successfully to predict the clinical efficacy of new antidepressant drugs. However, it is not likely that current animal models imitate all aspects of depression and are reliable, because we can not evaluate emotional state of rodents verbally and rodents have very different behavioral responses compared with ours. Despite these difficulties, understanding the benefits and limitations of animal models is very important for an advance in basic and clinical research of depression. The first part of the review evaluates animal models of depression in relation with stress that may contribute, in part, to development of depression: chronic mild stress, chronic unpredictable stress, maternal separation. The second part describes the most widely used animal models to screen for potential antidepressant: learned helplessness model and forced swimming test.

Effects of dexamethasone and DHEA on the changes of glutamate and polyamine uptake in rat astrocytes by lipopolysaccharide and antimycin A

Interactions among dexamethasone, dehydroepiandrosterone (DHEA), lipopolysaccharide (LPS), and antimycin A on the glutamate uptake and the polyamine uptake were investigated in primary cultures of rat cerebral cortical astrocytes to examine the effects of dexamethasone and DHEA on the regulatory role of astrocytes in conditions of increased extracellular concentrations of glutamate or polyamines. 1. (3H)Glutamate uptake: LPS and antimycin A decreased Vmax, but both drugs had little effect on Km. Dexamethasone also decreased basal Vmax without any significant effect on Km. And dexamethasone further decreased the antimycin A-induced decrease of Vmax. DHEA did not affect the kinetics of basal glutamate uptake and the change by LPS or antimycin A. 2. (14C)Putrescine uptake: LPS increased Vmax, and antimycin A decreased Vmax. They showed little effect on Km. Dexamethasone decreased Vmax of basal uptake and further decreased the antimycin A-induced decrease of Vmax, and also decreased Vmax to less than control in LPS-treated astrocytes. DHEA did not affect Km and the change of Vmax by LPS or antimycin A. 3. (14C)Spermine uptake: Antimycin A decreased Vmax, and LPS might increase Vmax. Km was little affected by the drugs. Dexamethasone decreased basal Vmax and might further decrease the antimycin A-induced decrease of Vmax. And dexamethasone also decreased Vmax to less than control in LPS-treated astrocytes. DHEA might increase basal Vmax and Vmax of LPS-treated astrocytes. 4. Vmax of glutamate uptake by astrocytes was increased by putrescine (1000 muM & 2000 muM) and spermidine (200 muM, 500 muM & 2000 muM). Spermine, 200 muM (and 100 muM), also increased Vmax, but a higher dose of 2000 muM decreased Vmax. Km of glutamate uptake was not significantly changed by these polyamines, except that higher doses of spermine showed tendency to decrease Km of glutamate uptake. In astrocytes, dexamethasone inhibited the glutamate uptake and the polyamine uptake in normal or hypoxic conditions, and the polyamine uptake might be stimulated by LPS and DHEA. Polyamines could aid astrocytes to uptake glutamate.

Effect of Panax ginseng on latency of passive avoidance response and neuronal damage of hippocampus

The effects of crude saponin (SAP) and alkaloid (ALK) fractions of Panax ginseng C.A. Meyer on the detrimental effects of electroconvulsive shock (ECS) and scopolamine on passive avoidance response (PAR) were studied in male Sprague-Dawley rats, referring their effects on the neuronal injury and plasticity of hippocampus in response to electrolytic lesion of left entorhinal cortex (ECL). The detrimental ECS effect on PAR was attenuated by pre- and post-treatments with SAP and ALK, respectively, or by pretreatment with aminoguanidine (AG), an inhibitor of diamine oxidase and NO synthase. And the detrimental scopolamine effect on PAR was also inhibited by pretreatment with ALK or AG, and by posttreatment with SAP or ALK, respectively. On the 7th day after ECL, the brain sections stained by cresyl violet and by acetylcholinesterase (AChE) histochemistry, respectively, showed the chromatolysis and numeral decrease of neurons and the reduction of AChE reactivity in the hippocampus CA1 area and to a lesser extent, in the dentate gyrus. The neuronal cell death of the CA1 area was significantly reduced by SAP, ALK, or AG, and the reduction of AChE reactivity was significantly attenuated by SAP or ALK and to a lesser extent by AG. These results suggests that the protective effect of ginseng SAP and ALK fractions on ECS- or scopolamine-induced impairment of PAR may be ascribed in part to preservation of hippocampal neurons, particularly cholinergic neurons.

A clinical data management by personal computer in orthopaedics / 대한정형외과학회잡지

No abstract available.

Effects of single and repeated electroconvulsive shock on the hypothalamus and brain stem contents of monoamine metabolites in mice / 신경정신의학

No abstract available.