The ion channel TRPA1 is a modulator of the cocaine reward circuit in the nucleus accumbens.

Drug addiction therapies commonly fail because continued drug use promotes the release of excessive and pleasurable dopamine levels. Because the connection between pleasure and drug use becomes hard-wired in the nucleus accumbens (NAc), which interfaces motivation, effective therapies need to modulate this mesolimbic reward system. Here, we report that mice with knockdown of the cation channel TRPA1 (transient receptor potential ankyrin 1) were resistant to the drug-seeking behavior and reward effects of cocaine compared to their wildtype litter mates. In our study, we demonstrate that TRPA1 inhibition in the NAc reduces cocaine activity and dopamine release, and conversely, that TRPA1 is critical for cocaine-induced synaptic strength in dopamine receptor 1-expressing medium spiny neurons. Taken together, our data support that cocaine-induced reward-related behavior and synaptic release of dopamine in the NAc are controlled by TRPA1 and suggest that TRPA1 has therapeutic potential as a target for drug misuse therapies.

New designer phenethylamines 2C-C and 2C-P have abuse potential and induce neurotoxicity in rodents.

2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.

25C-NBF, a new psychoactive substance, has addictive and neurotoxic potential in rodents.

The use of new psychoactive substances (NPSs) as a substitute for illegal drugs is increasing rapidly and is a serious threat to public health. 25C-NBF is a newly synthesized phenethylamine-type NPS that acts as a 5-hydroxyindoleacetic acid (5-HT) receptor agonist, but little is known about its pharmacological effects. Considering that NPSs have caused unexpected harmful effects leading to emergency and even death, scientific confirmation of the potential adverse effects of 25C-NBF is essential. In the present study, we investigated whether 25C-NBF has addictive and neurotoxic potential and causes neurochemical changes. In addictive potential assessments, high conditioned place preference (CPP) scores and stable self-administration (SA) were observed in the 25C-NBF groups (CPP [3 mg kg-1]; SA [0.01, 0.03, 0.1 mg kg-1]), suggesting the addictive liability of 25C-NBF. In neurotoxic potential assessments, 25C-NBF treatment (single super-high dose [1 × 15, 30, 40 mg kg-1]; repeated high dose [4 × 8, 15, 30 mg kg-1]) resulted in reduced motor activity (open field test), abnormal motor coordination (rota-rod test) and impaired recognition memory (novel object recognition test), suggesting that 25C-NBF is neurotoxic leading to motor impairment and memory deficits. Subsequently, immunohistochemistry showed that 25C-NBF treatment decreased tyrosine hydroxylase (TH) expression and increased ionized calcium-binding adapter molecule 1 (Iba-1) expression in the striatum. Taken together, our results clearly demonstrate the dangers of recreational use of 25C-NBF, and we suggest that people stop using 25C-NBF and other NPSs whose pharmacological effects are not precisely known.

Lespedeza bicolor Extract Improves Amyloid Beta25 - 35-Induced Memory Impairments by Upregulating BDNF and Activating Akt, ERK, and CREB Signaling in Mice.

Lespedeza bicolor, a traditional herbal medicine widely used in Australia, North America, and Eastern Asia, has various therapeutic effects on inflammation, nephritis, hyperpigmentation, and diuresis. In this study, to evaluate the effects of L. bicolor on cognitive function, we examined whether L. bicolor improved amyloid beta-induced memory impairment and assessed the possible mechanisms in mice. Catechin, rutin, daidzein, luteolin, naringenin, and genistein were identified in the powdered extract of L. bicolor by HPCL-DAD analyses. In behavioral experiments, L. bicolor (25 and 50 mg/kg, p. o.) significantly improved amyloid beta25 - 35 (6 nmol, intracerebroventricular)-induced cognitive dysfunction in the Y-maze, novel recognition, and passive avoidance tests. Our molecular studies showed L. bicolor (25 and 50 mg/kg, p. o.) significantly recovered the reduced glutathione content as well as increased thiobarbituric acid reactive substance and acetylcholinesterase activities in the hippocampus. Furthermore, we found that L. bicolor significantly increased the expression of brain-derived neurotrophic factor, and phospho-Akt, extracellular signal-regulated kinase, and cAMP response element binding caused by amyloid beta25 - 35 in the hippocampus. In conclusion, L. bicolor exerts a potent memory-enhancing effect on cognitive dysfunction induced by amyloid beta25 - 35 in mice.

Neuregulin 1 regulates amyloid precursor protein cell surface expression and non-amyloidogenic processing.

The amyloid precursor protein (APP) is a key molecule in Alzheimer's disease. The prevailing view is that APP is initially transported to the plasma membrane as a full-length protein. Its localization at the cell surface can trigger downstream signaling and APP cleavage. Our previous work has shown that Neuregulin 1 (NRG1) has neuroprotective effects in an Alzheimer's disease model. In the present study, we examine whether NRG1 signaling is involved in APP expression and non-amyloidogenic processing in neuronal cells. Here we show that NRG1 increased the cell surface expression of APP without changing the total amount of APP mRNA or protein expression in SH-SY5Y cells and in rat primary cortical neurons. In addition, NRG1 significantly increased the levels of the secreted form of APP, sAPPα, in the conditioned media but did not change the expression of ADAM10 on the cell surface or in the cell lysates. Furthermore, we found that the protein level of NRG1 was reduced in the hippocampus of Alzheimer's disease (AD) patients. Our results demonstrate that NRG1 increased APP expression on the cell surface and sAPPα secretion into the media of neuronal cell cultures. Taken together, these results suggest a role for NRG1 in non-amyloidogenic processing.

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in ß-Cells and Sustains Insulin Secretion in Diabetes.

Pancreatic ß-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state ß-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to ß-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylation-dependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo and decreased fatty acid oxidation ex vivo Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild type by only ∼2% of the >4000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for ß-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects ß-cell function by limiting mitochondrial lipid utilization and raise the possibility that inhibition of fatty acid oxidation in ß-cells is beneficial to diabetes treatment.

Red ginseng ameliorates acute cisplatin-induced nephropathy.

Korean red ginseng is one of the traditional herbal medicines most widely used in China, Korea, and Japan. To determine whether Korean red ginseng extract can mitigate acute renal nephropathy, we examined its renoprotective effects in a model of cisplatin-induced acute renal failure in Sprague Dawley rats. Korean red ginseng was administered to rats by oral gavage once a day at doses of 100, 300, or 500 mg/kg for 28 days. On day 23, the animals received an intraperitoneal injection of cisplatin (5 mg/kg) to induce acute renal failure. Body weight gain, urine volume, blood urea nitrogen and creatinine concentrations, and expression of p53 were measured. Terminal deoxynucleotidyl transferase dUTP nick end-labeling was used to analyze apoptosis. Kidney tissues from the control and experimental groups were analyzed by immunohistochemistry for inflammatory cytokines and histopathological examination. To identify the mechanism responsible for the renoprotective effects of Korean red ginseng, we measured malondialdehyde concentration as an end product of lipid peroxidation and the activities of the antioxidants superoxide dismutase and glutathione. Korean red ginseng significantly decreased the levels of indicators of renal dysfunction, inflammatory cytokine expression, apoptosis, and malondialdehyde content in the kidney and also significantly attenuated the histopathological changes associated with acute renal failure. These findings suggest that Korean red ginseng has renoprotective effects against cisplatin-induced acute renal failure by reducing oxidative stress and inflammation.

The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents.

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.

The mutated cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)-interacting protein 2 (CYFIP2 S968F) regulates cocaine-induced reward behaviour and plasticity in the nucleus accumbens.

BACKGROUND AND PURPOSE: Cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)-interacting protein 2 (CYFIP2), as a component of the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine-968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown. EXPERIMENTAL APPROACH: We performed cocaine reward-related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock-in mice to investigate the role of CYFIP2 in regulating cocaine reward. KEY RESULTS: CYFIP2 S968F mutation attenuated cocaine-induced behavioural sensitization and conditioned place preference. Cocaine-induced c-Fos was not observed in the NAc of CYFIP2 S968F knock-in mice. However, c-Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine-associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity-mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC-NAc pathway and observed that optogenetic activation of the NAc or mPFC-NAc pathway induced reward-related behaviours. This effect was not observed in the S968F mutation in CYFIP2. CONCLUSION AND IMPLICATIONS: These results suggest that CYFIP2 plays a role in controlling cocaine-mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward.

Adinazolam, a Benzodiazepine-Type New Psychoactive Substance, Has Abuse Potential and Induces Withdrawal Symptoms in Rodents.

Adinazolam (ADZ) is a benzodiazepine-type new psychoactive substance (NPS) with anxiolytic, anticonvulsant, and antidepressant effects. High ADZ doses have been reported to impair psychomotor performance and memory; however, the abuse potential and drug dependence of ADZ have not yet been fully investigated. In this study, we evaluated whether ADZ has abuse potential and leads to drug dependence and withdrawal symptoms. The intravenous self-administration (IVSA) test revealed that ADZ (0.01, 0.03, and 0.1 mg/kg/infusion) was self-administered significantly above vehicle levels, suggesting the reinforcing effect of ADZ. Furthermore, we revealed that treatment discontinuation following chronic ADZ administration (3 and 6 mg/kg) caused several somatic withdrawal symptoms in mice, including body tremor. Moreover, it induced motivational withdrawal signs, such as anxiety-related behavior in the elevated plus maze (EPM) test and memory deficits in the Y-maze test. After the IVSA test, an enzyme-linked immunosorbent assay (ELISA) showed that ADZ administration significantly increased the dopamine contents in the thalamus, nucleus accumbens (NAc), and ventral tegmental area (VTA). This finding was also supported by the results of the Western blot. Taken together, our results suggest that ADZ has abuse potential and can lead to drug dependence and withdrawal syndrome.

Incidence of Infection among Subjects with Helicobacter pylori Seroconversion.

BACKGROUND/AIMS: Helicobacter pylori (H. pylori) seroconversion may occur during screening for gastric cancer. Our study aimed to assess the number of seroconverted subjects with H. pylori and their results in follow-up tests. METHODS: Data were consecutively collected on subjects who were H. pylori-seronegative and presented for gastric cancer screening. Subjects who were followed up using the same serology test and pepsinogen (PG) assays on the day of endoscopy were included in the study. RESULTS: During the follow-up of 57.7±21.4 months, 61 (15.0%) of 407 seronegative subjects showed seroconversion. H. pylori infection was detected in six (9.8%) of 61 seroconverted subjects. A diffuse red fundal appearance, with a significant increase in the Kyoto classification scores for gastritis, was observed in the infected subjects (p<0.001). Compared to the false-seropositive subjects, infected subjects showed higher serology titers (p<0.001) and PG II levels (p<0.001) and lower PG I/II ratios (p=0.002), in the follow-up tests. CONCLUSION: Seroconversion occurred in 3.3% of seronegative subjects per year; however, only 9.8% had H. pylori infection. The majority (90.2%) of the seroconverted subjects showed false seropositivity without significant changes in the follow-up test results. The diffuse red fundal appearance could be an indicator of H. pylori infection.

Korean Red Ginseng inhibits methamphetamine addictive behaviors by regulating dopaminergic and NMDAergic system in rodents.

BACKGROUND: Methamphetamine (METH) is the most widely used psychostimulant and has been known to exhibit reinforcing effects even after long abstinence. We showed the inhibitory effect of Korean Red Ginseng extract (RGE) on METH-induced addictive behaviors in animal models mimicking the human drug-use pattern. METHODS: We first investigated the effect of RGE on the acquisition of METH-induced dependence using self-administration and conditioned place preference (CPP) tests. Additionally, further experiments such as METH-induced motivational behavior and seeking behavior were conducted. To study the underlying mechanism, dopamine receptor, dopamine transporter, and N-methyl-D-aspartate receptor were assessed through Western blot analysis. RESULTS: Treatment with RGE significantly reduced METH-induced self-administration on a fixed-ratio 1 schedule of reinforcement. It could be also decreased a progressive ratio schedule, and inhibited METH-primed reinstatement. In CPP, RGE significantly prevented the development of METH-induced CPP. Moreover, RGE not only shortened the withdrawal period clearly, but also prevented the reinstatement of CPP. RGE treatment also reversed METH-induced overexpression of dopamine transporter, dopamine receptor D1, and NMDA receptor in the nucleus accumbens. CONCLUSION: Our findings reflect that RGE has therapeutic potential to suppress METH-induced addictive behaviors by regulating dopaminergic and NMDAergic system.

Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents.

Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.

Impact of diabetes mellitus on recurrence and progression in patients with non-muscle invasive bladder carcinoma: a retrospective cohort study.

OBJECTIVE: The aim of the present study was to investigate the relationship between diabetes mellitus (DM) and tumor features in patients with non-muscle invasive bladder cancer (NMIBC). METHODS: Data from 251 patients who underwent transurethral resection (TUR) for NMIBC from January 2000 to June 2010 were analyzed retrospectively. Patients were divided into two groups: Group I, 159 patients (63%) who did not have DM at the time of surgery; and (ii) Group II, 92 patients (37%) who had DM at the time of surgery. Recurrence- and progression-free survival was assessed in both groups. Preoperative HbA1c levels, as parameter of glycemic control, were determined in Group II patients, with patients divided into two subgroups: (i) HbA1c ≥ 7.0%; and (ii) HbA1c <7.0%. The clinical features of the bladder tumor were compared in these two subgroups. RESULTS: Compared with Group I, Group II patients were older and had a higher rate of hypertension, recurrence, and progression (P < 0.05). Univariate survival analysis showed that gender, DM, smoking, and serum creatinine were associated with recurrence-free survival (P < 0.05), whereas DM, stage, grade, intravesical instillation, and serum creatinine were associated with progression-free survival. In multivariate survival analysis, DM was found to be an independent factor for recurrence- (hazard ratio [HR] 2.11; 95% confidence interval [CI] 1.4-3.2; P = 0.001) and progression-free survival (HR 9.35; 95% CI 3.1-28.6; P = 0.001). Furthermore, patients with HbA1c ≥ 7.0% exhibited a significantly higher rate of multiplicity (P = 0.001), tumor grade (P = 0.03), and intravesical treatment (P = 0.04). CONCLUSIONS: In conclusion, DM seems to be an independent predictor of recurrence- and progression-free survival in NMIBC patients. Further prospective studies are needed to establish the prognostic significance of postoperative glycemic control in this patient population.

Endoscopic drainage for management of infected necrosis following EUS-TA in a patient with pancreatic cancer: A case report.

RATIONALE: Endoscopic ultrasonography-guided tissue acquisition (EUS-TA) has become the norm for the diagnosis of pancreatic solid lesions. EUS-TA is relatively safe, but various complications can occur. Infected pancreatic necrosis (IPN) is a rare but serious complication. The latest guidelines suggest that all invasive interventions in patients with IPN should be delayed until walled-off necrosis appears. PATIENT CONCERNS: A 73-year-old man was referred to our hospital with double primary cancers including gallbladder and pancreas. We performed EUS-TA on metastatic pancreatic tail cancer to confirm histologic diagnosis. Six days after the procedure, he developed abdominal pain and fever. DIAGNOSES: The patient's laboratory findings showed leukocytosis and C-reactive protein elevation. Fluid collection around pancreas tail and stomach was detected in computed tomography (CT) scan, and the patient was diagnosed with IPN. INTERVENTIONS AND OUTCOMES: EUS-guided endoscopic transmural drainage (EUS-TD) was performed for the treatment of IPN. Two days after the procedure with antibiotics, his CRP level decreased abruptly, and he received chemotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) 5 days after the procedure. He was discharged from our hospital without complications 15 days after chemotherapy. LESSONS: In selected patients with PDAC, early endoscopic drainage may be recommended as treatment for IPN resulting from complications of EUS-TA.

Longstanding postoperative fluid collection influences recurrence of pancreatic malignancy.

BACKGROUND/AIMS: Postoperative abdominal fluid collection (PAFC) is a frequent complication of pancreatobiliary cancer surgery. The effects of the existence and duration of PAFC are not well known. This study aimed to assess the effects of PAFC on patient prognosis after surgery for pancreatobiliary adenocarcinoma and the association of longstanding PAFC with the recurrence of pancreatic cancer. METHODS: We retrospectively analyzed the data of 194 consecutive patients with pancreatobiliary adenocarcinoma who underwent curative operations from August 2005 to December 2019. The presence of PAFC was assessed using computed tomography within a week of surgery; PAFC lasting > 4 weeks was defined as longstanding PAFC. RESULTS: Among 194 patients, PAFC occurred in 165 (85.1%), and 74 of these had longstanding PAFC. The recurrence rate of pancreatobiliary adenocarcinoma was significantly higher in patients with longstanding PAFC than in patients with non-longstanding PAFC (p = 0.025). Recurrence was also significantly associated with high T stage (T3, T4; p = 0.040), lymph node involvement (p < 0.001), perineural invasion (p < 0.006), and non-receipt of adjuvant chemotherapy (p = 0.025). Longstanding PAFC was significantly associated with the recurrence of pancreatic adenocarcinoma (p = 0.016). However, cancer-specific survival was related to neither the presence nor the duration of PAFC. CONCLUSION: The presence of longstanding PAFC was associated with the recurrence of pancreatic adenocarcinoma. However, a larger prospective study is necessary to confirm the findings.

Korean Red Ginseng reduces chronic social defeat stress-induced mood disorders via N-methyl-D-aspartate receptor modulation in mice.

BACKGROUND: A chronic social defeat stress (CSDS) model has been proposed as relevant to stress-induced behavioral change in humans. In this study, we examined the effect of Korean Red Ginseng (KRG) on CSDS-induced mood disorders and protein expression in an animal model. METHODS: To evaluate the effect of KRG on social defeat stress, test mice were exposed in the resident aggressor's home cage compartment for 14 days beginning 1 h after KRG treatment (10, 20, and 40 mg/kg, per oral (p.o.)). After the exposure, behavioral tests to measure anxiety, social interaction, and depression-like behavior were performed. To investigate the underlying mechanism, N-methyl-D-aspartate receptor expression levels in CSDS-induced mice were evaluated using Western blot analysis. RESULTS: CSDS induced anxiety-like behaviors by decreasing central activity in the open-field test and open-arm approach in the elevated plus maze test and led to social avoidance behavior in the social interaction test. CSDS mice showed upregulated NR1, NR2A, and NR2B expression in the hippocampus. KRG 20 and 40 mg/kg ameliorated anxiety-like activities and KRG 20 mg/kg alleviated social avoidance by decreasing time in the corner zone. KRG treatment recovered CSDS-induced NR1, NR2A, and NR2B protein levels in the hippocampus. CONCLUSION: These results indicate that KRG has a therapeutic effect on CSDS-induced mood disorder by alleviating N-methyl-D-aspartate receptor overexpression in the hippocampus.

Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia-related behaviours based on an imbalance of neurochemicals in the brain.

BACKGROUND AND PURPOSE: Methoxphenidine is a dissociative-based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action. EXPERIMENTAL APPROACH: Addictive potential of methoxphenidine was examined using intravenous self-administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests (open field test, elevated plus maze test, novel object recognition test, social interaction test and tail suspension test) performed to assess whether methoxphenidine caused schizophrenia-related symptoms in mice. Additionally, neurotransmitter enzyme-linked immunosorbent assay and western blot were used to confirm methoxphenidine-induced neurochemical changes in specific brain regions related to abnormal behaviours. KEY RESULTS: Methoxphenidine caused addictive behaviours via reinforcing and rewarding effects. Consistently, methoxphenidine induced over-activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, methoxphenidine caused all categories of schizophrenia-related symptoms, including positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression) and cognitive impairment. Consistently, methoxphenidine led to the disruption of the hippocampal-prefrontal cortex pathway that is considered to be pathological involved in schizophrenia. CONCLUSIONS AND IMPLICATIONS: We demonastrate that methoxphenidine causes addictive and schizophrenia-like behaviours and induces neurochemical changes in brain regions associated with these behaviours. We propose that methoxphenidine could be used in developing useful animal disease models and that it also requires legal restrictions on its recreational use.

[Nodular Gastritis as a Precursor Lesion of Atrophic and Metaplastic Gastritis].

BACKGROUND/AIMS: Chronic atrophic gastritis (CAG) and metaplastic gastritis (MG) are precancerous conditions of Helicobacter pylori (H. pylori)-related gastric cancer. This study aimed to identify the characteristics of nodular gastritis (NG) showing CAG or MG after nodule regression. METHODS: H. pylori-infected patients with NG were included after upper gastrointestinal endoscopy. Patients were excluded if their latest endoscopy had been performed ≤36 months after the initial diagnosis of NG. Small-granular-type NG was defined as the condition with 1-2 mm regular subepithelial nodules. Large-nodular-type NG was defined as those with 3-4 mm, irregular subepithelial nodules. The endoscopic findings after nodule regression were recorded. RESULTS: Among the 97 H. pylori-infected patients with NG, 61 showed nodule regression after a mean follow-up of 73.0±22.0 months. After nodule regression, 16 patients showed a salt-and-pepper appearance and/or transparent submucosal vessels, indicating CAG. Twenty-nine patients showed diffuse irregular elevations and/or whitish plaques, indicating MG. Sixteen patients with other endoscopic findings (14 normal, one erosive gastritis, and one chronic superficial gastritis) showed a higher proportion of H. pylori eradication (12/16, 75.0%) than those in the CAG group (5/16, 31.3%) and MG group (6/29, 20.7%; p=0.001). Patients with small-granular-type NG tended to progress toward CAG (14/27, 51.9%), whereas those with large-nodular-type NG tended to progress toward MG (25/34, 73.5%; p<0.001). CONCLUSIONS: In patients with a persistent H. pylori infection, NG tended to progress to CAG or MG when the nodules regressed. Small-granular-type NG tended to progress to CAG, whereas large-nodular-type NG tended to progress to MG.