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Background and aim Early-life stress is thought to affect aggressive behavior in humans and rodents. Laboratory experiments have demonstrated that Sansoninto (SST; 酸棗仁湯 suān zǎo ren tāng), a traditional herbal medicine, attenuates stress-induced abnormal behavior in rodents. However, it is unknown whether SST attenuates stress-induced aggressive behavior. The current study examined the effects of SST on aggressive behavior of mice who suffered from social isolation (SI) stress in adolescence. Experimental procedure Five-week old mice were socially isolated for 6 weeks, and SST administration was started at 4 weeks after starting SI. Aggressive behavior and locomotor activity were examined in SST-treated mice. The content of dopamine and its metabolites in the hypothalamus were examined using high-performance liquid chromatography analysis. Gene expression analyses of monoamine oxidase-B (MAO-B), catechol-O-methyltransferase (COMT), and tyrosine hydroxylase in the hypothalamus were performed using quantitative reverse transcription polymerase chain reaction. Results and conclusion SST attenuated SI-induced aggressive behavior and increased levels of homovanillic acid, a metabolite of dopamine. However, SST did not affect dopamine levels. SI enhanced locomotion in a novel environment and increased COMT mRNA levels. In contrast, SST-treated mice showed no significant enhancement of locomotion. SST attenuated the increase in COMT mRNA levels. Given that the dopaminergic system has been implicated in aggressive behavior, these findings suggest that SST toned down dopaminergic signaling, resulting in amelioration of aggression. SST may be useful for treatment of aggressive behavior in patients with neurotic symptoms.

Neurotransmitters metabolism has a key role in the physiopathology of schizophrenia as demonstrated by studies measuring monoamine metabolites in patient’s cerebrospinal fluid (CSF) since the beginning of the antipsychotic use. This comprehensive review aims to understand the anomalies of CSF monoamines in schizophrenia and their correlation with clinical and paraclinical features. We also review the influence of antipsychotic treatment on CSF monoamines and discuss the connection with metabolic and inflammatory processes. Studies comparing CSF homovanillic acid (HVA) levels between patients and controls are miscellaneous, due to the heterogeneity of samples studies. However, low HVA is associated with more positive symptoms and a poorer outcome and negatively correlated with brain ventricle size. Based on humans and animals’ studies, antipsychotic treatments increase HVA during the first week of administration and decrease progressively over the time with a fall-off after withdrawal. 5‐hydroxyindolacetic acetic acid levels do not seem to be different in the patient’s CSF compared to controls. Considering metabolic co-factors of neurotrans-mitters synthesis, there is evidence supporting an increase of kynurenic acid in the CSF of patients with schizophrenia. Few studies explore folate metabolism in CSF. Literature also emphasizes the relationship between folate metabolism, inflammation and monoamine’s metabolism. Those results suggest that the CSF monoamines could be correlated with schizophrenia symptoms and treatment outcome. However, further studies, exploring the role of CSF monoamines as biomarkers of disease severity and response to treatment are needed. They should assess the antipsychotic prescription, inflammatory markers and folate metabolism as potential confounding factors.

Mizue Ichinose,1,2 Itaru Miura,1 Sho Horikoshi,1,3 Shinnosuke Yamamoto,1,4 Keiko Kanno-Nozaki,1 Kenya Watanabe,5 Hirooki Yabe1 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Hoshigaoka Hospital, Koriyama, Japan; 3Department of Psychiatry, Horikoshi Psychosomatic Clinic, Fukushima, Japan; 4Department of Psychiatry, Fukushima Red Cross Hospital, Fukushima, Japan; 5Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, JapanCorrespondence: Itaru MiuraDepartment of Neuropsychiatry, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, 960-1295, JapanTel +81-24-547-1331Fax +81-24-548-6735Email itaru@fmu.ac.jpObjective: Although switching antipsychotics is a common strategy in the treatment of schizophrenia, caution is needed because of the risk of worsening of psychosis, particularly when switching to a dopamine D2 partial agonist. Homovanillic acid (HVA), a dopamine metabolite, is thought to be a possible indicator of the response to antipsychotics. We examined the effects of switching to brexpiprazole monotherapy from other antipsychotics on plasma HVA levels and side effects during maintenance treatment of schizophrenia.Methods: The antipsychotics of 37 Japanese patients with schizophrenia or schizoaffective disorder were switched to brexpiprazole for the improvement of side effects. We evaluated clinical symptoms and extrapyramidal symptoms (EPS) and took fasting blood samples at baseline and endpoint (eight weeks after completing the switch) to measure plasma levels of HVA, prolactin, and metabolic parameters.Results: Switching to brexpiprazole significantly decreased the Drug-Induced Extrapyramidal Symptoms Scale total score (p=0.008), prolactin levels (p< 0.001), body weight (p=0.046), and body-mass index (p=0.034), and increased HDL cholesterol (p=0.008). On the other hand, switching to brexpiprazole did not change plasma levels of HVA or Positive and Negative Syndrome Scale scores.Conclusion: Switching to brexpiprazole significantly improved EPS, high prolactin levels, and metabolic side effects without elevating plasma HVA levels. Brexpiprazole may stabilize dopaminergic neural transmission and could be a useful strategy to decrease the burden in patients with schizophrenia during the maintenance phase. Because of the small sample size, further studies with larger sample sizes are needed to confirm and extend our results.Keywords: brexpiprazole, extrapyramidal symptoms, EPS, homovanillic acid, prolactin, schizophrenia, switching

A 7-month-old boy was referred with developmental delay and axial hypotonia (video 1). Screening for inborn errors of metabolism was negative and single nucleotide polymorphism array was normal (46,XY). Myotonic dystrophy (type 1) and spinal muscular atrophy were excluded. Whole exome sequencing yielded biallelic mutations in the tyrosine hydroxylase gene (c.698 G>A, p.Arg233His and c.1211C>T, p.Thr404Met). Subsequent CSF analysis revealed a significantly lowered homovanillic acid/5-hydroxyindoleacetic acid ratio, confirming tyrosine hydroxylase deficiency.1 Treatment with monotherapy levodopa resulted in profoundly improved motor development (video 1). After several weeks of treatment, the patient developed levodopa-induced dyskinesias (video 1),2 insomnia, and hyperactive behavior. All symptoms ameliorated with levodopa reduction.

PGC-1α expression increases in skeletal muscles during exercise and regulates the transcription of many target genes. In this study, we conducted a metabolomic analysis on the blood of transgenic mice overexpressing PGC-1α in its skeletal muscle (PGC-1α-Tg mice) using CE-TOFMS. The blood level of homovanillic acid (dopamine metabolite) and the gene expression of dopamine metabolic enzyme in the skeletal muscle of PGC-1α-Tg mice were high. The blood level of 5-methoxyindoleacetic acid was also high in PGC-1α-Tg mice. The blood levels of branched-chain α-keto acids and β-alanine were low in PGC-1α-Tg mice. These metabolites in the skeletal muscle were present in low concentration. The changes in these metabolites may reflect the skeletal muscle condition with increasing PGC-1α, such as exercise.

Propionate has been reported to exert antidepressant effects, but high-dose propionate may induce autism-like symptoms in experimental animals through induction of dysbiosis of neurotransmitters. The bi-directional effects of propionate seem to be dose-dependent. However, due to the pathological discrepancies between depression and autism, conclusions drawn from autism may not be simply transferable to depression. The effect and underlying action mechanisms of high-dose propionate on depression remains undetermined. To investigate the effects of propionate on depression, propionate dose gradients were intravenously administrated to rats exposed to chronic unpredictable mild stress (CUMS) for 1 week. Results of these behavioral tests demonstrate that low-dose propionate (2 mg/kg body weight/day) induces antidepressant effect through bodyweight recovery, elevated reward-seeking behaviors, and reduced depression-like behaviors, while high-dose propionate (200 mg/kg body weight/day) induces prodepressant effects opposite of those of low-dose propionate. A comprehensive profiling of neurotransmitters in the hippocampus demonstrated that CUMS induces reduction of NE (Norepinephrine), DA (Dopamine). GABA (γ-aminobutyric acid) was recovered by low-dose propionate, while high-dose propionate exerted more complicated effects on neurotransmitters, including reduction of NE, DA, 5-Hydroxytryptamine and Tryptophan, and increase of GABA, Kynurenine, Homovanillic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine. The neurotransmitters disturbed by high-dose propionate suggest metabolic disorders in the hippocampus, which were confirmed by the clear group separation in PCA of metabolomic profiling. The results of this study demonstrate the double-edged dose-dependent effects of propionate on depression and suggest potential cumulative toxicity of propionate as a food additive to mood disorders.

Epidemiological studies have reported an association between air pollution and central nervous system disorders. However, its biological mechanisms are poorly understood. This study aimed to determine the effect of short-term environmental exposure to PM10 and associated heavy metals on changes in blood and urinary nervous markers in dusty conditions. A total of 44 healthy non-smokers were identified with a mean age of 36 years. Blood and urine samples were taken from these people 24 h before and after the dust storm to measure the biomarkers of the central nervous system. Cortisol, white blood cells (WBCs), neuron-specific enolase (NSE), and S100β were measured as blood markers, while vanillylmandelic acid (VMA) and homovanillic acid (HVA) were tracked as urine markers. These people had 7 h of environmental exposure in dusty conditions. Eleven heavy metals (Al, As, Cd, Cr, Cu, Fe, Mn, Ni, Co, Pb, and Zn) associated with PM10 were measured. The average PM10 concentration on dust days was 3.25 times higher than on normal days (309.81 μg m−3 vs. 86.11 μg m−3). The results of the statistical paired T-test showed that the mean S100β from pre-exposure to post-exposure increased by 5.85 ng L−1 (P ≤ 0.004). The NSE mean of the pre-exposure (3.37 ± 3.48 μg L−1) was significantly different from the NSE mean after exposure)4.15 ± 3.74 μg L−1 ((P = 0.002). The post-exposure WBC mean was 0.59 times higher than that before exposure, albeit not statistically significant (P = 0.269). The mean VMA after exposure increased by 0.55 mg g−1 CRT (Creatinine) compared to that before exposure. This difference was statistically significant (P = 0.000). Changes in S100β after exposure to dust storms had a high correlation with changes in Cr, Pb, and Fe metal concentrations, respectively (r = 0.81, r = 0.72, r = 0. 65). NSE changes were significantly associated with changes in Mn, Cd, and Fe (r = 0.71, r = 0.99, r = 0.71). Heavy metals associated with PM10 can damage neurons and astrocytes, promoting neuropsychiatric disorders in people with exposure.

Dopamine (DA) has important roles in learning, memory, and motivational processes and is highly susceptible to oxidation. In addition to dementia, Alzheimer's disease (AD) patients frequently exhibit decreased motivation, anhedonia, and sleep disorders, suggesting deficits in dopaminergic neurotransmission. Vitamin C (ascorbate, ASC) is a critical antioxidant in the brain and is often depleted in AD patients as a result of disease-related oxidative stress and dietary deficiencies. To probe the effects of ASC deficiency and AD pathology on the DAergic system, gulo-/- mice, which like humans depend on dietary ASC to maintain adequate tissue levels, were crossed with APP/PSEN1 mice and provided sufficient or depleted ASC supplementation from weaning until 12 months of age. Ex vivo fast-scan cyclic voltammetry showed that chronic ASC depletion and APP/PSEN1 genotype both independently decreased dopamine release in the nucleus accumbens, a hub for motivational behavior and reward, while DA clearance was similar across all groups. In striatal tissue containing nucleus accumbens, low ASC treatment led to decreased levels of DA and its metabolites 3,4-dihydroxyohenyl-acetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA). Decreased enzyme activity observed through lower pTH/TH ratio was driven by a cumulative effect of ASC depletion and APP/PSEN1 genotype. Together the data show that deficits in dopaminergic neurotransmission resulting from age and disease status are magnified in conditions of low ASC which decrease DA availability during synaptic transmission. Such deficits may contribute to the non-cognitive behavioral changes observed in AD including decreased motivation, anhedonia, and sleep disorders.

Background Aromatic L-amino acid decarboxylase (AADC) deficiency is a primary neurotransmitter defect of the biosynthesis of catecholamines and serotonin. The phenotype consists of varying degrees of neurological impairment, including motor and non-motor symptoms. Treatment outcomes correlate with the time point of diagnosis and treatment initiation; therefore, reliable diagnostic markers are necessary. Increased vanillactic acid (VLA) concentrations in the analysis of organic acids in urine have been reported in AADC deficiency. However, this elevation is often subtle and easily missed. In this study, we evaluate the semi-quantitative determination of VLA and vanillylmandelic acid (VMA) concentrations and establish the ratio of a VLA/VMA as a novel diagnostic marker for AADC deficiency. Methods Urine samples obtained from 10,095 non-AADC deficient controls and 14 confirmed AADC deficient patients were used for organic acid analysis by liquid-liquid extraction of the acidified samples and gas chromatographic-mass spectrometric separation after trimethylsilylation. The semi-quantitative determination of VLA and VMA concentrations and the calculation of a VLA/VMA ratio were evaluated as a diagnostic marker for AADC deficiency. Results The mean VLA and VMA concentrations in 10,095 non-AADCD samples was 0.3 mmol/mol creatinine (SD = 1.18, range 0–57.79) and 5.59 mmol/mol creatinine (SD = 3.87, range 0.04–60.62), respectively. The mean concentration of VLA in 14 patient-derived samples was 10.24 mmol/mol creatinine, (SD = 11.58, range = 0.37–33.06) and 0.45 mmol/mol creatinine for VMA (SD = 0.29, range 0.11–1.27). The mean VLA/VMA ratio in non-AADC controls was 0.07 (SD = 0.37, range 0.0–23.24), whereas AADC deficient patients revealed a mean VLA/VMA ratio of 23.16 (SD = 22.83, range 0.97–74.1). The VLA/VMA ratio thus allows a reliable identification of patients with AADC deficiency, especially in the young age cohort as it decreases with age. To take this into account, age-adjusted thresholds have been developed. Conclusion Determination of individual concentrations of VLA and VMA in urine does not allow a reliable diagnosis of AADC deficiency. In this study, we could demonstrate that a semi-quantitative analysis of organic acids in urine allows the formation of metabolite ratios and that the VLA/VMA ratio is a reliable, easily accessible, new parameter for the diagnosis of AADC deficiency.

Chronic fatigue syndrome (CFS) is a disorder characterized by persistent and relapsing fatigue along with long-lasting and debilitating fatigue, myalgia, cognitive impairment, and many other common symptoms. The present study was conducted to explore the protective effect of hemin on CFS in experimental mice. Male albino mice were subjected to stress-induced CFS in a forced swimming test apparatus for 21 days. After animals had been subjected to the forced swimming test, hemin (5 and 10 mg/kg; i.p.) and hemin (10 mg/kg) + tin(IV) protoporphyrin (SnPP), a hemeoxygenase-1 (HO-1) enzyme inhibitor, were administered daily for 21 days. Various behavioral tests (immobility period, locomotor activity, grip strength, and anxiety) and estimations of biochemical parameters (lipid peroxidation, nitrite, and GSH), mitochondrial complex dysfunctions (complexes I and II), and neurotransmitters (dopamine, serotonin, and norepinephrine and their metabolites) were subsequently assessed. Animals exposed to 10 min of forced swimming session for 21 days showed a fatigue-like behavior (as increase in immobility period, decreased grip strength, and anxiety) and biochemical alteration observed by increased oxidative stress, mitochondrial dysfunction, and neurotransmitter level alteration. Treatment with hemin (5 and 10 mg/kg) for 21 days significantly improved the decreased immobility period, increased locomotor activity, and improved anxiety-like behavior, oxidative defense, mitochondrial complex dysfunction, and neurotransmitter level in the brain. Further, these observations were reversed by SnPP, suggesting that the antifatigue effect of hemin is HO-1 dependent. The present study highlights the protective role of hemin against experimental CFS-induced behavioral, biochemical, and neurotransmitter alterations.

Background Aromatic l -amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder that results from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. Loss of dopamine and serotonin production in the brain from infancy prevents achievement of motor developmental milestones. Methods We retrospectively evaluated data obtained from requests to Medical Neurogenetics Laboratories for analyses of neurotransmitter metabolites in the cerebrospinal fluid, AADC enzyme activity in plasma, and/or Sanger sequencing of the DDC gene. Our primary objective was to estimate the prevalence of AADC deficiency in an at-risk population. Results Approximately 20,000 cerebrospinal fluid samples were received with a request for neurotransmitter metabolite analysis in the eight-year study period; 22 samples tested positive for AADC deficiency based on decreased concentrations of 5-hydroxyindoleacetic acid and homovanillic acid, and increased 3-O-methyldopa, establishing an estimated prevalence of approximately 0.112%, or 1:900. Of the 81 requests received for plasma AADC enzyme analysis, 25 samples had very low plasma AADC activity consistent with AADC deficiency, resulting in identification of nine additional cases. A total of five additional patients were identified by Sanger sequencing as the primary request leading to the diagnosis of AADC deficiency. Conclusions Overall, these analyses identified 36 new cases of AADC deficiency. Sequencing findings showed substantial diversity with identification of 26 different DDC gene variants; five had not previously been associated with AADC deficiency. The results of the present study align with the emerging literature and understanding of the epidemiology and genetics of AADC deficiency.

Aim Mismatch negativity (MMN) deficit is one of the most robust and replicable findings in schizophrenia, and primarily reflects deficient functioning of the N-methyl-D-aspartate (NMDA) receptor system. Although the dopamine receptor is known not to modulate MMN over the short term, it is unclear whether the dopamine system affects MMN in the long term. Methods We explored correlations between MMN and levels of plasma dopamine and serotonin metabolites in 18 patients with schizophrenia psychiatrically evaluated with the Positive and Negative Syndrome Scale (PANSS). Results A significant negative correlation exists between MMN amplitude and plasma levels of dopamine metabolites. Plasma serotonin metabolite levels were not correlated with MMN. The PANSS total score and Negative score also showed negative correlations with MMN amplitude. Conclusion The usual strong therapeutic blockade of dopamine receptors applied in cases of schizophrenia may reduce MMN over the long term.

Despite that millions of people suffer from major depressive disorder (MDD), the mechanism underlying MDD remains elusive. Recently, it has been reported that entorhinal cortex (EC) functions on the regulation of depressive-like phenotype relying on the stimulation of glutamatergic afferent from EC to hippocampus. Based on this, we used liquid chromatography-tandem mass spectrometry method to explore metabolic alterations in the EC of mice after exposed to chronic restraint stress (CRS). Molecular validation was conducted via the application of western blot and RT-qPCR. Through this study, we found significant upregulation of glutamate, ornithine aspartic acid, 5-hydroxytryptophan, L-tyrosine and norepinephrine in CRS group, accompanied with downregulation of homovanillic acid. Focusing on these altered metabolic pathways in EC, we found that gene levels of GAD1, GLUL and SNAT1 were increased. Upregulation of SERT and EAAT2 in protein expression level were also validated, while no significant changes were found in TH, AADC, MAOA, VMAT2, GAD1, GLUL and SNAT1. Our findings firstly provide evidence about the alteration of metabolites and related molecules in the EC of mice model of depression, implying the potential mechanism in MDD pathology.

BACKGROUND Epidemiological research indicates that iron deficiency (ID) in infancy correlates with long-term cognitive impairment and behavioral disturbances, despite therapy. However, the mechanisms underlying these effects are unknown. OBJECTIVE We investigated how ID affected postweaning behavior and monoamine concentration in rat brains to determine whether ID during the juvenile period affected gene expression and synapse formation in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). METHODS Fischer 344/Jcl postweaning male rats aged 21-39 d were fed low-iron diets (0.35 mg/kg iron; ID group) or standard AIN-93 G diets [3.5 mg/kg iron; control (CN) group]. After day 39, all rats were fed the iron-adequate diet. The locomotor activity was evaluated by the open field and elevated plus maze tests at 8 and 12 wk of age. Monoamine concentrations in the brain were analyzed using HPLC at 9 and 13 wk of age. Comprehensive gene expression analysis was performed in the PFC and NAcc at 13 wk of age. Finally, we investigated synaptic density in the PFC and NAcc by synaptophysin immunostaining. RESULTS Behavioral tests revealed a significant reduction of the age-related decline in the total distance traveled in ID rats compared with CN rats (P < 0.05), indicating that ID affected hyperactivity, which persisted into adulthood (13 wk of age). At this age, reelin (Reln) mRNA expression (adjusted P < 0.01) decreased and synaptic density (P < 0.01) increased in the NAcc in the ID group. Regarding the mesolimbic pathway, homovanillic acid concentration increased in the NAcc, whereas the dopamine concentration decreased in the ventral midbrain. CONCLUSIONS Our results suggest that ID during the postweaning period in male rats, despite complete iron repletion following ID, led to long-term hyperactivity via monoamine disturbance in the brain and an alteration in the synaptic plasticity accompanied by downregulation of Reln expression in the NAcc.

Objectives Mild cognitive impairment is a common non-motor feature of Parkinson's disease, termed PD-MCI. But there is a scarcity of data on the role of glial cell line-derived neurotrophic factor (GDNF) and neurotransmitters in pathogenesis of PD-MCI. The aim of this project was to detect the serum levels of GDNF and multiple neurotranmitters and explore their relationships with cognitive performance in PD-MCI patients. Methods Neuropsychological testing was administered to PD patients and healthy controls to investigate different domains of cognitive function. Serum levels of GDNF and four cognition-related neurotransmitters including Dopamine metabolites Homovanillic acid (HVA), acetylcholine (Ach), γ-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) were detected by enzyme-linked immunosorbent assay and liquid chromatography-electrospray ionization tandem mass spectrometry analysis respectively. Results The more serious cognitive impairment of PD, the lower levels of GDNF, HVA and 5-HT. In PD-MCI patients, the levels of GDNF, HVA, Ach, 5-HT, and GABA had a significant positive correlation with Digit span backward test (DSB-T) scores and negative correlation with the scores of Trail Making Test A (TMT-A) and Trail Making Test B (TMT-B) respectively. Effect size analysis showed that GDNF and GDNF*Ach have a significant effect on DSB-T, TMT-A and TMT-B respectively; GDNF*HVA, GDNF*5-HT and GDNF*GABA play important part in Auditory Verbal Learning Test separately. Conclusions Serum GDNF may be involved in the impairment of attention, memory and executive function of PD-MCI patients, by acting alone or in conjunction with neurotransmitters (HVA, 5-HT, GABA, and Ach).

Background. Long-term alcohol consumption leads to changes in the brain through the interaction of ethanol with neurotransmitter systems. The intermittent alcohol intoxication is a new experimental state in narcology and its correction is of a great practical importance. Purpose. Assessment of the effect of chronic and intermittent alcohol intoxication on the component content of dopaminergic and serotonergic neurotransmitter systems and pool of neuroactive amino acids in the hypothalamus and striatum of rats, as well as the correction of the revealed disturbances. Material and methods. 76 albino male rats with a weight 180-220 g were used for the experiment. The contents of free amino acids and biogenic amines were determined by HPLC. Correction of neurotransmitter disturbance was performed using «Tritarg» and «Titacin» amino acid composition. Results. In the hypothalamus in chronic and intermittent alcohol intoxication with 4-day interval concentrations of dopamine, tryptophan and 5-hydroxytryptophan increase, and in intermittent alcohol intoxication with 1-day interval the levels of tyrosine, homovanillic acid and noradrenalin increase. In the striatum in chronic alcohol intoxication the levels of tyrosine, dopamine and biochemical parameters of the serotonergic system increase, and with both forms of intermittent alcohol intoxication concentrations of tryptophan and 5-hydroxytryptophan increase. The introduction of the amino acid composition «Tritarg» normalizes the parameters of the serotonergic neurotransmitter system in the hypothalamus, «Titacin» does not have a corrective effect. Conclusions. Chronic and intermittent alcohol intoxication with 4-day interval causes the similar changes in striatum and hypothalamus which is expressed by the activation of dopamine and serotonin metabolism. In intermittent alcohol intoxication with 1-day interval the severity of neurotransmitter disturbances in these parts of the brain was slightly lower.

Experiments were carried out on recombinant B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B) mouse lines created by transferring a 102.73–118.83 Mbp fragment of chromosome 13, containing the 5-HT1A receptor gene, from CBA or C57BL/6 strains to a C57BL/6 genetic background, correspondingly. We have recently shown different levels of 5-HT1A receptor functionality in these mouse lines. The administration of BDNF (300 ng/mouse, i.c.v.) increased the levels of exploratory activity and intermale aggression only in B6-M76B mice, without affecting depressive-like behavior in both lines. In B6-M76B mice the behavioral alterations were accompanied by a decrease in the 5-HT2A receptor functional activity and the augmentation of levels of serotonin and its main metabolite, 5-HIAA (5-hydroxyindoleacetic acid), in the midbrain. Moreover, the levels of dopamine and its main metabolites, HVA (homovanillic acid) and DOPAC (3,4-dihydroxyphenylacetic acid), were also elevated in the striatum of B6-M76B mice after BDNF treatment. In B6-M76C mice, central BDNF administration led only to a reduction in the functional activity of the 5-HT1A receptor and a rise in DOPAC levels in the midbrain. The obtained data suggest the importance of the 102.73–118.83 Mbp fragment of mouse chromosome 13, which contains the 5-HT1A receptor gene, for BDNF-induced alterations in behavior and the brain monoamine system.

Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. Objective: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. Methods: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). Results: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. Conclusions: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

This study determined the effect of norepinephrine and light exposure on melatonin secretion in goose pineal explants. Additionally, it investigated changes in the content of norepinephrine, dopamine, and their metabolites [3,4-dihydroxyphenylacetic acid; vanillylmandelic acid (VMA); homovanillic acid] in goose pineal glands in vivo under 12 h of light and 12 h of darkness (LD), a reversed cycle (DL), constant light (LL), and constant darkness (DD). In vitro content of melatonin was measured by radioimmunoassay; contents of catecholamines and their metabolites were measured by high-performance liquid chromatography. Exposure of pineal explants to LD or DL established rhythmic melatonin secretion; this rhythm was much better entrained with norepinephrine exposure during photophase than without it. When the explants were kept in LL or DD, the rhythm was abolished, unless NE was administered during natural scotophase of a daily cycle. In vivo, norepinephrine and dopamine levels did not display rhythmic changes, but their respective metabolites, HMV and VMA, displayed well-entrained diurnal rhythms. These results indicate that norepinephrine and sympathetic innervation play key roles in regulation of pineal secretory activity in geese, and that pineal levels of VMA and HMV provide precise information about the activity of sympathetic nerve fibers in goose pineal glands.

Objective IL-6 and catecholamines play roles in the pathophysiology of major depressive disorder (MDD). Aim The present study investigated associations between plasma IL-6 and plasma catecholamine metabolites in patients with MDD. Participants and methods A total of 148 patients (male/female 65/83, age 49.5±12.1 years) who met the criteria for MDD based on the Diagnostic and Statistical Manual of Mental Disorders IV and 40 participants as healthy controls (HC; male/female 23/17, age 44.0±10.5 years) were enrolled in the present study. Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were analyzed using high-performance liquid chromatography, and plasma IL-6 levels were measured using ELISA. Results No correlations were observed among plasma IL-6 levels, MHPG levels, and HVA levels in patients with MDD. Plasma IL-6 levels in patients with MDD were significantly higher than in the HC. A positive correlation was found between plasma IL-6 levels and Hamilton Rating Scale for Depression-17 scores. Conclusion No correlations existed between plasma IL-6 levels and plasma catecholamine metabolite levels in patients with MDD, and the severity of depressive state was related to plasma IL-6 levels in MDD.

Cedrol has been reported to be effective in reducing anxiety of male mice. The limited application of females in animal models of anxiety makes it difficult to systematically investigate new drug substitutes with potential anxiolytic activity. In the present study, we investigated the behavioral response of female ICR mice to cedrol after intraperitoneal (i.p.) administration using the elevated plus maze (EPM) and the light-dark box (LDB) test, followed by determination of neurochemical changes in brain. The data suggested that cedrol at dose of 1200-1600 mg·kg-1 exhibited anxiolytic activity on the female mice, as reflected by greater percentage of entries into the open arms and time spent in the open arms in the EPM, and greater transitions between chambers and percentage of time spent in the light chamber in the LDB. Cedrol increased the level of 5-hydroxytryptamine (5-HT), decreased the level of dopamine (DA), reduced the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and increased the ratio of 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, compared with the control group, indicative of an anxiolytic-like effect on female mice via the 5-HTnergic or DAnergic pathways.

One of the reasons for using paracetamol during pregnancy is fever. The brain structure responsible for maintaining proper body temperature, but also for controlling some endocrine aspects is hypothalamus. In this study we examined the effect of early pretreatment of paracetamol on hypothalamic neurotransmission in rats’ offspring. We used two-month old rats previously exposed to paracetamol at doses of 5 (P5) and 15 mg/kg (P15) during gestational development and next postnatally. The concentration of monoamines, their metabolites and amino acids in hypothalamus was chromatographically determined. The results of biochemical analysis were compared with the Control animals (Con). We found differences between groups in the concentration of main noradrenaline metabolite in hypothalamus. The control group had significantly higher level of 3-methoxy-4-hydroxyphenylglycol (MHPG) compared with rats exposed to paracetamol (F(2,27) = 7.96, p These results demonstrated that paracetamol had a significant effect on dopaminergic and noradrenergic neurotransmission and changed the concentration of glutamic acid in hypothalamus - heat-regulating center and important element of hypothalamic-pituitary- gonadal axis.

Two novel phenanthrenoids, juncuenin H (1) and dijuncuenin B (2), together with eight known phenanthrenoids, effusol (3), dehydroeffusol (4), juncusol (5), dehydrojuncusol (6), juncuenin B (7), dehydrojuncuenin B (8), juncuenin A (9), and dehydrojuncuenin A (10), were isolated from the underground parts of Juncus setchuenensis. The structures of the compounds were determined by 1D and 2D NMR and mass spectroscopy. The anxiolytic activities of compounds 1, 6, 9, and 10 were evaluated. In order to explore the mechanisms underlying their anxiolytic activities, the levels of serotonin (5-HT), dopamine (DA), and their metabolites in the cerebral cortex and hippocampus of mice treated with compound 1 were determined by quantitative mass spectrometry. The mice treated with compound 1 had significantly lower levels of 5-HT, 3-methoxytyramine (3-MT), 5-hydroxyindole-3-acetic acid (5-HIAA), homovanillic acid (HVA), and 3, 4-dihydroxyphenylacetic acid (DOPAC) in the cerebral cortex than those of the vehicle control-treated mice. The levels of HVA and 5-HIAA in the hippocampus were also significantly lower in the mice treated with compound 1 than in the control group mice. These results suggest that the metabolic changes, reflected in the levels of DA and/or 5-HT, may contribute to the anxiolytic activity of the phenanthrenoids studied herein.

Introduction Analysis of urinary catecholamine metabolites is one of the primary modalities to diagnose patients with neuroblastoma. Although catecholamine excretion patterns have been recognised in the past, their biological rationale and clinical relevance remain largely unknown. Therefore, this study was designed to identify unique catecholamine excretion patterns and elucidate their underlying biology and clinical relevance. Patients and methods A panel of 25 neuroblastoma cell lines was screened for catecholamine excretion. Detection of the catecholamine enzymes was performed using Western blot. Based on catecholamine enzymes presence and excreted catecholamine metabolites, excretion profiles were defined. The prevalence of these profiles was investigated in vivo using diagnostic urines from 301 patients with neuroblastoma and immunohistochemistry on primary tumours. The clinical relevance of the profiles was determined by linking the profiles to clinical characteristics and outcome of patients with neuroblastoma. Results Four excretion profiles (A-D) were identified in vitro, which correlated with the relative protein expression of the catecholamine enzymes. These profiles were also identified in urine samples from patients with neuroblastoma and correlated with the presence of the catecholamine enzymes in the tumour. Strikingly, in 66% of the patients, homovanillic acid and vanillylmandelic acid excretions were discordant with the catecholamine profiles. Clinical characteristics and outcome gradually improved from patients with profile A (predominantly high risk) towards profile D (predominantly observation), with 5-years overall survival of 35% and 93%, respectively. Conclusions Catecholamine profiles in vitro and in vivo reflect, to a large extent, the presence of the individual catecholamine enzymes and represent distinct subgroups of patients with neuroblastoma.

Withaferin A (WA) was evaluated for its neuro-protective efficacy on ageing induced striatal dopamine (DA) and behavioural changes in aged rats. Wistar albino rats were divided into group I – young (3 months), Group II – aged (24 months), Group III – aged rats supplemented with WA (50 mg/kg b.w once in a day for 30 days) and Group IV – young rats supplemented with WA (50 mg/kg b.w). The HPLC assay revealed significant decline in the levels of DA and homovanillic acid (HVA) in substantia nigra (SN) and striatum (ST) of aged rat. A marked decline in motor activity of aged rat was observed through open field, beam walking and grid walking motor experiments. These results indicate that ageing reduces nigro-striatal activity as well as nigro-striatal DA levels. Interestingly, the administration of WA (50 mg\kg b.w) resulted in a substantial resurge of DA and HVA in SN and ST and a significant reversal of motor impairment in aged rats. This study is the first report that evidently determines the neuro-protective efficacy of WA on dopaminergic system of SN and ST in aged rats.

Cathinone, the active principle of khat (Catha edulis), stimulates, excites and produces euphoric feelings in khat users. Locomotor and rearing activities, either individual or in groups, of male Swiss albino mice were decreased significantly compared to the control. Motor coordination tests (rotarod, rope climb and grip tests) have shown decreased motor performance in the mice treated with cathinone compared to the control. The elevated plus maze test has shown significant anxiety in the mice compared to the control. Contents of dopamine and its metabolite, homovanillic acid, were increased in the limbic areas compared to the control group. In contrast, contents of 3,4-dihydroxyphenyl acetic acid were depleted significantly and dose dependently compared to the control group in the limbic areas of mice. In conclusion, natural cathinone has depleted motor coordination, accelerated anxiety in mice and altered the contents of dopamine and its metabolites.

BACKGROUND Granulocyte colony-stimulating factor (G-CSF) activates the PI3K/Akt pathway to exert neuroprotective effects. The current study aimed to determine if G-CSF reverses behavioral deficits, even after motor malfunction occurs in Paraquat (PQ)-treated mice. METHODS Male C57BL/6 mice (8 weeks old) were divided into 3 groups: PQ + G-CSF-treated group (n=8); PQ + saline-treated group (n=8); and saline-treated control group (n=8). Spontaneous locomotor activity was evaluated together with the pole test. The DA, 3, 4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA) levels in the bilateral striatum were determined by HPLC. The number of substantia nigra pars compacta tyrosine hydroxylase (TH)-immunoreactive neurons was calculated using an unbiased cell counting stereology method, the activities of total GSH-PX and SOD, and the malondialdehyde (MDA) content were assessed. RESULTS After G-CSF treatment, spontaneous motor activity and the Tturn and TLA times in the CSF group were significantly lower than the control group, and the striatal dopamine level in the striatum and the number of TH-positive neurons in the substantia nigra (SN) were significantly increased compared to the control group (5478 ± 654 vs. 3647±488 DA neurons, P < 0.05). Compared to the control group, the GSH-PX and SOD activities were increased, while the MDA level was significantly decreased in the SN (P

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), DHPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen 18 F-DOPA and cardiac 18 F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.

The choroid plexus form cerebrospinal fluid (CSF) within four ventricles the brain. The composition of CSF is very similar to the of the brain’s extracellular, and its composition depends on filtration and diffusion from the blood. Few conditions cause CSF volume and pressure to fall below normal (dehydration may be one), but many conditions can cause it to increase, sometimes under pressure. This may lead to blocked flow CSF from one or more ventricles, which causes an increase in intracranial pressure, and CSF buildup i.e. to hydrocephalus. Hydrocephalus results from one of three possible causes: over secretion of CSF, impaired absorption of CSF or obstruction of CSF pathways. The concentration of metabolites of the monoamines homovanillic acid (HVA) and 5-hydrocephalus acetic acid (5-HIAA) were determined with HPLC-ED in the CSF of 17 patients (children of 1 age) with hydrocephalus. Determined 5-HIAA concentrations are in the range of 0,99–113,89 ng/mL and HVA 0,98–165,92 ng/mL in CSF due to pressure changes occurring in hydrocephalus is increasing the turnover of serotonin and dopamine to its metabolites. The correlation no could be established between the levels of 5-HIAA and HVA and type of hydrocephalus, and the duration of disease.

Zebrafish embryos and larvae are vertebrate models increasingly used in translational neuroscience research. Behavioral impairment induced by the exposure to neuroactive or neurotoxic compounds is commonly linked to changes in modulatory neurotransmitters in the brain. Although different analytical methods for determining monoaminergic neurochemicals in zebrafish larvae have been developed, these methods have been used only on whole larvae, as the dissection of the brain of hundreds of larvae is not feasible. This raises a key question: Are the changes in the monoaminergic profile of the whole larvae predictive of the changes in the brain? In this study, the levels of ten monoaminergic neurotransmitters were determined in the head, trunk, and the whole body of zebrafish larvae in a control group and in those treated for 24 h with 5 M deprenyl, a prototypic monoamine-oxidase B inhibitor, eight days post-fertilization. In control larvae, most of the monoaminergic neurochemicals were found at higher levels in the head than in the trunk. Significant changes were found in the distribution of some neurochemicals after deprenyl-treatment, with serotonin and norepinephrine increasing in both the head and the trunk, whereas dopamine, L-DOPA, and homovanillic acid levels were only modulated in the head. In fact, the highly significant increase in dopamine levels observed in the head after deprenyl-treatment was not detected in the whole-body analysis. These results indicate that the analysis of neurotransmitters in the zebrafish larvae whole-body should not be used as a general surrogate of the brain., This work was supported by the “Agencia Estatal de Investigación” from the Spanish Ministry of Science and Innovation and the IDAEA-CSIC, a Centre of Excellence Severo Ochoa (CEX2018-000794-S), through the SYNERGY Project “Environmental risk of complex mixtures of emerging persistent and mobile chemicals in aquatic ecosystems (MixPersiRisk)” financed with Severo Ochoa funds. The work was partially supported by the network of recognized research groups by the Catalan Government (2017 SGR_902).

Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson's disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype. National Medical Research Council (NMRC) Published version This research was supported by the Open Fund-Large Collaborative Grant [OFLCG18May-0026]; and Open Fund-Individual Research Grant [NMRC/OFIRG/0074/2018] administered by the Singapore Ministry of Health’s National Medical Research Council.

Little is known about the uptake, biodistribution, and biological responses of nanoparticles (NPs) and their toxicity in developing animals. Here, male and female juvenile Sprague-Dawley rats received four consecutive daily doses of 10 mg/kg Al2 O3 NP (diameter: 24 nm [transmission electron microscope], hydrodynamic diameter: 148 nm) or vehicle control (water) by gavage between postnatal days (PNDs) 17-20. Basic neurobehavioral and cardiac assessments were performed on PND 20. Animals were sacrificed on PND 21, and selected tissues were collected, weighed, and processed for histopathology or neurotransmitter analysis. The biodistribution of Al2 O3 NP in tissue sections of the intestine, liver, spleen, kidney, and lymph nodes were evaluated using enhanced dark-field microscopy (EDM) and hyperspectral imaging (HSI). Liver-to-body weight ratio was significantly increased for male pups administered Al2 O3 NP compared with control. HSI suggested that Al2 O3 NP was more abundant in the duodenum and ileum tissue of the female pups compared with the male pups, whereas the abundance of NP was similar for males and females in the other tissues. The abundance of NP was higher in the liver compared with spleen, lymph nodes, and kidney. Homovanillic acid and norepinephrine concentrations in brain were significantly decreased following Al2 O3 NP administration in female and male pups, whereas 5-hydroxyindoleacetic acid was significantly increased in male pups. EDM/HSI indicates intestinal uptake of Al2 O3 NP following oral administration. Al2 O3 NP altered neurotransmitter/metabolite concentrations in juvenile rats' brain tissues. Together, these data suggest that orally administered Al2 O3 NP interferes with the brain biochemistry in both female and male pups.

Interferon-alpha (IFN-α) is a cytokine widely used in the treatment of brain cancers and virus infections with side effects including causing depression. Monoamine neurotransmitter systems have been found playing important roles in peripheral IFN-α-induced depression, but how peripheral IFN-α accesses the central nervous system and contributes to the development of depression is poorly known. This study aimed to develop a non-human primate model using long-term intracerebroventricular (i.c.v.) administration of IFN-α (5 days/week for 6 weeks), to observe the induced depressive-like behaviors and to explore the contributions of monoamine neurotransmitter systems in the development of depression. In monkeys receiving i.c.v. IFN-α administration, anhedonia was observed as decreases of sucrose consumption, along with depressive-like symptoms including increased huddling behavior, decreases of spontaneous and reactive locomotion in home cage, as well as reduced exploration and increased motionless in the open field. Chronic central IFN-α infusion significantly increased the cerebrospinal fluid (CSF) concentrations of noradrenaline (NA), and 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). These CSF monoamine metabolites showed associations with some specific depression-related behaviors. In conclusion, central IFN-α administration induced anhedonia and depression-related behaviors comparable to the results with peripheral administration, and the development of depression was associated with the dysfunction of monoamine neurotransmitters.

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the “experience-expectant brain,” with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study,N= 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR;n= 269) or without adults with 24-h access to same-aged peers (PR;n= 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with thesallele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for theLallele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype.

Background Some individuals with schizophrenia present with a dopamine supersensitivity state (DSS) induced by a long-term administration of excessive antipsychotics; this is recognized as dopamine supersensitivity psychosis (DSP). The mechanisms underlying DSP are not established. Here, we investigated dopamine signaling in DSS rats. Methods Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. We then screened DSS rats from HAL-treated rats by a voluntary locomotion test. The striatal levels of dopamine (DA) and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined, as were the levels of protein kinase v-akt murine thymoma viral oncogene homolog (AKT), glycogen synthase kinase-3 (GSK-3), and phosphorylated GSK-3 in the striatal regions. Results In the DSS rats, the DA, DOPAC, and HVA levels were significantly decreased. In a western blot analysis, the DSS rats exhibited a significant decrease in GSK-3α/β and an increase in the pGSK-3β/GSK-3β ratio, whereas AKT was not changed. Conclusions Our results indicated that the DSS rats had hypofunction of the basal dopamine release and AKT/GSK-3 signaling even at 7 days after the antipsychotic was discontinued. Protracted reductions in pre- and post-dopamine D2 receptor signaling might cause prolonged DSS.

Background Depression is a major public health challenge that imposes a great societal burden. Depression has been attributed to the decreased level of neurotransmitters and brain-derived neurotrophic factor (BDNF) levels. Chinese herbal medicine Jie Yu Chu Fan (JYCF) capsule has been shown to be effective in the management of depression. However, the mechanism has yet to be determined. This study aimed to explore the activity of JYCF against depression by establishing a mouse model of chronic unpredictable mild stress (CUMS) with fluoxetine as the positive control drug. Methods The open field test, sucrose preference test, forced swim test, and tail suspension test were carried out to observe the behavioral changes of animals. The levels of norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine, as well as their respective metabolic products 5-hydroxyindoleacetic acid, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid in the mouse hippocampi were quantified by high-performance liquid chromatography (HPLC). Cell proliferation and apoptosis, and early and mature nerve cells in the hippocampi were observed by immunofluorescence. Reverse transcription polymerase chain reaction was used to identify BDNF expression in the hippocampi. Results After 5 weeks of unpredictable stimulation, a CUMS mouse model was successfully obtained, as indicated by sharply decreased sucrose preference and locomotor activity, as well as an increased immobility time in the forced swim test. Our results demonstrated that treatment with JYCF (1 and 5 g/kg) and fluoxetine (20 mg/kg) dramatically reversed the behavioral abnormalities in CUMS mice. At 1 g/kg, JYCF significantly increased NE, DA, and HVA levels in the hippocampi of CUMS mice. JYCF up-regulated the mRNA expression of BDNF and promoted cell proliferation in hippocampi of CUMS mice. Conclusions Our study demonstrated that JYCF exhibits antidepressant activity comparable to that of fluoxetine in CUMS mice. Moreover, the antidepressant-like activity of JYCF was shown to be mediated by enhancing hippocampal nerve cell neurogenesis through increasing the levels of monoamine neurotransmitters and BDNF expression.

Impaired dopamine activity in the dorsolateral prefrontal cortex (DLPFC) is thought to contribute to cognitive deficits in diseases such as schizophrenia, attention deficit hyperactivity disorder (ADHD) and traumatic brain injury. Catechol-O-methyltransfease (COMT) metabolizes dopamine and is an important regulator of dopamine signaling in the DLPFC. In mammalian species, two isoforms of COMT protein, membrane-bound COMT (MB-COMT) and soluble COMT (S-COMT), are encoded by one COMT gene and expressed widely. While S-COMT is thought to play a dominant role in the peripheral tissues, MB-COMT is suggested to have a greater role in dopamine metabolism in the brain. However, whether a selective inhibitor for MB-COMT may effectively block dopamine metabolism remains unknown. We generated a knockout of MB-COMT in PC12 cells using CRISPR-cas9 technology to evaluate the effect of both MB and S-COMT on dopamine metabolism. Deletion of MB-COMT in PC12 cells significantly decreased homovanillic acid (HVA), completely depleted 3-methyoxytyramine (3-MT), and significantly increased 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Comparison of the effect of a MB-COMT selective inhibitor LI-1141 on dopamine metabolism in wild type and MB-COMT knockout PC12 cells allowed us to confirm the selectivity of LI-1141 with respect to MB-COMT in cells. Under conditions in which LI-1141 was shown to inhibit only MB-COMT but not S-COMT, it effectively changed dopamine metabolites similar to the effect induced by tolcapone, a non-selective COMT inhibitor, suggesting that selective inhibition of MB-COMT will be effective in blocking dopamine metabolism, providing an attractive therapeutic approach in improving cognition for patients.

BACKGROUND. Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition. METHODS. Retrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables. RESULTS. Patients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8±2.4 weeks) and low birth weight (−1.14±0.97 SD below that predicted for gestational age). With time, weight and height approached normal. values. All patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p

Aims: The patients with Parkinson’s disease (PD) present with lower urinary tract symptoms (LUTS), but the efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) on LUTS is unknown. The medial prefrontal cortex (mPFC) is a known higher micturition center which are modulated by STN-DBS. We aim to clarify STN-DBS-related changes in the neuronal activity of the mPFC in terms of bladder contraction, using normal and PD rats. Methods: Experiments were performed under urethane anesthesia in normal and 6-hydroxydopamine hemi-lesioned PD rats. STN-DBS was applied to the left STN, with simultaneous monitoring of bladder contractions. Local field potential (LFP) of mPFC was recorded before, during, and after STN-DBS (n = 6: normal rats, n = 6: PD rats). Extracellular fluid was collected from the mPFC before, during, and after STN-DBS (n = 5: normal rats, n = 6: PD rats). Results: STN-DBS significantly increased bladder inter-contraction interval. STN-DBS significantly decreased mPFC alpha power in normal rat and increased alpha power in PD rat. The mPFC levels of levodopa, dopamine, serotonin, and their metabolites were significantly decreased during and after STN-DBS in PD rats, whereas the levels of serotonin and its metabolites and homovanillic acid (HVA) were significantly decreased after STN-DBS in normal rats. Conclusion: STN-DBS increased bladder inter-contraction intervals in both normal and PD rats probably through changes in neural activity, as evaluated by the alpha power and catecholamine levels in mPFC. The effect of STN-DBS on the levels of catecholamine in mPFC was different between normal and PD rats.

This study aimed to evaluate the possible mechanism of Ningdong granule (NDG) for the treatment of Tourette syndrome (TS). The rats with stereotyped behavior were established by microinjection with TS patients’ sera; then, the model rats were divided into NDG and haloperidol (Hal) group, and the nonmedication model rats were regarded as treatment control (TS group). The stereotyped behavior of the rats was recorded, the level of dopamine (DA) in striatum, and the content of homovanillic acid (HVA) in sera were tested, and dopamine transporter (DAT) expression was measured in the study. The experimental results showed that NDG effectively inhibited the stereotyped behavior (P<0.01), decreased the levels of DA in the striatum (P<0.05), increased the content of sera HVA (P<0.01), and enhanced the protein and mRNA expression of DAT in the striatum (P<0.01). Additionally, the results also revealed Hal could improve the stereotyped behavior as well but had no remarkable influence on DAT expression and DA metabolism. In conclusion, NDG attenuates stereotyped behavior, and its mechanism of action might be associated with the upregulation of DAT expression to regulate DA metabolism in the brain.

Fipronil (FPN), a widely used pesticide for agricultural and non-agricultural pest control, is possibly neurotoxic for mammals. Brain monoaminergic systems, involved in virtually all brain functions, have been shown to be sensitive to numerous pesticides. Here, we addressed the hypothesis that chronic exposure to FPN could modify brain monoamine neurochemistry. FPN (10 mg/kg) was chronically administered for 21 days through oral gavage in rats. Thereafter, the tissue concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid, serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and noradrenaline (NA) were measured in 30 distinct brain regions. FPN significantly decreased DA and its metabolite levels in most striatal territories, including the nucleus accumbens and the substantia nigra (SN). FPN also diminished 5-HT levels in some striatal regions and the SN. The indirect index of the turnovers, DOPAC/DA and 5-HIAA/5-HT ratios, was increased in numerous brain regions. FPN reduced the NA content only in the nucleus accumbens core. Using the Bravais&ndash, Pearson test to study the neurochemical organization of monoamines through multiple correlative analyses across the brain, we found fewer correlations for NA, DOPAC/DA, and 5-HIAA/5-HT ratios, and an altered pattern of correlations within and between monoamine systems. We therefore conclude that the chronic administration of FPN in rats induces massive and inhomogeneous changes in the DA and 5-HT systems in the brain.

The present investigation was undertaken to demonstrate the comparisons and contrasts of the conditional stimuli's (CS's) actions with those of morphine in morphine withdrawn rats. The study shows that specific stimuli altered behavioral and physiological withdrawal signs such as: hypothermia, shakes, ptosis, piloerection, writhing and aggression. Also, one stimulus was able to effect two biochemical measures (blood glucose and striatal homovanillic acid) similar to the action of morphine. Rats were given two equally spaced injections of morphine sulfate paired with different stimuli (bell, drug, oil of anise, saccharin). The stimuli were paired with an injection for 15-25 days. Twenty-four hours after the last morphine injection the appropriate stimulus was presented. The rats learned to increase their body temperature, reduce wet shakes, increase ptosis, reduce writhing and reduce aggressive responses following the presentation of oil of anise. The bell stimulus only increased temperature. The gustatory stimulus increased temperature and the drug stimuli had no effect on withdrawal signs. The changes observed were specific only to animals that had the respective stimuli paired with morphine prior to challenge treatment. The duration of the CS in the oi l of anise study was important, the onset required a time period of greater than 2 min

Pyridoxine, one of the vitamin B6 vitamers, plays a crucial role in amino acid metabolism and synthesis of monoamines as a cofactor. In the present study, we observed the effects of pyridoxine deficiency on novel object recognition memory. In addition, we examined the levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenethylamine (DA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid and the number of proliferating cells and neuroblasts in the hippocampus. We also examined the effects of pyridoxine deficiency on protein profiles applying a proteomic study. Five-week-old mice fed pyridoxine-deficient diets for 8 weeks and showed a significant decrease in the serum and brain (cerebral cortex, hippocampus, and thalamus) levels of pyridoxal 5&prime, phosphate, a catalytically active form of vitamin-B6, and decline in 5-HT and DA levels in the hippocampus compared to controls fed a normal chow. In addition, pyridoxine deficiency significantly decreased Ki67-positive proliferating cells and differentiated neuroblasts in the dentate gyrus compared to controls. A proteomic study demonstrated that a total of 41 spots were increased or decreased more than two-fold. Among the detected proteins, V-type proton ATPase subunit B2 (ATP6V1B2) and heat shock cognate protein 70 (HSC70) showed coverage and matching peptide scores. Validation by Western blot analysis showed that ATP6V1B2 and HSC70 levels were significantly decreased and increased, respectively, in pyridoxine-deficient mice compared to controls. These results suggest that pyridoxine is an important element of novel object recognition memory, monoamine levels, and hippocampal neurogenesis. Pyridoxine deficiency causes cognitive impairments and reduction in 5-HT and DA levels, which may be associated with a reduction of ATP6V1B2 and elevation of HSC70 levels in the hippocampus.

Alterations in dopamine (DA) signaling and reductions in functional connectivity (FC; a measure of temporal correlations of activity between different brain regions) within dopaminergic reward pathways are implicated in the etiology of psychopathology and have been associated with increased concentrations of inflammatory markers, including C-reactive protein. Peripheral and central inflammatory cytokines that have been shown to disrupt DA signaling and corticostriatal FC are associated with C-reactive protein, an acute phase reactant that is used translationally as a marker of systemic inflammation. One factor that can significantly increase systemic inflammation to produce neuroadaptations in reward pathways is a diet that results in fat mass accumulation (e.g. obesogenic diet). The current study in female rhesus monkeys maintained in a standard laboratory chow (n = 18) or on obesogenic diet (n = 16) for 12-months tested the hypothesis that an obesogenic diet would alter central DA and homovanillic acid (HVA) concentrations, and be associated with increased CRP concentrations and decreased FC between corticostriatal regions at 12-months following dietary intervention. We specifically assessed FC between the nucleus accumbens (NAcc) and two sub-regions of the prefrontal cortex (PFC) previously associated with CRP concentrations, the ventromedial PFC (vmPFC) and the orbitofrontal cortex (OFC), which are also involved in emotional and motivational salience assessment, and in goal-directed behavior, impulse control and the salience/value of food, respectively. Results showed that CSF DA concentrations were decreased (p = 0.002), HVA:DA ratios were increased (p = 0.016), and body mass index was increased (p = 0.047) over the 12-months of consuming an obesogenic diet. At 12-months, females maintained in the obesogenic diet exhibited higher CRP concentrations than females consuming chow-only (p = 0.008). Linear regression analyses revealed significant CRP by dietary condition interactions on DA concentrations (β = -5.10; p = 0.017) and HVA:DA ratios (β = 5.14; p = 0.029). Higher CRP concentrations were associated with lower CSF DA concentrations (r = -0.69; p = 0.004) and greater HVA:DA ratios only in females maintained in the obesogenic dietary condition (r = 0.58; p = 0.024). Resting-state magnetic resonance neuroimaging (rs-fMRI) in a subset of females from each diet condition (n = 8) at 12-months showed that higher CRP concentrations were associated decreased FC between the NAcc and subregions of the prefrontal cortex (PFC; p's 0.05). Decreased FC between the NAcc and PFC subregions were also associated with lower concentrations of DA and greater HVA:DA ratios (p's 0.05). Overall, these data suggest that increased inflammatory signaling driving heightened CRP levels may mediate the adverse consequences of obesogenic diets on DA neurochemistry and corticostriatal connectivity.

Background A high-fat diet (HFD) can induce obesity and metabolic disorders that are closely associated with cognitive impairments, and the progression of several psychiatric disorders such as anxiety. We have previously demonstrated the anxiolytic-like effect of Gamma oryzanol (GORZ) in chronic restraint stressed mice. Objective We studied the neurochemical and molecular mechanisms that underlie the preventive effect of GORZ in HFD-induced anxiety-like behaviors, monoaminergic dysfunction, and inflammation. Methods Eight-week-old Institute of Cancer (ICR) male mice weighing 33-34 g were divided into the following groups and free-fed for 8 weeks: control (14% casein, AIN 93M); HFD; HFD + GORZ (0.5% GORZ). Body weight gain was checked weekly. The anxiolytic-like effects of GORZ were examined via open-field test (OFT) and elevated plus maze (EPM) test. Brain levels of monoamines [5-hydroxy tryptamine (5-HT), dopamine (DA), and norepinephrine (NE)] and their metabolites [5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], proinflammatory cytokines such as tumor necrosis factor-αα (Tnf-α) mRNA levels, and interleukin 1-β (Il-1β) mRNA levels in the cerebral cortex and amygdala were examined using high-performance liquid chromatography-electrochemical detection (HPLC-ECD), and real-time reverse transcription-polymerase chain reaction (RT-PCR), respectively. Results Mice fed a HFD for eight weeks showed anxiety-like behaviors in association with HFD-induced body weight gain. GORZ potentially blocked HFD-induced anxiety-like behaviors via significant improvement of the primary behavioral parameters in behavioral tests, with a minor reduction in HFD-induced body weight gain. Furthermore, GORZ treatment significantly downregulated HFD-induced upregulation of dopamine levels in the brain's amygdala. Significant reduction of the relative mRNA expression of Tnf-α and Il-1 β was also observed in the amygdala of HFD + GORZ mice, compared to HFD mice. Conclusions Our findings strongly suggest that 0.5% GORZ exerts anxiolytic-like effects, possibly through downregulation of dopamine, and via expression of proinflammatory cytokines Tnf-α and Il-1 β in the case of chronic HFD exposure.

Omeprazole (OM) is one of the most prescribed drugs worldwide for the treatment of hyperacidity and gastric reflux. However, concerns regarding its safety have emerged recently, and the drug is reported to enhance the risk for anxiety and cognitive deficits, particularly in elderly patients. The present study investigated these adverse effects, if any, in adult male rats. Associated changes in brain serotonin (5-hydroxytryptamine; 5-HT) and dopamine metabolism and the expression of 5-HT-1A receptors in the raphe and hippocampus were also determined. The drug was injected i.p. in doses of 10 and 20 mg/kg for 15 days. Both doses of OM decreased motor activity in an open field and impaired learning and memory in the Morris water maze test. Anxiety monitored in an elevated plus maze test was enhanced in rats treated with 20 mg/kg OM only. The levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid and of homovanillic acid, a metabolite of dopamine, determined by HPLC-EC, were decreased in the brain of OM treated rats. The expression of 5-HT-1A receptor, determined by qRT-PCR, was reduced markedly in the hippocampus and moderately in the raphe. Our results provide evidence that OM use can reduce raphe hippocampal serotonin neurotransmission to lead to anxiety/depression and cognitive impairment. There is a need for increased awareness and prescription guidelines for therapeutic use of OM and possibly also other proton pump inhibitors.

Perinatal exposure to bisphenol A (BPA) contributes to neurological disorders in offspring, but the underlying mechanisms are still poorly understood. The abnormal release of neuroactive metabolites in the tryptophan (TRP) and dopamine (DA) pathways is considered to be closely associated with some disorders. Thus, in this study, TRP and DA pathways in adult female mouse offspring were investigated when the pregnant mice were given either vehicle or BPA (2, 10, or 100 μg/kg/d) from day 6 of gestation until weaning. Then, the serum and brain samples of offspring were collected at 3, 6 and 9 months, and 12 neuroactive metabolites in the TRP and DA pathways were detected. The results showed that, in the TRP pathway, TRP levels decreased, whereas kynurenine (KYN) levels and TRP turnover increased in the brain. In the serum, TRP, KYN and 5-hydroxytryptamine (5-HT) levels decreased significantly. For the DA pathway, DA and DA metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA), reduced significantly in the brain and serum. DA turnover decreased dramatically in the brain but enhanced in the serum. The disturbance of these two metabolic pathways might be one of the potential mechanisms of BPA-induced neuropsychiatric disorders.

Juvenile Oncorhynchus mykiss (average weight: 22.3 g) were fed one of five selenomethionine diets (1.09, 8.79, 15.37, 30.79, or 61.58 mg Se/kg diet). After 4 weeks, hepatic catalase activity over 15.37 mg Se/kg diets was significantly decreased, and the glutathione peroxidase activity over 30.79 mg Se/kg diets was elevated compared to the controls. In the brain, the dopamine levels at 61.58 mg Se/kg diet and the serotonin levels over 15.37 mg Se/kg diets were significantly increased, whereas the 3,4-dihydroxyphenylacetic acid, homovanillic acid, and dopamine turnover, and the 5-hydroxyindoleacetic acid and serotonin turnover over 30.79 mg Se/kg diets were decreased. In muscle, the 3-nitrotyrosine level over 15.37 mg Se/kg diets, acetylcholine esterase activity over 30.79 mg Se/kg diets, and histological alterations over 8.79 mg Se/kg diets were increased. Our current results showed that selenomethionine disrupted dopamine and serotonin metabolism in the brain and damaged the neuromuscular system in skeletal muscle.

Perfluoroalkyl substances (PFAS) are contaminants that are applied in a wide range of consumer products, including ski products. The present study investigated the neuro-dopamine (DA) and cellular steroid hormone homeostasis of wild Bank voles (Myodes glareolus) from a skiing area in Norway (Trondheim), in relation to tissue concentrations of PFAS. We found a positive association between brain DA concentrations and the concentration of several PFAS, while there was a negative association between PFAS and dopamine receptor 1 (dr1) mRNA. The ratio between DA and its metabolites (3,4-dihydroxyphenylacetic acid: DOPAC and homovanillic acid: HVA) showed a negative association between DOPAC/DA and several PFAS, suggesting that PFAS altered the metabolism of DA via monoamine oxidase (Mao). This assumption is supported by an observed negative association between mao mRNA and PFAS. Previous studies have shown that DA homeostasis can indirectly regulate cellular estrogen (E2) and testosterone (T) biosynthesis. We found no association between DA and steroid hormone levels, while there was a negative association between some PFAS and T concentrations, suggesting that PFAS might affect T through other mechanisms. The results from the current study indicate that PFAS may alter neuro-DA and steroid hormone homeostasis in Bank voles, with potential consequences on reproduction and general health. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.