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Abstract: The single-nucleotide polymorphism (SNP) rs4680 in the catechol-O-methyltransferase gene ( COMT ) is a missense variant (Val158Met) associated with altered activity of the COMT enzyme and suggested as a predictive feature for developing some chronic pain conditions. However, there are controversial results on its role in fibromyalgia (FM). Here, the SNP Val158Met was analyzed in 294 FM patients (without comorbidities) and 209 healthy controls (without chronic pain). The concurrent impact of Val158Met genotypes and FM comorbid disorders (depression and sleep impairment) on FM risk were tested. In addition, the genotypic distribution of FM patients in relation to pain intensity was evaluated. The G allele (Val) resulted in being more represented in the FM group (57.8%) compared with the control group (48.8%; P = 0.037). Logistic regression highlighted that having the G/G (Val/Val) homozygous genotype was associated with 2 times higher risk of having FM compared with the A/A (Met/Met) carriers ( P = 0.038), whereas depression and sleep impairment increased FM risk by 12 and 8 times, respectively ( P < 0.001). However, considering only the FM patient group, the A/A homozygous genotype was significantly associated with severe pain intensity ( P = 0.007). This study highlighted associations between the SNP Val158Met and both FM and pain intensity, suggesting a link between dopaminergic dysfunction and vulnerability to chronic pain. Further studies should explore this SNP in FM patients in conjunction with COMT enzymatic activity and other symptoms connected with the dopaminergic system such as depression or sleep impairment., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

This narrative review examines the relationship between dopamine-related genetic polymorphisms, personality traits, and athletic success. Advances in sports genetics have identified specific single nucleotide polymorphisms (SNPs) in dopamine-related genes linked to personality traits crucial for athletic performance, such as motivation, cognitive function, and emotional resilience. This review clarifies how genetic variations can influence athletic predisposition through dopaminergic pathways and environmental interactions. Key findings reveal associations between specific SNPs and enhanced performance in various sports. For example, polymorphisms such as COMT Val158Met rs4680 and BDNF Val66Met rs6265 are associated with traits that could benefit performance, such as increased focus, stress resilience and conscientiousness, especially in martial arts. DRD3 rs167771 is associated with higher agreeableness, benefiting teamwork in sports like football. This synthesis underscores the multidimensional role of genetics in shaping athletic ability and advocates for integrating genetic profiling into personalized training to optimize performance and well-being. However, research gaps remain, including the need for standardized training protocols and exploring gene-environment interactions in diverse populations. Future studies should focus on how genetic and epigenetic factors can inform tailored interventions to enhance both physical and psychological aspects of athletic performance. By bridging genetics, personality psychology, and exercise science, this review paves the way for innovative training and performance optimization strategies.

The human brain has evolved unique capabilities compared to other vertebrates. The mechanistic basis of these derived traits remains a fundamental question in biology due to its relevance to the origin of our cognitive abilities and behavioral repertoire, as well as to human-specific aspects of neuropsychiatric and neurodegenerative diseases. Comparisons of the human brain to those of nonhuman primates and other mammals have revealed that differences in the neuromodulatory systems, especially in the dopaminergic system, may govern some of these behavioral and cognitive alterations, including increased vulnerability to certain brain disorders. In this review, we highlight and discuss recent findings of human- and primate-specific alterations of the dopaminergic system, focusing on differences in anatomy, circuitry, and molecular properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The N 6 -methyladenosine (m 6 A) modification of RNA has been reported to remodel gene expression in response to environmental conditions; however, the biological role of m 6 A in social insects remains largely unknown. In this study, we explored the role of m 6 A in the division of labour by worker ants (Solenopsis invicta). We first determined the presence of m 6 A in RNAs from the brains of worker ants and found that m 6 A methylation dynamics differed between foragers and nurses. Depletion of m 6 A methyltransferase or chemical suppression of m 6 A methylation in foragers resulted in a shift to 'nurse-like' behaviours. Specifically, mRNAs of dopamine receptor 1 (Dop1) and dopamine transporter (DAT) were modified by m 6 A, and their expression increased dopamine levels to promote the behavioural transition from foragers to nurses. The abundance of Dop1 and DAT mRNAs and their stability were reduced by the inhibition of m 6 A modification caused by the silencing of Mettl3, suggesting that m 6 A modification in worker ants modulates dopamine synthesis, which regulates labour division. Collectively, our results provide the first example of the epitranscriptomic regulation of labour division in social insects and implicate m 6 A regulatory mechanism as a potential novel target for controlling red imported fire ants., (© 2024 John Wiley & Sons Ltd.)

Background: Gastric cancer (GC) is the fifth most common cancer worldwide and the most commonly diagnosed cancer in Iran. The nervous system provides proximity to tumor cells by releasing neurotransmitters such as dopamine and presenting them to the corresponding receptor-bearing tumors. While nerve fibers infiltrate the tumor microenvironment, little is known about the expression levels of dopamine (DA), dopamine receptors (DRs), and catechol-O-methyltransferase (COMT) in GC patients., Methods: DRs and COMT expression were analyzed in 45 peripheral blood mononuclear cells (PBMCs) and 20 paired tumor and adjacent tissue of GC patients by quantitative polymerase chain reaction. DA was measured in plasma specimens using enzyme-linked immunosorbent assay. Protein-protein interaction analysis was carried out to identify GC-related hub genes., Results: Increased expression of DRD1-DRD3 was found in tumor specimens compared with adjacent non-cancerous specimens (P < 0.05). A positive correlation was found between DRD1 and DRD3 expression (P = 0.009); DRD2 and DRD3 expression (P = 0.04). Plasma levels of dopamine were significantly lower in patients (1298 pg/ml) than in controls (4651 pg/ml). DRD1-DRD4 and COMT were up-regulated in PBMCs of patients compared with controls (P < 0.0001). Bioinformatic analyses showed 30 hub genes associated with Protein kinase A and extracellular signal-regulated kinase signaling pathways., Conclusions: The findings indicated dysregulation of DRs and COMT mRNA expression in GC and suggest that the brain- gastrointestinal axis may mediate gastric cancer development. Network analysis revealed that combination treatments could be considered for optimizing and improving the precision treatment of GC., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: The reasons behind the cardinal symptoms of communication deficits and repetitive, stereotyped behaviors that characterize autism spectrum disorder (ASD) remain unknown. The dopamine (DA) system, which regulates motor activity, goal-directed behaviors, and reward function, is believed to play a crucial role in ASD, although the exact mechanism is still unclear. Investigations have shown an association of the dopamine receptor D4 (DRD4) with various neurobehavioral disorders., Methods: We analyzed the association between ASD and four DRD4 genetic polymorphisms, 5' flanking 120-bp duplication (rs4646984), rs1800955 in the promoter, exon 1 12 bp duplication (rs4646983), and exon 3 48 bp repeats. We also examined plasma DA and its metabolite levels, DRD4 mRNA expression, and correlations of the studied polymorphisms with these parameters by case-control comparative analyses. The expression of DA transporter (DAT), which is important in regulating the circulating DA level, was also evaluated., Results: A significantly higher occurrence of rs1800955 "T/TT" was observed in the probands. ASD traits were affected by rs1800955 "T" and the higher repeat alleles of the exon 3 48 bp repeats, rs4646983 and rs4646984. ASD probands exhibited lower DA and norepinephrine levels together with higher homovanillic acid levels than the control subjects. DAT and DRD4 mRNA expression were down-regulated in the probands, especially in the presence of DAT rs3836790 "6R" and rs27072 "CC" and DRD4 rs4646984 higher repeat allele and rs1800955 "T"., Conclusion: This pioneering investigation revealed a positive correlation between genetic variants, hypodopaminergic state, and impairment in socio-emotional and communication reciprocity in Indian subjects with ASD, warranting further in-depth analysis., (© 2023. Children's Hospital, Zhejiang University School of Medicine.)

Child genotype is an important biologically based individual difference conferring differential sensitivity to the effect of parental behavior. This study explored dopaminergic polygenic composite × parental behavior interactions in relation to young children's executive function. Participants were 135 36-month-old children and their mothers drawn from a prospective cohort followed longitudinally from pregnancy. A polygenic composite was created based on the number of COMT, DAT1 , DRD2 , and DRD4 alleles associated with increased reward sensitivity children carried. Maternal negative reactivity and responsiveness were coded during a series of structured mother-child interactions. Executive function was operationalized as self-control and working memory/inhibitory control. Path analysis supported a polygenic composite by negative reactivity interaction for self-control. The nature of the interaction was one of diathesis-stress, such that higher negative reactivity was associated with poorer self-control for children with higher polygenic composite scores. This result suggests that children with a higher number of alleles may be more vulnerable to the negative effect of negative reactivity. Negative reactivity may increase the risk for developing behavior problems in this population via an association with poorer self-control. Due to the small sample size, these initial findings should be treated with caution until they are replicated in a larger independent sample.

Sleep disruptions are quite common in psychological disorders, but the underlying mechanism remains obscure. Wolfram syndrome 1 (WS1) is an autosomal recessive disease mainly characterized by diabetes insipidus/mellitus, neurodegeneration and psychological disorders. It is caused by loss-of function mutations of the WOLFRAM SYNDROME 1 (WFS1) gene, which encodes an endoplasmic reticulum (ER)-resident transmembrane protein. Heterozygous mutation carriers do not develop WS1 but exhibit 26-fold higher risk of having psychological disorders. Since WS1 patients display sleep abnormalities, we aimed to explore the role of WFS1 in sleep regulation so as to help elucidate the cause of sleep disruptions in psychological disorders. We found in Drosophila that knocking down wfs1 in all neurons and wfs1 mutation lead to reduced sleep and dampened circadian rhythm. These phenotypes are mainly caused by lack of wfs1 in dopamine 2-like receptor (Dop2R) neurons which act to promote wake. Consistently, the influence of wfs1 on sleep is blocked or partially rescued by inhibiting or knocking down the rate-limiting enzyme of dopamine synthesis, suggesting that wfs1 modulates sleep via dopaminergic signaling. Knocking down wfs1 alters the excitability of Dop2R neurons, while genetic interactions reveal that lack of wfs1 reduces sleep via perturbation of ER-mediated calcium homeostasis. Taken together, we propose a role for wfs1 in modulating the activities of Dop2R neurons by impinging on intracellular calcium homeostasis, and this in turn influences sleep. These findings provide a potential mechanistic insight for pathogenesis of diseases associated with WFS1 mutations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Appropriate nutritional intake is essential for organismal survival. In holometabolous insects such as Drosophila melanogaster, the quality and quantity of food ingested as larvae determines adult size and fecundity. Here we have identified a subset of dopaminergic neurons (THD') that maintain the larval motivation to feed. Dopamine release from these neurons requires the ER Ca2+ sensor STIM. Larvae with loss of STIM stop feeding and growing, whereas expression of STIM in THD' neurons rescues feeding, growth and viability of STIM null mutants to a significant extent. Moreover STIM is essential for maintaining excitability and release of dopamine from THD' neurons. Optogenetic stimulation of THD' neurons activated neuropeptidergic cells, including median neuro secretory cells that secrete insulin-like peptides. Loss of STIM in THD' cells alters the developmental profile of specific insulin-like peptides including ilp3. Loss of ilp3 partially rescues STIM null mutants and inappropriate expression of ilp3 in larvae affects development and growth. In summary we have identified a novel STIM-dependent function of dopamine neurons that modulates developmental changes in larval feeding behaviour and growth., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kasturacharya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study examined neuro-protective potentials of N-acetyl-cysteine (NAC) and Zinc on expression levels of Dopamine and Glutamate in the Cerebrum, Hypothalami and Pituitary Glands in Di(2-ethylhexyl)-phthalate (DEHP)-induced neurotoxicity in rats. Thirty-six adult male Wistar rats were randomly divided into 6 groups (n = 6). Group 1 was control. Groups 2-6 received oral administrations of 100 mg/kg NAC, 0.5 mg/kg Zinc, 750 mg/kg DEHP, DEHP + NAC doses and DEHP + Zinc doses respectively for 21 days. Brain histology (Heamatoxyline and Eosine technique), histochemical and enzyme-linked-immunosorbent assays of Dopamine and Glutamate in homogenates of Cerebrum, Hypothalami and Pituitary Glands were evaluated. Data were statistically analyzed using One-way-ANOVA with Tukey-post-hoc test at p  ≤ 0.05. Histo-pathological evaluations of Cerebrum, Hypothalami and Pituitary Glands showed gross histo-alterations and neurodegenerative changes (Group 4), mild histo- and neuro-degenerative changes (Groups 5 and 6) and normal histology (Group 1). Histochemical analyses showed higher Dopamine levels in Hypothalami (Group 5) and Pituitary Glands (Groups 5 and 6), compared with Group 4. Furthermore, results showed lower Glutamate levels in Cerebrum, Hypothalami and Pituitary Glands of Groups 5 and 6, compared with Group 4. Overall, NAC and Zinc conferred neuro-protection and histo-protection against DEHP-induced neuro-toxicity, neuro-histopathology, decreased Dopamine levels and increased Glutamate levels.

Background: Molecular networks associated with dopaminergic (DA) neurogenesis remain undefined within mammalian models. To address this issue, the transient zebrafish model lmx1al: EGFP was generated, which expresses GFP in the DA precursor cells as well as in the DA neurons of the ventral diencephalon (VD). We found that the novel pseudogene gba3 has not been well studied in zebrafish neurogenesis., Objective: Crucial networks associated with gba3 transcripts were investigated because the biological functions of these networks have not been reported in DA neurogenesis in zebrafish., Methods: RNA isolation and sequencing were employed with GFP-expressing cells from 20-, 22-, and 24 h post-fertilization (hpf), while subsequent transcriptomic analysis generated differentially expressed genes with DA neurogenesis (DEG-DA) list. Hierarchical cluster analysis provided absolute guidance for the collection of gba3, an essential transcript that is strictly spatiotemporally expressed during DA neurogenesis, which was proven with whole-mount in situ hybridization (WISH) and knockdown and rescue of the gba3 transcripts in zebrafish embryos., Results: The gba3 transcripts were restricted to the midbrain at 24 hpf and the midbrain and pectoral fins at 30 hpf in zebrafish embryos. Functional studies with knockdown of gba3 found a diminished state in the midbrain and midbrain-hindbrain boundary (MHB) and an underdeveloped condition in the anteroposterior and dorsolateral axis relative to the wild type (WT) at 24 hpf. However, it was recovered after forced expression of gba3 transcripts at 24 hpf. Molecular markers for the DA precursors and mature neurons lmx1al, nurr1, th, and pitx3 were analyzed in the gba3 MOs. The levels of transcripts lmx1al, nurr1, and th were significantly reduced in the midbrain ventral diencephalon (VD) and hindbrain of gba3 morphants compared to the WT at 24 hpf, while expression patterns of pitx3 transcripts showed no differences in the identical regions between gba3 MOs and the controls., Conclusions: We discuss transcriptional networks in which transcripts of gba3 plausibly govern the specification of dopaminergic neurogenesis in zebrafish embryos., (© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Background: Research on the hypodopaminergic hypothesis of addictions showed that hypodopaminergic activity in males predicted the number of drugs used and is associated with drug-seeking behavior. Variant alleles may cause hypodopaminergic functioning as a result of the reduced density of dopamine receptors, decreased response to dopamine, increased dopamine clearance or metabolism in the reward system. The catechol-O-methyltransferase ( COMT ) is involved in the metabolism of dopamine. Personality traits may mediate the genetic predisposition to substance use disorders additively by various motivations associated with reward-seeking and regulating negative emotions, and also relate to self-control and environment selection., The Aim of the Study: The aim of this study was to investigate the association of the rs4680 polymorphism of COMT with personality dimensions and anxiety in patients addicted to stimulants other than cocaine (F15 according to WHO ICD-10 nomenclature) in the case of examined patients amphetamine., Methods: The study was conducted among patients addicted to stimulants other than cocaine (amphetamine). The study group included 247 patients addicted to stimulants (amphetamine) and the control group comprised 280 healthy male volunteers. The real-time PCR method was used to carry out genetic tests; personality dimensions were assessed using the standardized NEO-FFI and state and trait anxiety were assessed with STAI. All analyses were performed using STATISTICA 13., Results: The results of the 2 × 3 factorial ANOVA showed a statistically significant effect of the combined factor COMT rs4680 genotype on the group of patients diagnosed with other stimulants dependence/control (F 2,252 = 3.11, p = 0.0465, η 2 = 0.024). Additionally, we observed that the results of the 2 × 3 factorial ANOVA showed a statistically significant influence of the combined factor COMT rs4680 on the genotype in the group of patients diagnosis with other stimulants dependence/control (F 2,252 = 6.16, p = 0.0024, η 2 = 0.047)., Conclusions: In our research, the polymorphism G/G COMT rs4680 genotype was associated with higher scores of STAI traits and STAI states in the patients dependent on amphetamine. In the control group we observed no such interactions.

The metronome-like circadian regulation of sleep timing must still adapt to an uncertain environment. Recent studies in Drosophila indicate that neuromodulation not only plays a key role in clock neuron synchronization but also affects interactions between the clock network and brain sleep centers. We show here that the targets of neuromodulators, G Protein Coupled Receptors (GPCRs), are highly enriched in the fly brain circadian clock network. Single-cell sequencing indicates that they are not only enriched but also differentially expressed and contribute to clock neuron identity. We generated a comprehensive guide library to mutagenize individual GPCRs in specific neurons and verified the strategy by introducing a targeted sequencing approach. Combined with a behavioral screen, the mutagenesis strategy revealed a role of dopamine in sleep regulation by identifying two dopamine receptors and a clock neuron subpopulation that gate the timing of sleep.

Background: Up to 64% of patients diagnosed with posttraumatic stress disorder (PTSD) experience psychosis, likely attributable to aberrant dopamine neuron activity. We have previously demonstrated that positive allosteric modulators of α5-GABAARs can selectively decrease hippocampal activity and reverse psychosis-like physiological and behavioral alterations in a rodent model used to study schizophrenia; however, whether this approach translates to a PTSD model remains to be elucidated., Methods: We utilized a 2-day inescapable foot shock (IS) procedure to induce stress-related pathophysiology in male Sprague-Dawley rats. We evaluated the effects of intra-ventral hippocampus (vHipp) administration GL-II-73, an α5-GABAAR, or viral overexpression of the α5 subunit, using in vivo electrophysiology and behavioral measures in control and IS-treated rats., Results: IS significantly increased ventral tegmental area dopamine neuron population activity, or the number of dopamine neurons firing spontaneously (n = 6; P = .016), consistent with observation in multiple rodent models used to study psychosis. IS also induced deficits in sensorimotor gating, as measured by reduced prepulse inhibition of startle (n = 12; P = .039). Interestingly, intra-vHipp administration of GL-II-73 completely reversed IS-induced increases in dopamine neuron population activity (n = 6; P = .024) and deficits in prepulse inhibition (n = 8; P = .025), whereas viral overexpression of the α5 subunit in the vHipp was not effective., Conclusions: Our results demonstrate that pharmacological intervention augmenting α5-GABAAR function, but not α5 overexpression in itself, can reverse stress-induced deficits related to PTSD in a rodent model, providing a potential site of therapeutic intervention to treat comorbid psychosis in PTSD., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

ADHD is a major burden in adulthood, where co-morbid conditions such as depression, substance use disorder and obesity often dominate the clinical picture. ADHD has substantial shared heritability with other mental disorders, contributing to comorbidity. However, environmental risk factors exist but their interaction with genetic makeup, especially in relation to comorbid disorders, remains elusive. This review for the first time summarizes present knowledge on gene x environment (GxE) interactions regarding the dopamine system. Hitherto, mainly candidate (GxE) studies were performed, focusing on the genes DRD4, DAT1 and MAOA. Some evidence suggest that the variable number tandem repeats in DRD4 and MAOA may mediate GxE interactions in ADHD generally, and comorbid conditions specifically. Nevertheless, even for these genes, common variants are bound to suggest risk only in the context of gender and specific environments. For other polymorphisms, evidence is contradictory and less convincing. Particularly lacking are longitudinal studies testing the interaction of well-defined environmental factors with polygenic risk scores reflecting the dopamine system in its entirety., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The detection of chemicals using natural allosteric transcription factors is a powerful strategy for point-of-use molecular sensing, particularly using fieldable cell-free gene expression (CFE) systems. However, the reliance of detection schemes on characterized protein-based sensors limits the number of measurable analytes. One alternative solution to this issue is to develop new sensors by generating RNA aptamers against the target analyte and then incorporating them directly into a riboswitch scaffold for ligand-inducible genetic control of a reporter protein. However, this strategy has not generated more than a handful of successful portable cell-free molecular sensors. To address this gap, here we convert dopamine-binding aptamers into functional dopamine-sensing riboswitches that regulate gene expression in a freeze-dried CFE reaction. We then develop an assay for direct detection and semi-quantification of dopamine in human urine. We anticipate that this work will be broadly applicable for converting many in vitro -generated RNA aptamers into fieldable molecular diagnostics.

Omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are critical for cell membrane structure and function. Human beings have a limited ability to synthesise docosahexaenoic acid (DHA), the main n-3 LCPUFA required for neurological development. Inadequate levels of n-3 LCPUFA can affect the dopaminergic system in the brain and, when combined with genetic and other factors, increase the risk of developing aggression, inattention and impulse-control disorders. In this study, male prisoners were administered questionnaires assessing aggressive behaviour and executive functions. Participants also produced blood sampling for the measurement of the Omega-3 Index and the genotyping of dopaminergic genetic variants. Significant associations were found between functional genetic polymorphism in DBH rs1611115 and verbal aggression and between DRD2 rs4274224 and executive functions. However, the Omega-3 Index was not significantly associated with the tested dopaminergic polymorphisms. Although previous interactions between specific genotypes and n-3 LCPUFA were previously reported, they remain limited and poorly understood. We did not find any association between n-3 LCPUFA and dopaminergic polymorphisms in adult male prisoners; however, we confirmed the importance of genetic predisposition for dopaminergic genes ( DBH and DRD2 ) in aggressive behaviour, memory dysfunction and attention-deficit disorder.

SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR 1a ) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR 1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein- and β-arrestin (βarr)-dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mitigating side effects. Here, we describe the discovery of a brain-penetrant small molecule, N8279 (NCATS-SM8864), that biases GHSR 1a conformations toward Gα q activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR 1a -related brain disorders involving the pathological dysregulation of dopamine.

Psychostimulants have a paradoxical calming effect in the treatment of attention deficit hyperactivity disorder (ADHD), but their mechanism of action is unclear. Studies using dopamine (DA) transporter (DAT) knockout (KO) mice have suggested that the paradoxical calming effect of psychostimulants might occur through actions on serotonin (5-HT) neurotransmission. However, newer non-stimulant drugs, such as atomoxetine and guanfacine, suggest that targeting the norepinephrine (NE) system in the prefrontal cortex (PFC) might explain this paradoxical calming effect. Thus, we sought to clarify the mechanism of this paradoxical action of psychostimulants. Our ex vivo efflux experiments reveal that the NE transporter (NET) blocker desipramine elevates both norepinephrine (NE) and dopamine (DA), but not 5-HT levels, in PFC tissue slices from wild-type (WT) and DAT-KO, but not NET-KO mice. However, the 5-HT transporter (SERT) inhibitor fluoxetine elevates only 5-HT in all three genotypes. Systemic administration of desipramine or fluoxetine inhibits hyperactivity in DAT-KO mice, whereas local PFC infusion of desipramine alone produced this same effect. In contrast, pharmacological NE depletion and DA elevation using nepicastat also inhibits hyperactivity in DAT-KO mice. Together, these data suggest elevation of PFC DA and not NE or 5-HT, as a convergent mechanism for the paradoxical effects of psychostimulants observed in ADHD therapy., (© 2022. The Author(s).)

Purpose: Elevated urinary 3-methoxytyramine (3MT) level at diagnosis was recently put forward as independent risk factor for poor prognosis in neuroblastoma. Here, we investigated the biologic basis underlying the putative association between elevated 3MT levels and poor prognosis., Methods: Urinary 3MT levels and prognosis were investigated in both retrospective Italian (N = 90) and prospective Dutch (N = 95) cohorts. From the Dutch Cancer Oncology Group cohort (N = 122), patients with available urinary 3MT and gene expression data (n = 90) were used to generate a 3MT gene signature. The 3MT gene signature score was then used to predict survival outcome in the Children's Oncology Group (N = 247) and German Pediatric Oncology Group (N = 498) cohorts and compared with other known gene signatures. Immunohistochemistry of MYCN and dopamine β-hydroxylase proteins was performed on primary tumors., Results: Elevated urinary 3MT levels were associated with poor prognosis in a retrospective cohort and a prospective cohort. Moreover, elevated urinary 3MT levels were associated with eight differentially expressed genes, providing a 3MT gene signature that successfully predicted poor clinical outcome. Even among low-risk patients, high 3MT signature score was associated with poor 5-year overall survival (72% v 99% among low-risk patients with a low 3MT signature score), and the 3MT signature score was correlated with MYC activity in the tumor (R = 82%, P < .0001). Finally, a strong MYCN and weak dopamine β-hydroxylase staining of tumors derived from patients with elevated urinary 3MT levels was observed, linking MYC activity in the tumor to both catecholamine biosynthesis and elevated urinary 3MT levels., Conclusion: Elevated urinary 3MT is a promising biomarker for poor prognosis and reflects increased MYC activity in the tumor. Therefore, urinary 3MT levels should be measured at diagnosis and may assist in assessing risk., Competing Interests: Jan KosterConsulting or Advisory Role: Frame TherapeuticsNo other potential conflicts of interest were reported.

Parkinson's Disease (PD) is a widespread severe neurodegenerative disease that is characterized by pronounced deficiency of the dopaminergic system and disruption of the function of other neuromodulator systems. Although heritable genetic factors contribute significantly to PD pathogenesis, only a small percentage of sporadic cases of PD can be explained using known genetic risk factors. Due to that, it could be inferred that changes in gene expression could be important for explaining a significant percentage of PD cases. One of the ways to investigate such changes, while minimizing the effect of genetic factors on experiment, are the study of PD discordant monozygotic twins. In the course of the analysis of transcriptome data obtained from IPSC and NPCs, 20 and 1906 differentially expressed genes were identified respectively. We have observed an overexpression of TNF in NPC cultures, derived from twin with PD. Through investigation of gene interactions and gene involvement in biological processes, we have arrived to a hypothesis that TNF could play a crucial role in PD-related changes occurring in NPC derived from twins with PD, and identified INHBA , WNT7A and DKK1 as possible downstream effectors of TNF.

Methamphetamine (METH) is a highly addictive and powerful central nervous system psychostimulant with no FDA-approved pharmacotherapy. Parkin is a neuroprotective protein and its loss of function contributes to Parkinson's disease. This study used 3-month-old homozygous parkin knockout (PKO) rats to determine whether loss of parkin protein potentiates neurotoxicity of chronic METH to the nigrostriatal dopamine pathway. PKO rats were chronically treated with 10 mg/kg METH for 10 consecutive days and assessed for neurotoxicity markers in the striatum on the 5th and 10th day of withdrawal from METH. The PKO rats showed higher METH-induced hyperthermia; however, they did not display augmented deficits in dopaminergic and serotonergic neurotoxicity markers, astrocyte activation or decreased mitochondrial enzyme levels as compared to wild-type (WT) rats. Interestingly, saline-treated PKO rats had lower levels of dopamine (DA) as well as mitochondrial complex I and II levels while having increased basal levels of glial fibrillary acidic protein (GFAP), a marker of gliosis. These results indicate PKO display a certain resistance to METH neurotoxicity, possibly mediated by lowered DA levels and downregulated mitochondria., (Copyright © 2021. Published by Elsevier Inc.)

A consistent preclinical finding is that exposure to alcohol during adolescence produces a persistent hyperdopaminergic state during adulthood. The current experiments determine that effects of Adolescent Intermittent Ethanol (AIE) on the adult neurochemical response to EtOH administered directly into the mesolimbic dopamine system, alterations in dendritic spine and gene expression within the nucleus accumbens shell (AcbSh), and if treatment with the HDACII inhibitor TSA could normalize the consequences of AIE. Rats were exposed to the AIE (4 g/kg ig; 3 days a week) or water (CON) during adolescence, and all testing occurred during adulthood. CON and AIE rats were microinjected with EtOH directly into the posterior VTA and dopamine and glutamate levels were recorded in the AcbSh. Separate groups of AIE and CON rats were sacrificed during adulthood and Taqman arrays and dendritic spine morphology assessments were performed. The data indicated that exposure to AIE resulted in a significant leftward and upward shift in the dose-response curve for an increase in dopamine in the AcbSh following EtOH microinjection into the posterior VTA. Taqman array indicated that AIE exposure affected the expression of target genes ( Chrna7 , Impact , Chrna5 ). The data indicated no alterations in dendritic spine morphology in the AcbSh or any alteration in AIE effects by TSA administration. Binge-like EtOH exposure during adolescence enhances the response to acute ethanol challenge in adulthood, demonstrating that AIE produces a hyperdopaminergic mesolimbic system in both male and female Wistar rats. The neuroadaptations induced by AIE in the AcbSh could be part of the biological basis of the observed negative consequences of adolescent binge-like alcohol exposure on adult drug self-administration behaviors.

Symptoms of neurological diseases emerge through the dysfunction of neural circuits whose diffuse and intertwined architectures pose serious challenges for delivering therapies. Deep brain stimulation (DBS) improves Parkinson’s disease symptoms acutely but does not differentiate between neuronal circuits, and its effects decay rapidly if stimulation is discontinued. Recent findings suggest that optogenetic manipulation of distinct neuronal subpopulations in the external globus pallidus (GPe) provides long-lasting therapeutic effects in dopamine-depleted (DD) mice. We used synaptic differences to excite parvalbumin-expressing GPe neurons and inhibit lim-homeobox-6–expressing GPe neurons simultaneously using brief bursts of electrical stimulation. In DD mice, circuit-inspired DBS provided long-lasting therapeutic benefits that far exceeded those induced by conventional DBS, extending several hours after stimulation. These results establish the feasibility of transforming knowledge of circuit architecture into translatable therapeutic approaches.

The dopaminergic signaling pathway is involved in many physiological functions in vertebrates, but poorly documented in protostome species except arthropods. We functionally characterized a novel dopamine receptor in the Pacific oyster (Crassostrea gigas), activated by dopamine and tyramine with different efficacy and potency orders. This receptor - Cragi-DOP2R - belongs to the D 1 -like family of receptors and corresponds to the first representative of the Dop2/invertebrate-type dopamine receptor (Dop2/INDR) group ever identified in Lophotrochozoa. Cragi-DOP2R transcripts were expressed in various adult tissues, with higher expression levels in the visceral ganglia and the gills. Following an experiment under acute osmotic conditions, Cragi-DOP2R transcripts significantly increased in the visceral ganglia and decreased in the gills, suggesting a role of dopamine signaling in the mediation of osmotic stress. Furthermore, a role of the Cragi-DOP2R signaling pathway in female gametogenesis and in early oyster development was strongly suggested by the significantly higher levels of receptor transcripts in mature female gonads and in the early embryonic stages., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aggregation of alpha-synuclein (α-syn) into Lewy bodies and Lewy neurites is a pathological hallmark in the Parkinson´s disease (PD) brain. The formation of α-syn oligomers is believed to be an early pathogenic event and the A30P mutation in the gene encoding α-syn, causing familial PD, has been shown to cause an accelerated oligomerization. Due to the problem of preserving antigen conformation on tissue surfaces, α-syn oligomers are difficult to detect ex vivo using conventional immunohistochemistry with oligomer-selective antibodies. Herein, we have instead employed the previously reported α-syn oligomer proximity ligation assay (ASO-PLA), along with a wide variety of biochemical assays, to discern the pathological progression of α-syn oligomers and their impact on the dopaminergic system in male and female (Thy-1)-h[A30P]α-syn transgenic (A30P-tg) mice. Our results reveal a previously undetected abundance of α-syn oligomers in midbrain of young mice, whereas phosphorylated (pS129) and proteinase k-resistant α-syn species were observed to a larger extent in aged mice. Although we did not detect loss of dopaminergic neurons in A30P-tg mice, a dysregulation in the monoaminergic system was recorded in older mice. Taken together, ASO-PLA should be a useful method for the detection of early changes in α-syn aggregation on brain tissue, from experimental mouse models in addition to post mortem PD cases., (© 2021 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

A report of a family of Darier's disease with mood disorders drew attention when the causative gene was identified as ATP2A2 (or SERCA2), which encodes a Ca2+ pump on the endoplasmic reticulum (ER) membrane and is important for intracellular Ca2+ signaling. Recently, it was found that loss-of-function mutations of ATP2A2 confer a risk of neuropsychiatric disorders including depression, bipolar disorder and schizophrenia. In addition, a genome-wide association study found an association between ATP2A2 and schizophrenia. However, the mechanism of how ATP2A2 contributes to vulnerability to these mental disorders is unknown. Here, we analyzed Atp2a2 heterozygous brain-specific conditional knockout (hetero cKO) mice. The ER membranes prepared from the hetero cKO mouse brain showed decreased Ca2+ uptake activity. In Atp2a2 heterozygous neurons, decays of cytosolic Ca2+ level were slower than control neurons after depolarization. The hetero cKO mice showed altered behavioral responses to novel environments and impairments in fear memory, suggestive of enhanced dopamine signaling. In vivo dialysis demonstrated that extracellular dopamine levels in the NAc were indeed higher in the hetero cKO mice. These results altogether indicate that the haploinsufficiency of Atp2a2 in the brain causes prolonged cytosolic Ca2+ transients, which possibly results in enhanced dopamine signaling, a common feature of mood disorders and schizophrenia. These findings elucidate how ATP2A2 mutations causing a dermatological disease may exert their pleiotropic effects on the brain and confer a risk for mental disorders., (© The Author(s) 2021. Published by Oxford University Press.)

Parkinson's disease is a common neurodegenerative disease. The differential expression of alpha-synuclein within Lewy Bodies leads to this disease. Some missense mutations of alpha-synuclein may resultant in functional aberrations. In this study, our objective is to verify the functional adaptation due to early and late-onset mutation which can trigger or control the rate of alpha-synuclein aggregation. In this regard, we have proposed a computational model to study the difference and similarities among the Wild type alpha-synuclein and mutants i.e., A30P, A53T, G51D, E46K, and H50Q. Evolutionary sequence space analysis is also performed in this experiment. Subsequently, a comparative study has been performed between structural information and sequence space outcomes. The study shows the structural variability among the selected subtypes. This information assists inter pathway modeling due to mutational aberrations. Based on the structural variability, we have identified the protein-protein interaction partners for each protein that helps to increase the robustness of the inter-pathway connectivity. Finally, few pathways have been identified from 12 semantic networks based on their association with mitochondrial dysfunction and dopaminergic pathways., (© 2021. The Author(s).)

Chemical neurotransmission typically occurs through synapses. Previous ultrastructural examinations of monoamine neuron axon terminals often failed to identify a pre- and postsynaptic coupling, leading to the concept of "volume" transmission. Whether this results from intrinsic properties of these neurons remains undefined. We find that dopaminergic neurons in vitro establish a distinctive axonal arbor compared to glutamatergic or GABAergic neurons in both size and propensity of terminals to avoid direct contact with target neurons. While most dopaminergic varicosities are active and contain exocytosis proteins like synaptotagmin 1, only ~20% of these are synaptic. The active zone protein bassoon was found to be enriched in dopaminergic terminals that are in proximity to a target cell. Finally, we found that the proteins neurexin-1α SS4- and neuroligin-1 A+B play a critical role in the formation of synapses by dopamine (DA) neurons. Our findings suggest that DA neurons are endowed with a distinctive developmental connectivity program., (© 2021 Federation of American Societies for Experimental Biology.)

Dopamine is a major neuromodulator that is acutely involved in various cognitive processes, reward-motivated behaviors, and impulsivity. Abnormality in dopaminergic neurotransmission is implicated in the pathophysiology of alcohol use disorder (AUD). The present study examined the genetic influence of dopamine system on problematic drinking, impulsivity, and aggressiveness in a Korean male population with AUD. Five single nucleotide polymorphisms (SNPs) (rs4532 in DRD1, rs2283265 in DRD2, rs6280 in DRD3, rs1800497 in ANKK1, and rs4680 in COMT) and a variable number of tandem repeats (VNTRs) in DAT1 in 295 male patients with AUD were genotyped. For AUD-related clinical characteristics, the Alcohol Use Disorders Identification Test and the Obsessive-Compulsive Drinking Scale (OCDS) were used to assess the severity of hazardous drinking and craving symptoms, respectively. Participants also completed the UPPS-P Impulsive Behavior Scale (UPPS-P) and Buss-Perry Aggression Questionnaire (BPAQ). Analyses were performed using R package SNPassoc; statistical significance was set as p < 0.0083 after Bonferroni correction. A significant association was detected between DRD3 SNP rs6280 and OCDS scores. In regard to impulsivity and aggressiveness, rs4532 of DRD1 was significantly associated with UPPS-P score. Also, rs4532 demonstrated a nominally significant association with BPAQ score, although it did not reach statistical significance after correction for multiple comparisons. Results of this study support the idea that genetic variations in the dopamine system may contribute to alcohol cravings and impulsivity in patients with AUD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by altered social interaction and communication, and repetitive, restricted, inflexible behaviors. Approximately 1.5-2% of the general population meet the diagnostic criteria for ASD and several brain regions including the cortex, amygdala, cerebellum and basal ganglia have been implicated in ASD pathophysiology. The midbrain dopamine system is an important modulator of cellular and synaptic function in multiple ASD-implicated brain regions via anatomically and functionally distinct dopaminergic projections. The dopamine hypothesis of ASD postulates that dysregulation of dopaminergic projection pathways could contribute to the behavioral manifestations of ASD, including altered reward value of social stimuli, changes in sensorimotor processing, and motor stereotypies. In this review, we examine the support for the idea that cell-autonomous changes in dopaminergic function are a core component of ASD pathophysiology. We discuss the human literature supporting the involvement of altered dopamine signaling in ASD including genetic, brain imaging and pharmacologic studies. We then focus on genetic mouse models of syndromic neurodevelopmental disorders in which single gene mutations lead to increased risk for ASD. We highlight studies that have directly examined dopamine neuron number, morphology, physiology, or output in these models. Overall, we find considerable support for the idea that the dopamine system may be dysregulated in syndromic ASDs; however, there does not appear to be a consistent signature and some models show increased dopaminergic function, while others have deficient dopamine signaling. We conclude that dopamine dysregulation is common in syndromic forms of ASD but that the specific changes may be unique to each genetic disorder and may not account for the full spectrum of ASD-related manifestations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kosillo and Bateup.)

Betalains are the nitrogenous pigments that replace anthocyanins in the plant order Caryophyllales. Here, we describe unconventional decarboxylated betalains in quinoa (Chenopodium quinoa) grains. Decarboxylated betalains are derived from a previously unconsidered activity of the 4,5-DOPA-extradiol-dioxygenase enzyme (DODA), which has been identified as the key enzymatic step in the established biosynthetic pathway of betalains. Here, dopamine is fully characterized as an alternative substrate of the DODA enzyme able to yield an intermediate and structural unit of plant pigments: 6-decarboxy-betalamic acid, which is proposed and described. To characterize this activity, quinoa grains of different colors were analyzed in depth by chromatography, time-of-flight mass spectrometry, and reactions were performed in enzymatic assays and bioreactors. The enzymatic-chemical scheme proposed leads to an uncharacterized family of 6-decarboxylated betalains produced by a hitherto unknown enzymatic activity. All intermediate compounds as well as the final products of the dopamine-based biosynthetic pathway of pigments have been unambiguously determined and the reactions have been characterized from the enzymatic and functional perspectives. Results evidence a palette of molecules in quinoa grains of physiological relevance and which explain minor betalains described in plants of the Caryophyllales order. An entire family of betalains is anticipated., (© American Society of Plant Biologists 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

TOR1A-associated dystonia, otherwise known as DYT1 dystonia, is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a +/ΔE knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca 2+ signaling, D2 dopamine autoreceptor function and GABA B receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disease with multifactorial aetiology that influences the quality of life. However, the association of possible factors with PD is need to be investigated in Indian population, hence we aimed to determine the association of lifestyle, environmental factors, biochemical parameters and genetic insights of MT-ND1 gene in PD patients. Using a standardised questionnaire, PD patients and control group of about 146 subjects were interviewed on demographic, lifestyle and environmental factors. The subjects includes n = 73 Parkinson's patients [juvenile (n = 4); early-onset (n = 8); late-onset (n = 61)] with equal number of age and sex matched controls, further we had obtained institutional ethical clearance and informed consent from study participants. Biomarker investigations and MT-ND1 alterations were investigated by appropriate molecular techniques. During the average follow-up years of 5.1, significant association was observed among smoking, alcohol, caffeinated drinks, surgery, pesticide exposure at p < 0.05 in varied PD age groups. Occupational exposure to agriculture and industry showed an increased risk among the late-onset group. The biomarkers uric acid (UA) and dopamine (DA) were significant at p < 0.05 in all the three PD age groups. The MT-ND1 alteration with A3843 G variant was significant at p < 0.05 for AG allele in all the three PD groups but the highest prevalence was observed in late-onset group. From our study, smoking, alcohol, caffeinated drinks, occupational influence of agriculture and industry and pesticide exposure had more association with PD occurrence. Hence, to the best of our knowledge, this is the first kind of study in Tamil Nadu population, India to validate the various factors with PD. Therefore we suggest that further research is mandatory to detect other possible associations among PD, using comprehensive larger sample size., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Gene-environment interaction (GxE) determines the vulnerability of an individual to a spectrum of stress-related neuropsychiatric disorders. Increased impulsivity, excessive aggression, and other behavioural characteristics are associated with variants within the tryptophan hydroxylase-2 (Tph2) gene, a key enzyme in brain serotonin synthesis. This phenotype is recapitulated in naïve mice with complete, but not with partial Tph2 inactivation. Tph2 haploinsufficiency in animals reflects allelic variation of Tph2 facilitating the elucidation of respective GxE mechanisms. Recently, we showed excessive aggression and altered serotonin brain metabolism in heterozygous Tph2-deficient male mice (Tph2 +/- ) after predator stress exposure. Here, we sought to extend these studies by investigating aggressive and anxiety-like behaviours, sociability, and the brain metabolism of dopamine and noradrenaline. Separately, Tph2 +/- mice were examined for exploration activity in a novel environment and for the potentiation of helplessness in the modified swim test (ModFST). Predation stress procedure increased measures of aggression, dominancy, and suppressed sociability in Tph2 +/- mice, which was the opposite of that observed in control mice. Anxiety-like behaviour was unaltered in the mutants and elevated in controls. Tph2 +/- mice exposed to environmental novelty or to the ModFST exhibited increased novelty exploration and no increase in floating behaviour compared to controls, which is suggestive of resilience to stress and despair. High-performance liquid chromatography (HPLC) revealed significant genotype-dependent differences in the metabolism of dopamine, and norepinephrine within the brain tissue. In conclusion, environmentally challenged Tph2 +/- mice exhibit behaviours that resemble the behaviour of non-stressed null mutants, which reveals how GxE interaction studies can unmask latent genetically determined predispositions., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The interplay between α-synuclein and dopamine derivatives is associated with oxidative stress-dependent neurodegeneration in Parkinson's disease (PD). The formation in the dopaminergic neurons of intraneuronal inclusions containing aggregates of α-synuclein is a typical hallmark of PD. Even though the biochemical events underlying the aberrant aggregation of α-synuclein are not completely understood, strong evidence correlates this process with the levels of dopamine metabolites. In vitro, 3,4-dihydroxyphenylacetaldehyde (DOPAL) and the other two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET), share the property to inhibit the growth of mature amyloid fibrils of α-synuclein. Although this effect occurs with the formation of differently toxic products, the molecular basis of this inhibition is still unclear. Here, we provide information on the effect of DOPAC on the aggregation properties of α-synuclein and its ability to interact with membranes. DOPAC inhibits α-synuclein aggregation, stabilizing monomer and inducing the formation of dimers and trimers. DOPAC-induced oligomers did not undergo conformational transition in the presence of membranes, and penetrated the cell, where they triggered autophagic processes. Cellular assays showed that DOPAC reduced cytotoxicity and ROS production induced by α-synuclein aggregates. Our findings show that the early radicals resulting from DOPAC autoxidation produced covalent modifications of the protein, which were not by themselves a primary cause of either fibrillation or membrane binding inhibition. These findings are discussed in the light of the potential mechanism of DOPAC protection against the toxicity of α-synuclein aggregates to better understand protein and catecholamine biology and to eventually suggest a scaffold that can help in the design of candidate molecules able to interfere in α-synuclein aggregation.

Background: The genetics of binge-eating disorder (BED) is an emerging topic, with dopaminergic genes being implicated in its etiology due to the role that dopamine (DA) plays in food reward sensitivity and self-regulation of eating behavior. However, no study to date has examined if DA genes influence response to behavioral treatment of BED., Objective: The primary objective of this study was to examine the ability of DA-associated polymorphisms to predict BED treatment response measured using binge frequency over 12 months. As secondary objectives, this study examined cross-sectional relationships between these polymorphisms and anthropometrics in women living with and without BED and obesity., Methods: Women aged 18-64 years old were genotyped for the DA-related SNPs DRD2/ANKK1 Taq1A (rs1800497) and COMT (rs4680), as well as the DA-related uVNTRs DAT-1 (SLC6A3) and MAO-A. A multi-locus DA composite score was formed from these 4 polymorphisms using genotypes known to have a functional impact resulting in modified DA signaling. Binge frequency (Eating Disorder Examination - Interview) and body composition (Tanita BC-418) were assessed in a pre-post analysis to examine genetic predictors of treatment response in women living with obesity and BED. Secondary data analysis was conducted on a cross-sectional comparison of three groups of women enrolled in trial group treatment for BED: women living with obesity and BED (n = 72), obesity without BED (n = 27), and normal-weight without BED (n = 45)., Results: There were no significant genotype × time interactions related to anthropometrics or binge frequency for any individual DA genotypes, or to the composite score reflecting DA availability. At baseline, there were no significant between-group differences in frequencies of DA-related alleles, nor were there associations between genotypes and anthropometrics., Conclusions: Our study found no evidence to suggest that the DRD2/ANKK1 Taq1A, COMT, MAO-A, or DAT-1 polymorphisms are associated with response to behavioral intervention for BED as measured by changes in binge frequency. Future studies should examine a greater variety of dopaminergic polymorphisms, other candidate genes that target other neurotransmitter systems, as well as examine their impact on both behavioral and pharmacological-based treatment for BED., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The molecular mechanisms generating the mania-like abnormal behaviors caused by diacylglycerol (DG) kinase (DGK) η deficiency remain unclear. Here, we found that DGKη knockout markedly increased dopamine (DA) levels in the midbrain (DA-producing region, 2.8-fold) and cerebral cortex (DA projection region, 1.2-fold). Moreover, DGKη deficiency significantly augmented phosphorylated DA transporter (DAT) levels (1.4-fold increase), which induce DA efflux to the synaptic cleft, in the cerebral cortex. Moreover, phosphorylation levels of protein kinase C-β, which is activated by DG and involved in DAT phosphorylation, were also increased. DAT expressed in Neuro-2a cells recruited DGKη to the plasma membrane and colocalized with it. These results strongly suggest that dopaminergic hyperfunction caused by DGKη deficiency in the brain leads to mania-like behaviors., (© 2021 Federation of European Biochemical Societies.)

Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson's disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD-even when considering idiopathic forms of PD-has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders.

Fibromyalgia is a disease characterized by lowered pain threshold, mood disorders, and decreased muscular strength. It results from a complex dysfunction of the nervous system and due to unknown etiology, its diagnosis, treatment, and prevention are a serious challenge for contemporary medicine. Impaired serotonergic and dopaminergic neurotransmission are regarded as key factors contributing to fibromyalgia. The present research assessed the effect of serotonergic and dopaminergic system modulators (vortioxetine and ropinirole, respectively) on the pain threshold, depressive-like behavior, anxiety, and motor functions of mice with fibromyalgia-like symptoms induced by subcutaneous reserpine (0.25 mg/kg). By depleting serotonin and dopamine in the mouse brain, reserpine induced symptoms of human fibromyalgia. Intraperitoneal administration of vortioxetine and ropinirole at the dose of 10 mg/kg alleviated tactile allodynia. At 5 and 10 mg/kg ropinirole showed antidepressant-like properties, while vortioxetine had anxiolytic-like properties. None of these drugs influenced muscle strength but reserpine reduced locomotor activity of mice. Concluding, in the mouse model of fibromyalgia vortioxetine and ropinirole markedly reduced pain. These drugs affected emotional processes of mice in a distinct manner. Hence, these two repurposed drugs should be considered as potential drug candidates for fibromyalgia. The selection of a specific drug should depend on patient's key symptoms.

In this paper, the structural and functional imaging changes associated with sporadic and genetic Parkinson's disease and atypical Parkinsonian variants are reviewed. The role of imaging for supporting diagnosis and detecting subclinical disease is discussed, and the potential use and drawbacks of using imaging biomarkers for monitoring disease progression is debated. Imaging changes associated with nonmotor complications of PD are presented. The similarities and differences in imaging findings in Lewy body dementia, Parkinson's disease dementia, and Alzheimer's disease are discussed., (© 2021. The Author(s).)

A treatment option for constipation that improves the quality of life is needed since available laxatives do not effectively improve the quality of life in patients with constipation. A significant association between gut dysbiosis and constipation is recognized, suggesting that probiotics may be an important option for management of constipation. The underlying mechanism by which probiotics improve constipation remains unclear. In this study, we aimed to evaluate the effects of the probiotic Bifidobacterium bifidum G9-1 (BBG9-1) on loperamide-induced delayed colonic transit constipation and to elucidate its mechanism of action. First, the effect of BBG9-1 was evaluated in a rat model of constipation induced by subcutaneous administration of loperamide. BBG9-1 improved constipation parameters (number of feces, fecal water content, and fecal hardness) in constipated rats. Next, the relationship of organic acids and neurotransmitters to gut microbiota was investigated. BBG9-1 improved dysbiosis and prevented a decrease in butyric acid concentration in the gut, increased serum serotonin, and suppressed an increase in dopamine and a decrease in acetylcholine in serum. Further, an increase in the expression level of tryptophan hydroxylase 1, a 5-HT-synthetizing enzyme, was observed. These results suggest that BBG9-1 improves dysbiosis, which results in an increase in organic acids and improvement of neurotransmission. These actions may increase intestinal mobility, finally leading to alleviating constipation. The probiotic BBG9-1 may, therefore, be a potential option for the treatment of constipation., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: YM, TU, HY, MY, YT, HO are paid employees of Biofermin Pharmaceutical Co., Ltd. There are no patents, products in development or marketing products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Significance: The kidney plays an important role in the long-term control of blood pressure. Oxidative stress is one of the fundamental mechanisms responsible for the development of hypertension. Dopamine, via five subtypes of receptors, plays an important role in the control of blood pressure by various mechanisms, including the inhibition of oxidative stress. Recent Advances: Dopamine receptors exert their regulatory function to decrease the oxidative stress in the kidney and ultimately maintain normal sodium balance and blood pressure homeostasis. An aberration of this regulation may be involved in the pathogenesis of hypertension. Critical Issues: Our present article reviews the important role of oxidative stress and intrarenal dopaminergic system in the regulation of blood pressure, summarizes the current knowledge on renal dopamine receptor-mediated antioxidation, including decreasing reactive oxygen species production, inhibiting pro-oxidant enzyme nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and stimulating antioxidative enzymes, and also discusses its underlying mechanisms, including the increased activity of G protein-coupled receptor kinase 4 (GRK4) and abnormal trafficking of renal dopamine receptors in hypertensive status. Future Directions: Identifying the mechanisms of renal dopamine receptors in the regulation of oxidative stress and their contribution to the pathogenesis of hypertension remains an important research focus. Increased understanding of the role of reciprocal regulation between renal dopamine receptors and oxidative stress in the regulation of blood pressure may give us novel insights into the pathogenesis of hypertension and provide a new treatment strategy for hypertension.

To explore the neuroendocrine mechanisms underlying caste-specific behavior and its evolution from primitive to advanced eusocial bees, the monoamine levels and expression of genes involved in monoamine production and signaling in the brain were compared between the castes of Bombus ignitus. Higher levels of dopamine and its related substances were found in the brains of newly emerged queens than in the brains of emerged workers. The degree of caste differences in B. ignitus was smaller than that reported in Apis mellifera, indicating a link to different social stages in the two species. There was no differential expression in genes involved in dopamine biosynthesis between castes, suggesting that the high dopamine production in queens was not largely influenced by the expression of these genes at emergence, rather it might be influenced by tyrosine supply. Genome-wide analyses of gene expression by RNA-sequencing indicated that a greater number of genes involved in nutrition were actively expressed in the brains of newly emerged queens in comparison to the emerged workers. Some of the expression was confirmed by real-time quantitative PCR. The signaling pathways driven by the expression of these genes may be associated with dopamine signaling or the parallel activation of dopamine production.

In modern societies, there is a strive to improve the quality of life related to risk of crimes which inevitably requires a better understanding of brain determinants and mediators of aggression. Neurobiology provides powerful tools to achieve this end. Pre-clinical and clinical studies show that changes in regional volumes, metabolism-function and connectivity within specific neural networks are related to aggression. Subregions of prefrontal cortex, insula, amygdala, basal ganglia and hippocampus play a major role within these circuits and have been consistently implicated in biology of aggression. Genetic variations in proteins regulating the synthesis, degradation, and transport of serotonin and dopamine as well as their signal transduction have been found to mediate behavioral variability observed in aggression. Gene-gene and gene-environment interactions represent additional important risk factors for aggressiveness. Considering the social burden of pathological forms of aggression, more basic and translational studies should be conducted to accelerate applications to clinical practice, justice courts, and policy making., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Excessive fluoride exposure is related to adverse health outcomes, but whether dopamine (DA) relative genes are involved in the health effect of low-moderate fluoride exposure on children's intelligence remain unclear., Objectives: We conducted a cross-sectional study to explore the role of DA relative genes in the health effect of low-moderate fluoride exposure in drinking water., Methods: We recruited 567 resident children, aged 6-11 years old, randomly from endemic and non-endemic fluorosis areas in Tianjin, China. Spot urine samples were tested for urinary fluoride concentration, combined Raven`s test was used for intelligence quotient test. Fasting venous blood were collected to analyze ANKK1 Taq1A (rs1800497), COMT Val158Met (rs4680), DAT1 40 bp VNTR and MAOA uVNTR. Multivariable linear regression models were used to assess associations between fluoride exposure and IQ scores. We applied multiplicative and additive models to appraise single gene-environment interaction. Generalized multifactor dimensionality reduction (GMDR) was used to evaluate high-dimensional interactions of gene-gene and gene-environment., Results: In adjusted model, fluoride exposure was inversely associated with IQ scores (β = -5.957, 95% CI: -9.712, -2.202). The mean IQ scores of children with high-activity MAOA genotype was significantly lower than IQ scores of those with low-activity (P = 0.006) or female heterozygote (P = 0.016) genotype. We detected effect modification by four DA relative genes (ANKK1, COMT, DAT1 and MAOA) on the association between UF and IQ scores. We also found a high-dimensional gene-environment interaction among UF, ANKK1, COMT and MAOA on the effect of IQ (testing balanced accuracy = 0.5302, CV consistency: 10/10, P = 0.0107)., Conclusions: Our study suggests DA relative genes may modify the association between fluoride and intelligence, and a potential interaction among fluoride exposure and DA relative genes on IQ., (Copyright © 2020. Published by Elsevier Inc.)

The exact etiology of Parkinson's disease (PD) remains obscure, lacking effective diagnostic and prognostic biomarkers. In search of novel molecular factors that may contribute to PD pathogenesis, emerging evidence highlights the multifunctional role of the calcium-binding protein S100B that is widely expressed in the brain and predominantly in astrocytes. Preclinical evidence points towards the possible time-specific contributing role of S100B in the pathogenesis of neurodegenerative disorders including PD, mainly by regulating neuroinflammation and dopamine metabolism. Although existing clinical evidence presents some contradictions, estimation of S100B in the serum and cerebrospinal fluid seems to hold a great promise as a potential PD biomarker, particularly regarding the severity of motor and non-motor PD symptoms. Furthermore, given the recent development of S100B inhibitors that are able to cross the blood brain barrier, novel opportunities are arising in the research field of PD therapeutics. In this review, we provide an update on recent advances in the implication of S100B protein in the pathogenesis of PD and discuss relevant studies investigating the biomarker potential of S100B in PD, aiming to shed more light on clinical targeting approaches related to this incurable disorder.

The development of alcohol use disorder (AUD) is influenced by genetic, psychological, and social factors. However, the identification of the load of each of these factors and the association between them is still debatable. This study aimed to explore the load of the association between AUD and polymorphisms in genes of the dopaminergic system, as well as with drinking triggers. The study comprised 227 inpatients with AUD and 174 controls. The pattern and motivations for drinking were evaluated using the Alcohol Use Disorders Identification Test (AUDIT) and the Inventory of Drinking Situations (IDS). Analyses of genetic variation in genes encoding dopaminergic were performed using next generation sequencing. We observed an significant association between a polymorphism in DDC (rs11575457) and AUD. Positive reinforcement factors as urges/temptations to drink and pleasant emotion, in isolation, were the significantly related elements to drinking. In addition, negative (physical discomfort) and positive reinforcement factors (testing personal control; pleasant time with others) significantly reinforced the interaction with DDC genetic variant for increased odds of an individual presenting AUD. These results indicated a complex relationship between the dopaminergic system and the drug-seeking behavior profiles., (Copyright © 2020. Published by Elsevier B.V.)

Recent studies have shown that long-term alcohol intake from food can lead to numerous mental disorders in humans, and the social and health effects of excessive intake of alcohol currently represent serious problems for governments and families worldwide. However, to date, it has not been determined how alcohol affects the hypothalamic-pituitary-adrenal (HPA) axis. The zebrafish offers a good model for studying the toxicology of food-grade ethanol. In the present study, using zebrafish larvae exposed to 1% ethanol, we performed zebrafish behavioral analysis. Samples were collected for enzyme-linked immunosorbent assay (ELISA) and quantitative real time-polymerase chain reaction (qRT-PCR) experiments, and statistical analysis was performed. We found that ethanol decreased the locomotor activity of zebrafish larvae, which showed a more intense reaction to external stimuli. Ethanol also increased the level of HPA axis hormones in zebrafish larvae, influenced the level of neurotransmitters, and altered the expression of key genes in neurotransmitter metabolism. Ethanol exposure affects zebrafish behavior, increases the level of HPA axis hormones in zebrafish larvae, affects the level of neurotransmitters, and affects the expression of key genes in dopamine and serotonin metabolism. These findings may help to elucidate the effects of ethanol on HPA axis activity.

The renal dopaminergic system has been identified as a modulator of sodium balance and blood pressure. According to the Centers for Disease Control and Prevention, in 2018 in the United States, almost half a million deaths included hypertension as a primary or contributing cause. Renal dopamine receptors, members of the G protein-coupled receptor family, are divided in two groups: D1-like receptors that act to keep the blood pressure in the normal range, and D2-like receptors with a variable effect on blood pressure, depending on volume status. The renal dopamine receptor function is regulated, in part, by its expression in microdomains in the plasma membrane. Lipid rafts form platforms within the plasma membrane for the organization and dynamic contact of molecules involved in numerous cellular processes such as ligand binding, membrane sorting, effector specificity, and signal transduction. Understanding all the components of lipid rafts, their interaction with renal dopamine receptors, and their signaling process offers an opportunity to unravel potential treatment targets that could halt the progression of hypertension, chronic kidney disease (CKD), and their complications.