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1.
J Agric Food Chem ; 68(8): 2547-2553, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31995978

RESUMO

Anticholinergic organophosphate (OP) agents act on the diverse serine hydrolases, thereby revealing unexpected biological effects. Epidemiological studies indicate a relationship between the OP exposure and development of attention-deficit/hyperactivity disorder (ADHD)-like symptoms, whereas no plausible mechanism for the OP-induced ADHD has been established. The present investigation employs ethyl octylphosphonofluoridate (EOPF) as an OP-probe, which is an extremely potent inhibitor of endocannabinoid (EC, anandamide and 2-arachidonoylglycerol)-hydrolyzing enzymes: that is, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). An ex vivo experiment shows that EOPF treatment decreases FAAH and MAGL activities and conversely increases EC levels in the rat brain. Subsequently, EOPF (treated intraperitoneally once at 0, 1, 2, or 3 mg/kg) clearly induces ADHD-like behaviors (in elevated plus-maze test) in both Wistar and spontaneously hypertensive rats. The EOPF-induced behaviors are reduced by a concomitant administration of cannabinoid receptor inverse agonist SLV-319. Accordingly, the EC system is a feasible target for OP-caused ADHD-like behaviors in adolescent rats.


Assuntos
Amidoidrolases/antagonistas & inibidores , Transtorno do Deficit de Atenção com Hiperatividade/enzimologia , Encéfalo/enzimologia , Endocanabinoides/metabolismo , Inibidores Enzimáticos/efeitos adversos , Monoacilglicerol Lipases/antagonistas & inibidores , Compostos Organofosforados/efeitos adversos , Amidoidrolases/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Masculino , Monoacilglicerol Lipases/metabolismo , Ratos , Ratos Wistar
2.
Eur. j. anat ; 23(4): 243-251, jul. 2019. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-182997

RESUMO

Atomoxetine (ATX) is a noradrenaline reuptake inhibitor used to treat Attention deficit hyperactive syndrome (ADHD), or improve cognition in normal subjects. The cognitive effects of ATX require inputs from the hippocampus. Moreover, proliferation is said to be located in the dentate gyrus (DG) of the hippocampus.In the present study, we hypothesised that ATX improves memory and proliferation of the adult rat hippocampus. To test this hypothesis, 5 intraperitoneal injections of ATX (30 mg/kg/day) over 5 consecutive days were delivered to rats. 30 minutes after the last injection, spatial memory was tested using the Novel location recognition (NLR) test. Proliferation of hippocampal cells was quantified using immunohistochemistry for the proliferative marker Ki67. ATX-treated rats showed cognitive enhancement in the NLR task and increase in cell proliferation in the Subgranular zone (SGZ) of the DG, compared to saline-treated controls. The results demonstrate that ATX is able to enhance cognition through increasing the levels of proliferation in the adult rat brains


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Assuntos
Animais , Adulto , Ratos , Cloridrato de Atomoxetina/farmacologia , Cérebro/efeitos dos fármacos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/anatomia & histologia , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Imuno-Histoquímica , Habituação Psicofisiológica/efeitos dos fármacos , Modelos Animais de Doenças , Neurogênese/efeitos dos fármacos
3.
Med Sci Monit ; 25: 3918-3924, 2019 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-31129679

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a lifelong neurodevelopmental disorder that can affect many areas of the daily life of individuals and is associated with poor health outcomes and with debilitating deficits in executive function. Recently, increasing numbers of research studies have begun to investigate the associations between neural and behavioral manifestations of ADHD. This review summarizes recent research on the perception of time in ADHD and proposes that this symptom is a possible diagnostic characteristic. Controlled studies on time perception have compared individuals with ADHD with typically developing controls (TDCs) and have used methods that include the Zimbardo Time Perspective Inventory (ZTPI). Practical approaches to time perception and its evaluation have shown that individuals with ADHD have difficulties in time estimation and discrimination activities as well as having the feeling that time is passing by without them being able to complete tasks accurately and well. Although ADHD has been associated with neurologic abnormalities in the mesolimbic and dopaminergic systems, recent studies have found that when individuals with ADHD are treated medically, their perception of time tends to normalize. The relationship between ADHD and the perception of time requires greater attention. Further studies on time perception in ADHD with other abnormalities, including executive function, might be approaches that refine the classification and diagnosis of ADHD and should include studies on its varied presentation in different age groups.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Percepção do Tempo/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Função Executiva/fisiologia , Humanos
4.
Pharmacol Biochem Behav ; 182: 22-34, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31103523

RESUMO

Attention Deficit Hyperactivity Disorder (ADHD) is a persistent, and impairing pediatric-onset neurodevelopmental condition. Its high prevalence, and recurrent controversy over its widespread identification and treatment, drive strong interest in its etiology and mechanisms. Emerging evidence for a role for neuroinflammation in ADHD pathophysiology is of great interest. This evidence includes 1) the above-chance comorbidity of ADHD with inflammatory and autoimmune disorders, 2) initial studies indicating an association with ADHD and increased serum cytokines, 3) preliminary evidence from genetic studies demonstrating associations between polymorphisms in genes associated with inflammatory pathways and ADHD, 4) emerging evidence that early life exposure to environmental factors may increase risk for ADHD via an inflammatory mechanism, and 5) mechanistic evidence from animal models of maternal immune activation documenting behavioral and neural outcomes consistent with ADHD. Prenatal exposure to inflammation is associated with changes in offspring brain development including reductions in cortical gray matter volume and the volume of certain cortical areas -parallel to observations associated with ADHD. Alterations in neurotransmitter systems, including the dopaminergic, serotonergic and glutamatergic systems, are observed in ADHD populations. Animal models provide strong evidence that development and function of these neurotransmitters systems are sensitive to exposure to in utero inflammation. In summary, accumulating evidence from human studies and animal models, while still incomplete, support a potential role for neuroinflammation in the pathophysiology of ADHD. Confirmation of this association and the underlying mechanisms have become valuable targets for research. If confirmed, such a picture may be important in opening new intervention routes.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Inflamação/complicações , Adolescente , Animais , Transtorno do Deficit de Atenção com Hiperatividade/imunologia , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Sistema Nervoso Central/embriologia , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/fisiopatologia , Criança , Citocinas/metabolismo , Dopamina/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Modelos Animais , Norepinefrina/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fatores de Risco , Serotonina/metabolismo , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
5.
Neuropsychology ; 33(7): 947-955, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31094549

RESUMO

OBJECTIVE: Metabolic syndrome (MetS), the presence of three or more cardiovascular risk factors, has been associated with subtle and diffuse neural compromise but has not been consistently associated with cognitive dysfunction. Sustained attention is a fundamental cognitive operation that relies on multiple brain networks and is impaired in a broad array of neurologic conditions. We examined whether a well-validated measure of sustained attention would be sensitive to vascular risk, as compared with more standard neuropsychological measures of attention and executive functioning. METHOD: We assessed vascular risk factors (VRFs; blood pressure, waist circumference, cholesterol, glucose, and triglycerides) in 93 middle-to-older aged adults (45-75 years). MetS was defined based on current guidelines from the National Cholesterol Education Program Adult Training Program (NCEP ATP III). Participants were grouped according to number of VRFs: high risk (MetS; 3+ VRFs; N = 32), medium risk (1 or 2 VRFs; N = 35), and low risk (0 VRFs; N = 26). All participants underwent a neuropsychological battery of tests measuring executive functioning. Participants also performed the gradual-onset continuous performance task (gradCPT), a measure of sustained attention. RESULTS: There was a significant main effect of VRF group on sustained attention performance; participants with lower vascular risk were better able to sustain attention. No significant effects were detected on standard neuropsychological tests of executive function. CONCLUSION: Our results suggest that the gradCPT is sensitive to the potentially negative effects of MetS on subtle aspects of neurocognitive functioning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Idoso , Atenção , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Função Executiva , Feminino , Humanos , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/psicologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Medição de Risco , Fatores de Risco , Doenças Vasculares/metabolismo , Doenças Vasculares/psicologia
6.
Cornea ; 38(8): 1040-1042, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30950895

RESUMO

PURPOSE: To describe the development and resolution of corneal edema in 3 patients who were exposed to compounds that stimulate dopaminergic pathways. METHODS: We conducted a review of the literature on bilateral corneal edema secondary to amantadine use and report a case series of corneal edema seen in an outpatient ophthalmology specialty clinic, shortly after exposure to agents that enhance dopamine transmission. RESULTS: Cases 1 and 2 report a 25-year-old man with attention-deficit hyperactivity disorder and a 73-year-old man with Parkinson disease who were placed on dopaminergic medications to treat their conditions. The former was administered methylphenidate and the latter patient was administered ropinirole. Both patients developed corneal edema soon afterward. Case 3 is a 67-year-old man with a recent exposure to resin from Euphorbia resinifera, a cactus in his garden. After cessation of the offending medications and treatment for exposure to resiniferatoxin, the corneal edema progressively resolved and visual acuity returned to baseline in all 3 cases. CONCLUSIONS: Methylphenidate, ropinirole, and resiniferatoxin have different mechanisms of actions but have a common end point leading to increased dopamine. We believe that these agents are linked with the reversible corneal edema seen in our 3 patients. This strongly correlates with previous studies that have linked amantadine, a drug that blocks dopamine reuptake, to reversible corneal edema.


Assuntos
Edema da Córnea/induzido quimicamente , Dopaminérgicos/efeitos adversos , Adulto , Idoso , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Edema da Córnea/diagnóstico , Edema da Córnea/fisiopatologia , Diterpenos/efeitos adversos , Dopamina/metabolismo , Humanos , Indóis/efeitos adversos , Masculino , Metilfenidato/efeitos adversos , Neurotoxinas/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
7.
Brain Dev ; 41(7): 577-586, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30952459

RESUMO

BACKGROUND: The neural correlates of executive function disorders are thought to be predominantly localized within the prefrontal cortex (PFC). However, no study to date has investigated changes in this system across different age groups in children with attention deficit hyperactivity disorder (ADHD). Thus, this study aimed to explore changes in PFC function in children with ADHD. METHODS: Study participants included typically developing (TD) children (n = 140) and children with ADHD (n = 67) of primary school age. Behavioral executive functions and their neural basis were evaluated between the TD children and children with ADHD and also across different age periods (younger and older children). To examine executive function, inhibitory control was assessed using the reverse Stroop task, and PFC near-infrared spectroscopic measurements were used to investigate the neural mechanisms involved. RESULTS: Both ADHD symptoms and the ability to inhibit color interference improved with age. Compared to TD children, children with ADHD demonstrated decreased activation of the right and middle PFC across all age groups. Interestingly, the left PFC appeared to play a compensatory role. CONCLUSION: Children with ADHD exhibited changes in PFC function that varied with age. Longitudinal studies are required to assess the potential of using PFC function as an early biomarker of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Lobo Frontal/fisiopatologia , Fatores Etários , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Mapeamento Encefálico/métodos , Criança , Função Executiva/fisiologia , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos
8.
Cell ; 177(5): 1280-1292.e20, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31031006

RESUMO

Hyperactivity and disturbances of attention are common behavioral disorders whose underlying cellular and neural circuit causes are not understood. We report the discovery that striatal astrocytes drive such phenotypes through a hitherto unknown synaptic mechanism. We found that striatal medium spiny neurons (MSNs) triggered astrocyte signaling via γ-aminobutyric acid B (GABAB) receptors. Selective chemogenetic activation of this pathway in striatal astrocytes in vivo resulted in acute behavioral hyperactivity and disrupted attention. Such responses also resulted in upregulation of the synaptogenic cue thrombospondin-1 (TSP1) in astrocytes, increased excitatory synapses, enhanced corticostriatal synaptic transmission, and increased MSN action potential firing in vivo. All of these changes were reversed by blocking TSP1 effects. Our data identify a form of bidirectional neuron-astrocyte communication and demonstrate that acute reactivation of a single latent astrocyte synaptogenic cue alters striatal circuits controlling behavior, revealing astrocytes and the TSP1 pathway as therapeutic targets in hyperactivity, attention deficit, and related psychiatric disorders.


Assuntos
Astrócitos/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Comportamento Animal , Comunicação Celular , Neurônios/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Animais , Astrócitos/patologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/patologia , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Sinapses/genética , Trombospondina 1/genética , Trombospondina 1/metabolismo , Ácido gama-Aminobutírico/genética , Ácido gama-Aminobutírico/metabolismo
9.
PLoS One ; 14(2): e0206780, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785885

RESUMO

ADHD is associated with altered dopamine regulated reinforcement learning on prediction errors. Despite evidence of categorically altered error processing in ADHD, neuroimaging advances have largely investigated models of normal reinforcement learning in greater detail. Further, although reinforcement leaning critically relies on ventral striatum exerting error magnitude related thresholding influences on substantia nigra (SN) and dorsal striatum, these thresholding influences have never been identified with neuroimaging. To identify such thresholding influences, we propose that error magnitude related activities must first be separated from opposite activities in overlapping neural regions during error detection. Here we separate error detection from magnitude related adjustment (post-error slowing) during inhibition errors in the stop signal task in typically developing (TD) and ADHD adolescents using fMRI. In TD, we predicted that: 1) deactivation of dorsal striatum on error detection interrupts ongoing processing, and should be proportional to right frontoparietal response phase activity that has been observed in the SST; 2) deactivation of ventral striatum on post-error slowing exerts thresholding influences on, and should be proportional to activity in dorsal striatum. In ADHD, we predicted that ventral striatum would instead correlate with heightened amygdala responses to errors. We found deactivation of dorsal striatum on error detection correlated with response-phase activity in both groups. In TD, post-error slowing deactivation of ventral striatum correlated with activation of dorsal striatum. In ADHD, ventral striatum correlated with heightened amygdala activity. Further, heightened activities in locus coeruleus (norepinephrine), raphe nucleus (serotonin) and medial septal nuclei (acetylcholine), which all compete for control of DA, and are altered in ADHD, exhibited altered correlations with SN. All correlations in TD were replicated in healthy adults. Results in TD are consistent with dopamine regulated reinforcement learning on post-error slowing. In ADHD, results are consistent with heightened activities in the amygdala and non-dopaminergic neurotransmitter nuclei preventing reinforcement learning.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Aprendizagem/fisiologia , Adolescente , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Criança , Dopamina/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Neuroimagem/métodos , Recompensa , Estriado Ventral/metabolismo , Estriado Ventral/fisiopatologia
10.
Mol Brain ; 12(1): 11, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736828

RESUMO

We aimed to test the therapeutic effects of baicalin on attention deficit hyperactivity disorder (ADHD) in an animal model and to explain the potential mechanism. We investigated the therapeutic effects and mechanisms of baicalin in a spontaneously hypertensive rat (SHR) model of ADHD depending on the dopamine (DA) deficit theory. In this study, fifty SHRs were randomly divided into five groups: methylphenidate (MPH), baicalin (50 mg/kg, 100 mg/kg, or 150 mg/kg), and saline-treated. Ten Wistar Kyoto (WKY) rats were used as controls. All rats were orally administered the treatment for four weeks. Motor activity, spatial learning and memory ability were assessed with the open-field and Morris water-maze tests. The mRNA and protein levels of tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), synaptosomal-associated protein of molecular mass 25kD (SNAP25) and synataxin 1a in synaptosomes were detected with real-time polymerase chain reaction (PCR) and Western blot. In addition, DA levels were measured in the prefrontal cortex and striatum. The results indicated that both MPH and baicalin at doses of 150 mg/kg and 100 mg/kg significantly decreased the hyperactivity and improved the spatial learning memory deficit in the SHRs and increased the synaptosomal mRNA and protein levels of TH, SNAP25, VMAT2 and synataxin 1a compared with saline treatment. MPH significantly increased DA levels in both the prefrontal cortex (PFC) and striatum, while baicalin significantly increased DA levels only in the striatum. The results of the present study showed that baicalin treatment was effective for controlling the core symptoms of ADHD. Baicalin increased DA levels only in the striatum, which suggested that baicalin may target the striatum. The increased DA levels may partially be attributed to the increased mRNA and protein expression of TH, SNAP25, VMAT2, and syntaxin 1a. Therefore, these results suggested that the pharmacological effects of baicalin were associated with the synthesis, vesicular localization, and release of DA and might be effective in treating ADHD. However, further studies are required to better understand the molecular mechanisms underlying these findings.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Dopamina/metabolismo , Flavonoides/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos , Flavonoides/farmacologia , Crescimento e Desenvolvimento/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Movimento , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Endogâmicos SHR , Tempo de Reação/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Natação , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Sinaptossomos/ultraestrutura
11.
Psychopharmacology (Berl) ; 236(10): 2937-2958, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30737597

RESUMO

RATIONALE: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioural disorders with morphological and functional brain abnormalities. However, there is a growing body of evidence that abnormalities in the immune and endocrine systems may also account for the ADHD pathogenesis. OBJECTIVES: To test ADHD pathogenesis in neurological, immune and endocrine systems, this study examined the concentrations of cytokines, chemokines, oxidative stress markers, metabolic parameters, steroid hormones and steroidogenic enzymes in the serum and/or tissues of spontaneously hypertensive rats (SHRs, animal model of ADHD) and Wistar Kyoto rats (WKYs, control animals). Moreover, the volume of the medial prefrontal cortex (mPFC) as well as the density of dopamine 2 (D2) receptor-expressing cells and tyrosine hydroxylase (TH)-positive nerve fibres in it was also elucidated. METHODS: Peripheral blood, spleen and adrenal gland samples, as well as brain sections collected on day 35 (juvenile) and day 70 (maturating) from SHRs and WKYs, were processed by ELISA and immunohistochemistry, respectively. RESULTS: The results show significant increases of serum and/or tissue concentrations of cytokines, chemokines and oxidative stress markers in juvenile SHRs when compared to the age-matched WKYs. These increases were accompanied by a lowered volume of the mPFC and up-regulation of D2 in this brain region. In maturating SHRs, the levels of inflammatory and oxidative stress markers were normalised and accompanied by elevated contents of steroid hormones. CONCLUSIONS: Significant elevations of serum and/or tissue contents of cytokines, chemokines and oxidative stress markers as well as volumetric and neurochemical alterations in the mPFC of juvenile SHRs may suggest the cooperation of neurological and immune systems in the ADHD pathogenesis. Elevated levels of steroid hormones in maturating SHRs may be a compensatory effect involved in reducing inflammation and ADHD symptoms.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/imunologia , Encéfalo/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Mediadores da Inflamação/imunologia , Estresse Oxidativo/fisiologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Encéfalo/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Dopamina/imunologia , Dopamina/metabolismo , Sistema Endócrino/imunologia , Sistema Endócrino/metabolismo , Sistema Imunitário/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Sistema Nervoso/imunologia , Sistema Nervoso/metabolismo , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
12.
Behav Brain Res ; 364: 193-204, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30738103

RESUMO

Impulsivity is an important component of many psychiatric illnesses and has been associated with a number of psychiatric disorders such as bipolar disorder and attention deficit / hyperactivity disorder (ADHD). Exploring the different aspects of impulsive behaviour and assigning these to specific neurobiological pathways would advance our interpretation of disorders for which impulsivity is key. Pharmacological studies have implicated a number of neurotransmitters in impulsivity, which in turn have been shown to be affected by several genes in both rodent and human studies of impulsivity. Here, we examine impulsivity-related differences in gene expression in finer detail, using the 2-choice serial reaction time task (2-CSRTT) to assess the molecular signature of impulsivity in brain regions previously linked to impulsive behaviour. Wistar rats were rated as high, (n = 6), intermediate, (n = 12) or low impulsive (n = 6), based on premature responses in the 2-CSRTT, after which RNA was extracted from the nucleus accumbens core (NAcc) and ventral prefrontal cortex (vPFC). RNA from the NAcc and vPFC of high and low impulsivity rats (n = 6 per group) was analysed for differential gene expression patterns and exon usage using RNA poly-A tail sequencing. Pnisr, Mal, and Tspan2 were significantly increased in the NAcc of highly impulsive rats, whereas Ube3a was significantly decreased. No differences were seen in the vPFC. In addition to changes in gene expression, Tspan2 displayed differential exon usage in impulsive rats, while functionally, gene expression changes were related to membrane depolarisation and changes in exon usage were linked to sphingolipid breakdown. The changes in gene expression and exon usage observed in this study represent an important step towards defining the molecular architecture of impulsivity. This study therefore represents an important starting point for analysis of the biological role of impulsivity in addiction and other neurological conditions associated with impulsive phenotypes.


Assuntos
Comportamento de Escolha/fisiologia , Comportamento Impulsivo/fisiologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Éxons/genética , Masculino , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Proteínas do Tecido Nervoso/genética , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Tempo de Reação , Recompensa , Análise de Sequência de RNA/métodos , Tetraspaninas/genética , Transcriptoma/genética , Ubiquitina-Proteína Ligases/genética
13.
Behav Processes ; 162: 205-214, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30677472

RESUMO

One of the most notable aspects of the behavior of individuals with Attention Deficit Hyperactivity Disorder (ADHD) is increased variability in many aspects of their behavior, including response times and attentional focus. Among the many theories of ADHD is one that identifies its material cause as phasic malnutrition of the neurons required to maintain constancy of performance. Of the diverse predictions issuing from this theory, one concerns ubiquitous data: response times and their variance in decision tasks. This paper reviews that behavioral neuroenergetics theory and model, shows how they predict representative data, and suggests their relevance to researchers studying animal models of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Ácido Láctico/metabolismo , Neurônios/metabolismo , Animais , Astrócitos/metabolismo , Atenção , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Tomada de Decisões , Modelos Animais de Doenças , Metabolismo Energético , Humanos , Modelos Psicológicos , Tempo de Reação
14.
Behav Genet ; 49(3): 270-285, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30659475

RESUMO

We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10-7) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r2 = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteínas do Tecido Nervoso/genética , Proteínas R-SNARE/genética , RNA Longo não Codificante/genética , Adulto , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Estudos de Coortes , DNA Antissenso/genética , DNA Antissenso/metabolismo , Feminino , Predisposição Genética para Doença/genética , Genética Populacional/métodos , Estudo de Associação Genômica Ampla , Genótipo , Células HEK293 , Humanos , Masculino , Camundongos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/metabolismo , Fatores de Risco
15.
J Pediatr Endocrinol Metab ; 32(2): 203-206, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30681972

RESUMO

Background Resistance to thyroid hormone (RTH) commonly presents with goiter, attention deficit hyperactivity disorder (ADHD), short stature and tachycardia. However, due to its variable presentation with subtle clinical features, a third of the cases are mistreated, typically as hyperthyroidism. Case presentation A 15-year-old female with ADHD and oligomenorrhea was initially diagnosed as Hashimoto's thyroiditis but found to have a rare heterozygous mutation in c803 C>G (p Ala 268 Gly) in the THRß gene, confirming resistance to thyroid hormone. Conclusions Fluctuating thyroid function tests in addition to thyroid peroxidase antibody (TPO Ab) positivity complicated the diagnosis of RTH, initially diagnosed as Hashimoto's thyroiditis. A high index of suspicion is needed to prevent misdiagnosis and mistreatment.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Doença de Hashimoto/diagnóstico , Oligomenorreia/diagnóstico , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Diagnóstico Diferencial , Feminino , Genes erbA/genética , Doença de Hashimoto/genética , Doença de Hashimoto/metabolismo , Humanos , Mutação , Oligomenorreia/genética , Oligomenorreia/metabolismo , Prognóstico , Testes de Função Tireóidea , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-30496768

RESUMO

The pathophysiology of attention deficient hyperactivity disorder (ADHD) is still obscure. Some studies have discussed that magnesium levels are lower in the serum and erythrocytes of children with ADHD. However, these findings are controversial. The aim of our study is to identify whether magnesium levels are in fact lower in children with ADHD. We conducted a thorough search of the literature and examined the connection between magnesium insufficiency and ADHD. A total of twelve studies were included into the current meta-analysis. The results of our meta-analysis found that peripheral blood magnesium levels, either in plasma, serum, or whole blood, of children diagnosed with ADHD were significantly lower than those in controls (k = 8, Hedges' g = -0.547, 95% CI = -0.818 to -0.276, p < .001). The subgroup meta-analysis with serum sample sources also suggested that peripheral serum magnesium levels of children diagnosed with ADHD were significantly lower than those in controls (k = 6, Hedges' g = -0.733, 95% CI = -0.911 to -0.555, p < .001). The subgroup meta-analysis focusing on subjects with ADHD diagnosed by definite diagnostic criteria also suggested significantly lower peripheral serum magnesium levels in ADHD children than those in controls (k = 4, Hedges' g = -0.780, 95% CI = -0.985 to -0.574, p < .001). We also noted that magnesium levels in the hair of children diagnosed with ADHD were significantly lower than those in controls (k = 4, Hedges' g = -0.713, 95% CI = -1.359 to -0.067, p = .031). In this meta-analysis, we found that children diagnosed with ADHD have lower serum and hair magnesium levels than children without ADHD. Further study may be needed to investigate the behavioral influence on ADHD due to lower magnesium levels, the association between brain and serum magnesium levels, and the effects brought about by larger longitudinal cohort studies.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Cabelo/metabolismo , Magnésio/metabolismo , Biomarcadores/metabolismo , Criança , Humanos
17.
ACS Chem Neurosci ; 10(1): 460-471, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30153408

RESUMO

The dopamine transporter (DAT) is a transmembrane protein that terminates dopamine signaling in the brain by driving rapid dopamine reuptake into presynaptic nerve terminals. Several lines of evidence indicate that DAT dysfunction is linked to neuropsychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BPD), and autism spectrum disorder (ASD). Indeed, individuals with these disorders have been found to express the rare, functional DAT coding variant Val559, which confers anomalous dopamine efflux (ADE) in vitro and in vivo. To elucidate the impact of the DAT Val559 variant on membrane diffusion dynamics, we implemented our antagonist-conjugated quantum dot (QD) labeling approach to monitor the lateral mobility of single particle-labeled transporters in transfected HEK-293 and SK-N-MC cells. Our results demonstrate significantly higher diffusion coefficients of DAT Val559 compared to those of DAT Ala559, effects likely determined by elevated N-terminal transporter phosphorylation. We also provide pharmacological evidence that PKCß-mediated signaling supports enhanced DAT Val559 membrane diffusion rates. Additionally, our results are complimented with diffusion rates of phosphomimicked and phosphorylation-occluded DAT variants. Furthermore, we show DAT Val559 has a lower propensity for membrane clustering, which may be caused by a mutation-derived shift out of membrane microdomains leading to faster lateral membrane diffusion rates. These findings further demonstrate a functional impact of DAT Val559 and suggest that changes in transporter localization and lateral mobility may sustain ADE and contribute to alterations in dopamine signaling underlying multiple neuropsychiatric disorders.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno Autístico/metabolismo , Transtorno Bipolar/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteína Quinase C beta/metabolismo , Pontos Quânticos/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Autístico/genética , Transtorno Bipolar/genética , Membrana Celular/genética , Membrana Celular/metabolismo , Difusão , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Variação Genética/fisiologia , Células HEK293 , Humanos , Proteína Quinase C beta/genética , Valina/genética , Valina/metabolismo
18.
J Affect Disord ; 244: 100-106, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30332620

RESUMO

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by deficits in self-controlling attention, behavior, and emotions. In recent years, noninvasive optical techniques, such as near infrared spectroscopy (NIRS), have been used to measure the neural correlates of pharmacological-therapy outcomes in children and adolescents with ADHD. METHODS: We reviewed a short series of articles that investigated the results of functional NIRS (fNIRS) on developmental-age ADHD. The review was limited to fNIRS studies that investigated the cortical responses that occurred during neuropsychological tasks in ADHD patients who received methylphenidate or atomoxetine. RESULTS: The majority of the reviewed studies revealed the presence of increased oxygenated hemoglobin concentrations in the prefrontal cortex following pharmacotherapy in ADHD samples. A higher frequency of right-lateralized results was found. LIMITATIONS: The considered studies are characterized by substantial methodological heterogeneity in terms of the patients' medication status and washout period, explored cerebral regions, and neuropsychological tasks. CONCLUSIONS: fNIRS seems to be a promising tool for the detection of pharmacological-treatment biomarkers in samples of children and adolescents with ADHD.


Assuntos
Cloridrato de Atomoxetina/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Oxiemoglobinas/metabolismo , Envelhecimento/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Biomarcadores , Humanos , Metilfenidato/farmacologia , Córtex Pré-Frontal/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho
19.
Neurochem Int ; 123: 13-21, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30179648

RESUMO

The dopamine transporter (DAT) plays a critical role in dopamine (DA) homeostasis by clearing transmitter from the extraneuronal space after vesicular release. DAT serves as a site of action for a variety of addictive and therapeutic reuptake inhibitors, and transport dysfunction is associated with transmitter imbalances in disorders such as schizophrenia, attention deficit hyperactive disorder, bipolar disorder, and Parkinson disease. In this review, we describe some of the model systems that have been used for in vitro analyses of DAT structure, function and regulation, and discuss a potential relationship between transporter kinetic values and membrane cholesterol.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
20.
Behav Brain Res ; 359: 516-527, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30472113

RESUMO

Dopamine (DA) is a key neurotransmitter of the central nervous system, whose availability is regulated by the dopamine transporter (DAT). Deletion of DAT gene leading to hyperdopaminergia was previously performed on mouse models. This enabled recapitulation of the core symptoms of Attention-Deficit / Hyper-activity Disorder (ADHD), which include hyperactivity, inattention and cognitive impairment. We used recently developed DAT knockout (DAT-KO) rats to carry out further behavioral profiling on this novel model of hyperdopaminergia. DAT-KO rats display elevated locomotor activity and restless environmental exploration, associated with a transient anxiety profile. Furthermore, these rats show pronounced stereotypy and compulsive-like behavior at the Marble-Burying test. Homozygous DAT-KO rats mantain intact social interaction when tested in a social-preference task, while heterozygous (HET) rats show high inactivity associated with close proximity to the social stimulus. Ex-vivo evaluation of brain catecholamines highlighted increased levels of norepinephrine in the hippocampus and hypothalamus exclusively of heterozygous rats. Taken together, our data present evidence of unexpected asocial tendencies in heterozygous (DAT-HET) rats associated with neurochemical alterations in norepinephrine neurotransmission. We shed light on the behavioral and neurochemical consequences of altered DAT function in a higher, more complex model of hyperdopaminergia. Unraveling the role of DA neurotransmission in DAT-KO rats has very important implications in the understanding of many psychiatric illnesses, including ADHD, where alterations in DA system have been demonstrated.


Assuntos
Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/deficiência , Norepinefrina/metabolismo , Comportamento Social , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Comportamento Compulsivo/metabolismo , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Comportamento Exploratório/fisiologia , Medo/fisiologia , Asseio Animal/fisiologia , Heterozigoto , Homozigoto , Atividade Motora/fisiologia , Fenótipo , Ratos Transgênicos , Ratos Wistar
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