RESUMO
INTRODUCTION: Parkinson's disease (PD) causes gait abnormalities that may be associated with an arm swing reduction. Medication and freezing of gait (FoG) may influence gait characteristics. However, these comparisons do not consider differences in gait speed and clinical characteristics in individuals with PD. OBJECTIVE: This study aims to analyze the effect of FoG and medication on the biomechanics of the trunk and upper limbs during gait in PD, controlling for gait speed and clinical differences between groups. METHODS: Twenty-two people with a clinical diagnosis of idiopathic PD in ON and OFF medication (11 FoG), and 35 healthy participants (control) were selected from two open data sets. All participants walked on the floor on a 10-m-long walkway. The joint and linear kinematic variables of gait were compared: (1) Freezers and nonfreezers in the ON condition and control; (2) Freezers and nonfreezers in the OFF condition and control; (3) Group (freezers and nonfreezers) and medication. RESULTS: The disease affects the upper limbs more strongly but not the trunk. The medication does not significantly influence the joint characteristics but rather the linear wrist displacement. The FoG does not affect trunk movement and partially influences the upper limbs. The interaction between medications and FoG suggests that the medication causes more substantial improvement in freezers than in nonfreezers. CONCLUSION: The study shows differences in the biomechanics of the upper limbs of people with PD, FoG, and the absence of medication. The future rehabilitation protocol should consider this aspect.
Assuntos
Transtornos Neurológicos da Marcha , Marcha , Doença de Parkinson , Tronco , Extremidade Superior , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Fenômenos Biomecânicos , Masculino , Feminino , Idoso , Extremidade Superior/fisiopatologia , Pessoa de Meia-Idade , Tronco/fisiopatologia , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/tratamento farmacológico , Marcha/fisiologia , Dopaminérgicos , Antiparkinsonianos/uso terapêuticoRESUMO
Dopamine agonist withdrawal syndrome (DAWS) results from the reduction or suspension of dopamine agonist medications; it encompasses mainly psychiatric symptoms, including suicidal behaviors. In patients with Parkinson's disease (PD), the impact of DAWS can be significant in terms of distress and disability; however, we must take this syndrome into account as a threatening condition because suicidal behaviors could be developing in the context of DAWS. Here we present a brief case of DAWS affecting a young man with PD, whom abruptly discontinued DA treatment and developed psychiatric symptoms within two weeks which led to a suicidal attempt.
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Transtornos Disruptivos, de Controle do Impulso e da Conduta , Doença de Parkinson , Síndrome de Abstinência a Substâncias , Humanos , Masculino , Transtornos Disruptivos, de Controle do Impulso e da Conduta/complicações , Dopaminérgicos , Agonistas de Dopamina/efeitos adversos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/diagnóstico , Tentativa de SuicídioRESUMO
Adolescence is a phase of substantial changes in the brain, characterized by maturational remodeling of many systems. This remodeling allows functional plasticity to adapt to a changing environment. The dopaminergic system is under morphological and physiological changes during this phase. In the present study, we investigated if changes in the dopaminergic tone alter mice behavior in a receptor and sex-specific manner, specifically at the beginning of the puberty period. We administered L-Dopa, SKF-38393 (D1 dopamine receptor agonist), and Quinpirole (D2 dopamine receptor agonist) and tested male and female mice's motor, anxiety- and depressive-like behavior. While females displayed an impaired exploratory drive, males presented an intense depressive-like response. Our results provide insights into the function of dopaminergic development in adolescent behavior and highlight the importance of studies in this time window with male and female subjects.
Assuntos
Agonistas de Dopamina , Levodopa , Humanos , Camundongos , Masculino , Feminino , Animais , Adolescente , Quimpirol/farmacologia , Levodopa/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Agonistas de Dopamina/farmacologia , Dopaminérgicos/farmacologia , Ergolinas/farmacologia , Receptores de Dopamina D1 , Dopamina , Ansiedade/tratamento farmacológicoRESUMO
Background: Cerebral palsy (CP) should not be considered a diagnosis, but rather a syndrome related to several etiologies, including, but not limited to, neurological sequelae of a perinatal brain injury. Case report: 24-years-old man with dystonia and delayed motor and cognitive development had been previously diagnosed with CP. Molecular genetic testing identified a heterozygosity variant in GNAO 1 gene. A therapeutic trial with levodopa was started, with improvement of dystonia. Discussion: GNAO1 gene variant disorders share similarities with other causes of CP syndrome, and thus investigation of this variant should be included in instances of CP syndrome without a clear history of previous perinatal brain injury. GNAO1 dystonic phenotype (DYT-GNAO1) should be considered as dopa-responsive dystonia in some cases.
Assuntos
Paralisia Cerebral , Dopaminérgicos , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP , Levodopa , Humanos , Paralisia Cerebral/tratamento farmacológico , Paralisia Cerebral/genética , Dopaminérgicos/uso terapêutico , Distonia/tratamento farmacológico , Distonia/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Heterozigoto , Levodopa/uso terapêutico , Fenótipo , Masculino , Adulto JovemRESUMO
INTRODUCTION: This study aims to evaluate the effects of medication, and the freezing of gait (FoG) on the kinematic and kinetic parameters of gait in people with Parkinson's disease (pwPD) compared to neurologically healthy. METHODS: Twenty-two people with a clinical diagnosis of idiopathic PD in ON and OFF medication (11 FoG), and 18 healthy participants (control) were selected from two open data sets. All participants walked on the floor on a 10-meter-long walkway. The joint kinematic and ground reaction forces (GRF) variables of gait and the clinical characteristics were compared: (1) PD with FoG (pwFoG) and PD without FoG (pwoFoG) in the ON condition and control; (2) PD with FoG and PD without FoG in the OFF condition and control; (3) Group (PD with FoG and PD without FoG) and Medication. RESULTS: (1) FoG mainly affects distal joints, such as the ankle and knee; (2) PD ON showed changes in the range of motion of both distal and proximal joints, which may explain the increase in step length and gait speed expected with the use of L-Dopa; and (3) the medication showed improvements in the kinematic and kinetic parameters of the gait of people with pwFoG and pwoFoG equally; (4) pwPD showed a smaller second peak of the vertical component of the GRF than the control. CONCLUSION: The presence of FoG mainly affects distal joints, such as the ankle and knee. PD presents a lower application of GRF during the impulse period than healthy people, causing lower gait performances.
Assuntos
Transtornos Neurológicos da Marcha , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/diagnóstico , Fenômenos Biomecânicos , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Marcha , Dopaminérgicos/uso terapêutico , Extremidade InferiorRESUMO
Fear extinction (FExt) is used to treat patients with posttraumatic stress disorder (PTSD). However, fear related to traumatic events can be persistent and return even after successful extinction. The neurochemical control of extinction seems to be performed by several neurotransmitters, including dopamine (DA), through D1 and D2 receptors. Recently, we showed that intranasally applied DA (IN-DA) facilitated the FExt, but the mechanisms by which it promoted this effect are still unknown. This study focused on investigating whether these effects are mediated by the action of DA on D2-like receptors since these receptors seem to be related to neurochemical and molecular changes underlying extinction. Also, we investigated whether IN-DA treatment would affect conditioned fear-induced antinociception (Fear-IA). Rats treated with IN-DA (1 mg/kg) twenty-five minutes after sulpiride (SUL; 40 mg/kg, i.p., D2-antagonist) were subjected to the extinction of contextual fear. IN-DA applied before the extinction session induced the FExt and prevented Fear-IA. These effects were impaired by pre-treatment with SUL, suggesting that the IN-DA effects are mediated by DA on D2-like receptors. SUL per se also facilitated the FExt but did not affect Fear-IA. These data suggest IN-DA as a promising pharmacological tool to supplement the psychotherapy of patients suffering from PTSD.
Assuntos
Condicionamento Psicológico/fisiologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Dopamina/farmacologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Receptores de Dopamina D2/fisiologia , Sulpirida/farmacologia , Administração Intranasal , Animais , Condicionamento Psicológico/efeitos dos fármacos , Dopaminérgicos/farmacologia , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos , Sulpirida/antagonistas & inibidoresRESUMO
Early weaning (EW) is associated with obesity later in life. Here, using an EW model in rats, we investigated changes in feeding behavior and the dopaminergic and endocannabinoid systems (ECS) in the adult offspring. Lactating Wistar rats were divided into two groups: EW, dams were wrapped with a bandage to interrupt suckling during the last 3 days of breastfeeding; CONT; dams fed the pups throughout the period without hindrances. EW animals were compared with CONT animals of the same sex. At PN175, male and female offspring of both groups could freely self-select between high-fat and high-sugar diets (food challenge test). EW males preferred the high-fat diet at 30 min and more of the high-sugar diet after 12 h compared to CONT males. EW females did not show differences in their preference for the palatable diets compared to CONT females. Total intake of standard diet from PN30-PN180 was higher in both male and female EW animals, indicating hyperphagia. At PN180, EW males showed lower type 2 dopamine receptor (D2r) in the nucleus accumbens (NAc) and dorsal striatum, while EW females had lower tyrosine hydroxylase in the ventral tegmental area and NAc, D1r in the NAc, and D2r in the prefrontal cortex. In the lateral hypothalamus, EW males had lower fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, whereas EW females showed lower N-arachidonoyl-phosphatidylethanolamine phospholipase-D and increased FAAH. Early weaning altered both the dopaminergic and ECS parameters at adulthood, contributing to the eating behavior changes of the progeny in a sex-dependent manner.
Assuntos
Dopaminérgicos/metabolismo , Endocanabinoides/metabolismo , Preferências Alimentares/psicologia , Fatores de Tempo , Desmame , Análise de Variância , Animais , Modelos Animais de Doenças , Comportamento Alimentar , Ratos , Ratos Wistar/metabolismoRESUMO
Dopamine seems to mediate fear conditioning through its action on D2 receptors in the mesolimbic pathway. Systemic and local injections of dopaminergic agents showed that D2 receptors are preferentially involved in the expression, rather than in the acquisition, of conditioned fear. To further examine this issue, we evaluated the effects of systemic administration of the dopamine D2-like receptor antagonists sulpiride and haloperidol on the expression and extinction of contextual and cued conditioned fear in rats. Rats were trained to a context-CS or a light-CS using footshocks as unconditioned stimuli. After 24 h, rats received injections of sulpiride or haloperidol and were exposed to the context-CS or light-CS for evaluation of freezing expression (test session). After another 24 h, rats were re-exposed to the context-CS or light-CS, to evaluate the extinction recall (retest session). Motor performance was assessed with the open-field and catalepsy tests. Sulpiride, but not haloperidol, significantly reduced the expression of contextual and cued conditioned fear without affecting extinction recall. In contrast, haloperidol, but not sulpiride, had cataleptic and motor-impairing effects. The results reinforce the importance of D2 receptors in fear conditioning and suggest that dopaminergic mechanisms mediated by D2 receptors are mainly involved in the expression rather than in the extinction of conditioned freezing.
Assuntos
Condicionamento Clássico , Extinção Psicológica , Medo , Receptores de Dopamina D2 , Animais , Dopaminérgicos , Ratos , Ratos WistarRESUMO
BACKGROUND: Dopaminergic medication improves gait in people with Parkinson disease (PD). However, it remains unclear if dopaminergic medication modulates cortical activity while walking. OBJECTIVE: We investigated the effects of dopaminergic medication on cortical activity during unobstructed walking and obstacle avoidance in people with PD. METHODS: A total of 23 individuals with PD, in both off (PDOFF) and on (PDON) medication states, and 30 healthy older adults (control group [CG]) performed unobstructed walking and obstacle avoidance conditions. Cortical activity was acquired through a combined functional near-infrared spectroscopy electroencephalography (EEG) system, along with gait parameters, through an electronic carpet. Prefrontal cortex (PFC) oxygenated hemoglobin (HbO2) and EEG absolute power from FCz, Cz, and CPz channels were calculated. RESULTS: HbO2 concentration reduced for people with PDOFF during obstacle avoidance compared with unobstructed walking. In contrast, both people with PDON and the CG had increased HbO2 concentration when avoiding obstacles compared with unobstructed walking. Dopaminergic medication increased step length, step velocity, and ß and γ power in the CPz channel, regardless of walking condition. Moreover, dopaminergic-related changes (ie, on-off) in FCz/CPz γ power were associated with dopaminergic-related changes in step length for both walking conditions. CONCLUSIONS: PD compromises the activation of the PFC during obstacle avoidance, and dopaminergic medication facilitates its recruitment. In addition, PD medication increases sensorimotor integration during walking by increasing posterior parietal cortex (CPz) activity. Increased γ power in the CPz and FCz channels is correlated with step length improvements achieved with dopaminergic medication during unobstructed walking and obstacle avoidance in PD.
Assuntos
Córtex Cerebral/fisiopatologia , Dopaminérgicos/farmacologia , Transtornos Neurológicos da Marcha , Doença de Parkinson , Desempenho Psicomotor , Caminhada , Idoso , Córtex Cerebral/diagnóstico por imagem , Eletroencefalografia , Feminino , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Índice de Gravidade de Doença , Espectroscopia de Luz Próxima ao Infravermelho , Caminhada/fisiologiaRESUMO
Dopamine is an important neurotransmitter that plays a key role in a wide range of both locomotive and cognitive functions in humans. Disturbances on the dopaminergic system cause, among others, psychosis, Parkinson's disease and Huntington's disease. Antipsychotics are drugs that interact primarily with the dopamine receptors and are thus important for the control of psychosis and related disorders. These drugs function as agonists or antagonists and are classified as such in the literature. However, there is still much to learn about the underlying mechanism of action of these drugs. The goal of this investigation is to analyze the intrinsic chemical reactivity, more specifically, the electron donor-acceptor capacity of 217 molecules used as dopaminergic substances, particularly focusing on drugs used to treat psychosis. We analyzed 86 molecules categorized as agonists and 131 molecules classified as antagonists, applying Density Functional Theory calculations. Results show that most of the agonists are electron donors, as is dopamine, whereas most of the antagonists are electron acceptors. Therefore, a new characterization based on the electron transfer capacity is proposed in this study. This new classification can guide the clinical decision-making process based on the physiopathological knowledge of the dopaminergic diseases.
Assuntos
Dopaminérgicos/farmacologia , Desenho de Fármacos , Doença de Huntington/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , Dopaminérgicos/uso terapêutico , HumanosRESUMO
ABSTRACT. Corticobasal degeneration (CBD) is a sporadic tauopathy that presents with a varied combination of motor, cognitive, and behavioral features, making its diagnosis difficult. CBD has high morbidity and poor prognosis, with no effective therapy at present. We searched the PubMed/MEDLINE database for articles published from 1990 to 2019, using the keywords "corticobasal degeneration" AND "treatment." The PRISMA method was adopted. Retrieved articles were characterized as having one of two methodological approaches: (1) studies aimed at primary tauopathy treatment and (2) symptomatic management. Review articles (based on CBD expert groups), case reports, case series, and pilot clinical trials were selected. Few attempts have been made to study drug options and drug efficacy in CBD systematically, and an effective treatment is not yet available. Treatment is symptomatic and based on similarity with other diseases due to the scarcity of studies specifically addressing CBD. CBD seems not to spark interest in more clinical trials for its low prevalence and reliability in clinical diagnosis.
RESUMO. A degeneração corticobasal (DCB) é uma tauopatia esporádica que se apresenta com uma combinação variada de características motoras, cognitivas e comportamentais, dificultando seu diagnóstico. O CBD tem alta morbidade e mau prognóstico, sem terapia efetiva no momento. Pesquisamos o banco de dados PubMed / MEDLINE para artigos publicados de 1990 a 2019, usando as palavras-chave "degeneração corticobasal" e "tratamento". O método PRISMA foi adotado. Os artigos recuperados foram caracterizados como tendo uma de duas abordagens metodológicas: (1) estudos voltados para o tratamento da tauopatia primária e (2) manejo sintomático. Artigos de revisão (baseados em grupos de especialistas em CBD), relatos de casos, séries de casos e ensaios clínicos piloto foram selecionados. Poucas tentativas foram feitas para estudar as opções de drogas e eficácia de drogas no CBD de forma sistemática, e um tratamento eficaz ainda não está disponível. O tratamento é sintomático e baseado na semelhança com outras doenças devido à escassez de estudos que abordem especificamente o CBD. O CBD parece não despertar o interesse em mais ensaios clínicos por sua baixa prevalência e confiabilidade no diagnóstico clínico.
Assuntos
Humanos , Terapêutica , Dopaminérgicos , Demência , Degeneração NeuralRESUMO
Background. Although dopaminergic medication improves dual task walking in people with Parkinson disease (PD), the underlying neural mechanisms are not yet fully understood. As prefrontal cognitive resources are involved in dual task walking, evaluation of the prefrontal cortex (PFC) is required. Objective. To investigate the effect of dopaminergic medication on PFC activity and gait parameters during dual task walking in people with PD. Methods. A total of 20 individuals with PD (69.8 ± 5.9 years) and 30 healthy older people (68.0 ± 5.6 years) performed 2 walking conditions: single and dual task (walking while performing a digit vigilance task). A mobile functional near infrared spectroscopy system and an electronic sensor carpet were used to analyze PFC activation and gait parameters, respectively. Relative concentrations of oxygenated hemoglobin (HbO2) from the left and right PFC were measured. Results. People with PD in the off state did not present changes in HbO2 level in the left PFC across walking conditions. In contrast, in the on state, they presented increased HbO2 levels during dual task compared with single task. Regardless of medication state, people with PD presented increased HbO2 levels in the right PFC during dual task walking compared with single task. The control group demonstrated increased PFC activity in both hemispheres during dual task compared with single task. People with PD showed increases in both step length and velocity in the on state compared with the off state. Conclusions. PD limits the activation of the left PFC during dual task walking, and dopaminergic medication facilitates its recruitment.
Assuntos
Dopaminérgicos/farmacologia , Função Executiva/efeitos dos fármacos , Marcha/efeitos dos fármacos , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Idoso , Função Executiva/fisiologia , Feminino , Neuroimagem Funcional , Marcha/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Desempenho Psicomotor/fisiologia , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-like mechanism of action of terpineol while using molecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100-200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a ß-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antidepressivos/uso terapêutico , Moduladores de Receptores de Canabinoides/uso terapêutico , Depressão/tratamento farmacológico , Dopaminérgicos/uso terapêutico , Monoterpenos/uso terapêutico , Animais , Sítios de Ligação , Depressão/etiologia , Elevação dos Membros Posteriores/efeitos adversos , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Receptores de Canabinoides/química , Receptores de Canabinoides/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismoRESUMO
BACKGROUND: Motor Imagery (MI) represents the cognitive component of the movement and recruits dopaminergic systems. OBJECTIVE: To investigate the role of dopaminergic system through the action of methylphenidate and risperidone over beta coherence during execution, action observation and motor imagery. METHODS: Electroencephalography (EEG) data were recorded before and after the substance intake. For statistical analysis, a three-way ANOVA was used to identify changes in beta coherence induced by the group, task and the moment variables. Statistical significance was set at p≤0.007. RESULTS: We found a main effect for group for C3/CZ, and a main effect for task for CZ/C4 pairs of electrodes. Furthermore, significant differences were found in the post-drug administration between groups for C3/CZ pair of electrodes, and between task for C4/CZ pair of electrodes. CONCLUSION: The administration of methylphenidate and risperidone was able to produce electrocortical changes of the cortical central regions, even when featuring antagonistic effects on the dopaminergic pathways. Moreover, the execution task allowed beta-band modulation increase.
Assuntos
Dopaminérgicos/uso terapêutico , Imagens, Psicoterapia , Adulto , Eletroencefalografia , Humanos , MovimentoRESUMO
Dopaminergic signaling and neurodevelopment alterations are associated with several neuropsychiatric disorders. Knockout mice for dopamine transporters (DAT) as well as site-specific knockout mice lacking dopaminergic D2 autoreceptors in dopaminergic neurons (DA-D2RKO) display behavioral alterations such as hyperlocomotion and abnormal prepulse inhibition. However, it is possible that dopaminergic imbalances may have different effects during varied neurodevelopmental windows. In our previous study, we observed that elevated levels of dopamine during the perinatal developmental window increased exploratory behavior of juvenile (4-week-old) Swiss female mice and impaired hedonic behavior in males. In this study, we investigated whether these behavioral alterations persist through young adulthood. In order to do so, we administered daily doses of l-Dopa to mice pups beginning from postnatal day 1 (PD1) to PD5. At the age of 8 weeks, we submitted the young adult males and females to the open field test, elevated plus maze, forced swimming test, and sucrose preference test. We observed that augmentation of dopamine levels during the perinatal developmental window increased locomotor behavior in females, but not males. We also observed an increase in anxiety-behavior in females and anxiolytic-like behavior in males. In addition, we observed stress-coping behavior in males and an increase of hedonic behavior in females. Our results show that dopamine signaling is important for behavioral development and that transient imbalances of dopamine levels can cause permanent behavioral alterations - alterations which are different in males than in females. These data may help in better understanding the spectrum of symptoms associated with different neuropsychiatric disorders.
Assuntos
Dopaminérgicos/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Levodopa/administração & dosagem , Locomoção/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Caracteres Sexuais , Animais , Animais Recém-Nascidos , Dopamina/metabolismo , Esquema de Medicação , Comportamento Exploratório/fisiologia , Feminino , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , GravidezRESUMO
PURPOSE: To evaluate the physical and chemical compatibilities of treprostinil sodium and dopamine hydrochloride. METHODS: Treprostinil sodium (4,000, 76,000, and 500,000 ng/mL) were mixed with dopamine hydrochloride (0.6, 3.2, 6, and 40 mg/mL). Samples were obtained at hours 0, 1, 2, and 4 for physical compatibility and chemical stability testing. Physical compatibility was assessed by visual examination and measurements of turbidity and pH. Drug concentrations were assessed using stability-indicating liquid chromatography mass spectrophotometry (LCMS) for treprostinil sodium and stability-indicating high-performance liquid chromatography (HPLC) for dopamine hydrochloride. RESULTS: Treprostinil sodium 4,000 and 76,000 ng/mL, when mixed with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL, were stable for 4 hours. Treprostinil sodium 500,000 ng/mL was stable when mixed with dopamine hydrochloride 0.6 mg/mL for 4 hours, but when mixed with dopamine hydrochloride 3.2, 6, and 40 mg/mL, significant precipitation was seen. CONCLUSION: Treprostinil sodium 4,000 and 76,000 ng/mL were stable for 4 hours during simulated Y-site coadministration with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL. Treprostinil sodium 500,000 ng/mL is stable when mixed with dopamine hydrochloride 0.6 mg/mL.
Assuntos
Anti-Hipertensivos/química , Dopaminérgicos/química , Dopamina/química , Incompatibilidade de Medicamentos , Epoprostenol/análogos & derivados , Administração Intravenosa , Epoprostenol/química , Concentração de Íons de Hidrogênio , Fatores de TempoRESUMO
Abstract Background: Motor Imagery (MI) represents the cognitive component of the movement and recruits dopaminergic systems. Objective: To investigate the role of dopaminergic system through the action of methylphenidate and risperidone over beta coherence during execution, action observation and motor imagery. Methods: Electroencephalography (EEG) data were recorded before and after the substance intake. For statistical analysis, a three-way ANOVA was used to identify changes in beta coherence induced by the group, task and the moment variables. Statistical significance was set at p≤0.007. Results: We found a main effect for group for C3/CZ, and a main effect for task for CZ/C4 pairs of electrodes. Furthermore, significant differences were found in the post-drug administration between groups for C3/CZ pair of electrodes, and between task for C4/CZ pair of electrodes. Conclusion: The administration of methylphenidate and risperidone was able to produce electrocortical changes of the cortical central regions, even when featuring antagonistic effects on the dopaminergic pathways. Moreover, the execution task allowed beta-band modulation increase.
Resumo Introdução: A imagética motora (IM) representa o componente cognitivo do movimento e recruta os sistemas dopaminérgicos. Objetivo: Investigar o papel do sistema dopaminérgico por meio da ação do metilfenidato e da risperidona sobre a coerência em beta durante a execução, observação de ação e imagética motora. Métodos: Os dados de eletroencefalografia (EEG) foram registrados antes e depois da ingestão das substâncias. Para a análise estatística, uma ANOVA de três vias foi utilizada para identificar mudanças na coerência beta induzidas pelas variáveis grupo, tarefa e momento. A significância estatística foi estabelecida em p≤0,007. Resultados: Encontramos um efeito principal para o grupo C3/CZ e um efeito principal para a tarefa nos pares de eletrodos CZ/C4. Além disso, diferenças significativas foram encontradas após a administração da droga entre os grupos para o par de eletrodos C3/CZ e entre tarefa para o par de eletrodos C4/CZ. Conclusão: A administração de metilfenidato e risperidona foi capaz de produzir alterações eletrocorticais das regiões somatomotoras, mesmo apresentando efeitos antagônicos nas vias dopaminérgicas. Além disso, a tarefa de execução provocou maior modulação da banda beta.
Assuntos
Humanos , Adulto , Dopaminérgicos/uso terapêutico , Imagens, Psicoterapia , Eletroencefalografia , MovimentoRESUMO
Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients.
Assuntos
Dopaminérgicos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Antagonistas Colinérgicos/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Humanos , Levodopa/uso terapêutico , Expectativa de Vida , Inibidores da Monoaminoxidase/uso terapêutico , Estresse Oxidativo , Doença de Parkinson/diagnósticoRESUMO
Dopamine has emerged as a fundamental regulator of inflammation. In this regard, it has been shown that dopaminergic signalling pathways are key players promoting homeostasis between the central nervous system and the immune system. Dysregulation in the dopaminergic system affects both innate and adaptive immunity, contributing to the development of numerous autoimmune and inflammatory pathologies. This makes dopamine receptors interesting therapeutic targets for either the development of new treatments or repurposing of already available pharmacological drugs. Dopamine receptors are broadly expressed on different immune cells with multifunctional effects depending on the dopamine concentration available and the pattern of expression of five dopamine receptors displaying different affinities for dopamine. Thus, impaired dopaminergic signalling through different dopamine receptors may result in altered behaviour of immunity, contributing to the development and progression of autoimmune pathologies. In this review we discuss the current evidence involving the dopaminergic system in inflammatory bowel disease, multiple sclerosis and Parkinson's disease. In addition, we summarise and analyse the therapeutic approaches designed to attenuate disease development and progression by targeting the dopaminergic system. Graphical Abstract Targetting the dopaminergic system in autoimmunity. Effector T-cells (Teff) orchestrate inflamamtion involved in autoimmunity, whilst regulatory T-cells (Tregs) suppress Teff activity promoting tolerance to self-constituents. Dopamine has emerged as a key regulator of Teff and Tregs function, thereby dopamine receptors have becoming important therapeutic targets in autoimmune disorders, especially in those affecting the brain and the gut, where dopamine levels strongly change with inflammation.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Autoimunidade/efeitos dos fármacos , Dopaminérgicos/administração & dosagem , Dopaminérgicos/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Animais , Doenças Autoimunes/imunologia , Autoimunidade/fisiologia , Dopamina/imunologia , Dopamina/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/imunologia , Doença de Parkinson/metabolismo , Receptores Dopaminérgicos/imunologia , Receptores Dopaminérgicos/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Glyphosate, a non-selective herbicide, causes in mammals cellular mutagenesisand toxic effects at the embryonic, fetal, and placental levels, even at lowconcentrations. This study investigated in rats the effects of perinatal exposureto glyphosate-base herbicide on maternal behavior and the hypothalamic andstriatal levels of dopamine and serotonin. The pups physical and behavioraldevelopment were observed. Glyphosate-base herbicide (50 or 150 mg/kg, peros) was administered in dams during gestation (15º gestational day to 7ºlactation day. The female body weight was recorded throughout the pregnancyand lactation. The dams reproductive performance was observed at postnatalday 2, the open field behavior at postnatal day 5 and the maternal behavior atpostnatal day 6. At weaning, the dams hypothalamic and striatal levels ofdopamine and serotonin were measured. Maternal exposure to both glyphosatebase herbicide doses: i) had few effects on maternal body weight gain; ii)decreased the number and body weight of the pups; iii) impaired the maternalcare; iv) both doses decreased the activity of striatal and hypothalamic dopaminergic systems; v) 50 mg/kg increased and 150 mg/kg decreased theserotoninergic hypothalamic activity. In offspring, no effects on physicaldevelopment but a delay on reflex development. Conclusions: perinatal exposureto glyphosate-base herbicide decreased the maternal care by a reduced striataldopaminergic activity and delayed the pups reflex development.(AU)
O glifosato é um herbicida não seletivo, que causa mutagênese celular e efeitostóxicos embrionário, fetal e placentário, mesmo em baixas concentrações. Esteestudo investigou, em ratos, os efeitos da exposição perinatal ao herbicida àbase de glifosato sobre o comportamento materno e os níveis hipotalâmicos eestriatais de dopamina e serotonina. O desenvolvimento físico e comportamentaldos filhotes foi observado. O herbicida (50 ou 150 mg / kg, per os) foiadministrado às mães durante a gestação (15º dia gestacional ao 7º dia delactação. O peso corporal foi registrado durante a gestação e lactação Odesempenho reprodutivo das mães foi observado no dia pós-natal 2, ocomportamento de campo aberto no dia pós-natal 5 e o comportamento maternono dia pós-natal 6. Ao desmame os níveis hipotalâmicos e estriatais da dopaminae da serotonina foram medidos. A exposição materna às duas doses do glifosato:i) teve poucos efeitos sobre o ganho de peso corporal materno; ii) diminuiu onúmero e peso corporal dos filhotes; iii) prejudicou o cuidado materno; iv)ambas as doses diminuíram a atividade dos sistemas dopaminérgicos estriatal ehipotalâmico; v) 50 mg / kg e 150 mg / kg do glifosato diminuíram a atividadehipotalâmica serotoninérgica. Na prole, não houve efeitos no desenvolvimentofísico, mas observou-se atraso no desenvolvimento reflexológico. Poucos efeitosna atividade geral do filhote foram observados. Conclusões: a exposiçãoperinatal ao herbicida à base de glifosato diminuiu o cuidado materno por umaatividade redução da atividade dopaminérgica estriatal e atrasou odesenvolvimento dos reflexos dos filhotes.(AU)