RESUMO
PURPOSE: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. MATERIALS AND METHODS: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the µ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. RESULTS: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. CONCLUSIONS: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.
Assuntos
Fentanila , Camundongos Endogâmicos C57BL , Receptores Opioides mu , Caracteres Sexuais , Animais , Fentanila/farmacologia , Masculino , Feminino , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Camundongos , Metilação de DNA/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Naloxona/farmacologia , Comportamento Animal/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Epigênese Genética/efeitos dos fármacosRESUMO
Greater exposure to stressors over the life course is believed to promote striatum-dependent over hippocampus-dependent learning and memory processes under stressful conditions. However, little research in this context has actually assessed lifetime stressor exposure and, moreover, it remains unknown whether greater cumulative lifetime stressor exposure exerts comparable effects on striatum-dependent learning and hippocampus-dependent learning in non-stressful contexts. To investigate this issue, we used the Stress and Adversity Inventory for Adults (Adult STRAIN) and Multicued Search Task to investigate the relation between cumulative lifetime stressor exposure and striatum-dependent stimulus-response learning and hippocampus-dependent contextual learning under non-stressful conditions among healthcare professionals (N = 205; 157 females, 48 males; Age: M = 34.23, SD 9.3, range 20-59 years). Individuals with moderate, but not low, cumulative lifetime stressor exposure exhibited impaired learning for stimulus-response associations. In contrast, learning for context associations was unrelated to participants' lifetime stressor exposure profiles. These results thus provide first evidence that cumulative lifetime stressor exposure may have negative consequences on human striatum-dependent stimulus-response learning under non-stressful environmental conditions.
Assuntos
Aprendizagem , Estresse Psicológico , Humanos , Masculino , Feminino , Adulto , Estresse Psicológico/fisiopatologia , Pessoa de Meia-Idade , Adulto Jovem , Aprendizagem/fisiologia , Hipocampo/fisiologia , Corpo Estriado/fisiologiaRESUMO
Parkinson's disease (PD) is a complex disorder, primarily of idiopathic origin, with environmental stressors like rotenone and manganese linked to its development. This study explores their potential interaction and resulting neurotoxicity, aiming to understand how environmental factors contribute to PD. In an eight-day experiment, male Wistar rats weighing 280-300 g were subjected to rotenone, manganese, or a combination of both. Various parameters were assessed, including body weight, behavior, serum markers, tissue damage, protein levels (tyrosine hydroxylase, Dopamine- and cAMP-regulated neuronal phosphoprotein -DARPP-32-, and α-synuclein), and mitochondrial function. Manganese heightened rotenone's impact on reducing food intake without causing kidney or liver dysfunction. However, the combined exposure intensified neurotoxicity, which was evident in augmented broken nuclei and decreased tyrosine hydroxylase and DARPP-32 levels in the striatum. While overall mitochondrial function was preserved, co-administration reduced complex IV activity in the midbrain and liver. In conclusion, our findings revealed a parallel toxic effect induced by rotenone and manganese. Notably, while these substances do not target the same dopaminergic regions, a notable escalation in toxicity is evident in the striatum, the brain region where their toxic effects converge. This study highlights the need for further exploration regarding the interaction of environmental factors and their possible impact on the etiology of PD.
Assuntos
Manganês , Ratos Wistar , Rotenona , Tirosina 3-Mono-Oxigenase , Animais , Rotenona/toxicidade , Masculino , Manganês/toxicidade , Ratos , Tirosina 3-Mono-Oxigenase/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , alfa-Sinucleína/metabolismo , Síndromes Neurotóxicas/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacosRESUMO
Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.
Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Sintomas Prodrômicos , Substância Negra , Animais , Masculino , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Doenças Neuroinflamatórias/patologia , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ansiedade/etiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologiaRESUMO
Chronic ethanol exposure often triggers neuroinflammation in the brain's reward system, potentially promoting the drive for ethanol consumption. A main marker of neuroinflammation is the microglia-derived monocyte chemoattractant protein 1 (MCP1) in animal models of alcohol use disorder in which ethanol is forcefully given. However, there are conflicting findings on whether MCP1 is elevated when ethanol is taken voluntarily, which challenges its key role in promoting motivation for ethanol consumption. Here, we studied MCP1 mRNA levels in areas implicated in consumption motivation-specifically, the prefrontal cortex, hippocampus, and striatum-as well as in the cerebellum, a brain area highly sensitive to ethanol, of C57BL/6 mice subjected to intermittent and voluntary ethanol consumption for two months. We found a significant increase in MCP1 mRNA levels in the cerebellum of mice that consumed ethanol compared to controls, whereas no significant changes were observed in the prefrontal cortex, hippocampus, or striatum or in microglia isolated from the hippocampus and striatum. To further characterize cerebellar neuroinflammation, we measured the expression changes in other proinflammatory markers and chemokines, revealing a significant increase in the proinflammatory microRNA miR-155. Notably, other classical proinflammatory markers, such as TNFα, IL6, and IL-1ß, remained unaltered, suggesting mild neuroinflammation. These results suggest that the onset of neuroinflammation in motivation-related areas is not required for high voluntary consumption in C57BL/6 mice. In addition, cerebellar susceptibility to neuroinflammation may be a trigger to the cerebellar degeneration that occurs after chronic ethanol consumption in humans.
Assuntos
Consumo de Bebidas Alcoólicas , Cerebelo , Quimiocina CCL2 , Corpo Estriado , Etanol , Hipocampo , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal , Animais , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Camundongos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Cerebelo/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Masculino , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Corpo Estriado/efeitos dos fármacos , Etanol/efeitos adversos , Consumo de Bebidas Alcoólicas/efeitos adversos , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/patologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/induzido quimicamenteRESUMO
The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina , Doença de Huntington , Camundongos , Animais , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Sarcosina/farmacologia , Neuroproteção , Glicina/farmacologia , Corpo Estriado/metabolismo , Doença de Huntington/tratamento farmacológicoRESUMO
Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT1 receptors (AT1-R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT1-R role in the development and maintenance of AMPH-induced sensitization. Also, the AT1-R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT1-R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT1-R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT1-R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT1-R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT1-R blockade altered the performance of social interaction. Our results highlight the AT1-R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT1-R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT1-R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.
Assuntos
Anfetamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Angiotensina II , Benzimidazóis , Compostos de Bifenilo , Corpo Estriado , Dopamina , Animais , Anfetamina/farmacologia , Masculino , Dopamina/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Angiotensina II/farmacologia , Compostos de Bifenilo/farmacologia , Benzimidazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Ratos Wistar , Ratos , Receptor Tipo 1 de Angiotensina/metabolismo , Tetrazóis/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Interação Social/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Levodopa (L-DOPA) is the classical gold standard treatment for Parkinson's disease. However, its chronic administration can lead to the development of L-DOPA-induced dyskinesias (LIDs). Dysregulation of the nitric oxide-cyclic guanosine monophosphate pathway in striatal networks has been linked to deficits in corticostriatal transmission in LIDs. This study investigated the effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on behavioural and electrophysiological outcomes in sham-operated and 6-hydroxydopamine-lesioned rats chronically treated with vehicle or L-DOPA, respectively. In sham-operated animals, systemic administration of SNP increased the spike probability of putative striatal medium spiny neurons (MSNs) in response to electrical stimulation of the primary motor cortex. In 6-hydroxydopamine-lesioned animals, SNP improved the stepping test performance without exacerbating abnormal involuntary movements. Additionally, SNP significantly increased the responsiveness of putative striatal MSNs in the dyskinetic striatum. These findings highlight the critical role of the NO signalling pathway in facilitating the responsiveness of striatal MSNs in both the intact and dyskinetic striata. The study suggests that SNP has the potential to enhance L-DOPA's effects in the stepping test without exacerbating abnormal involuntary movements, thereby offering new possibilities for optimizing Parkinson's disease therapy. In conclusion, this study highlights the involvement of the NO signalling pathway in the pathophysiology of LIDs.
Assuntos
Discinesias , Doença de Parkinson , Ratos , Animais , Levodopa/efeitos adversos , Nitroprussiato/farmacologia , Oxidopamina/toxicidade , Neurônios Espinhosos Médios , Óxido Nítrico/metabolismo , Discinesias/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Antiparkinsonianos/efeitos adversosRESUMO
BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway. Even with scientific and technological advances, the therapeutic approaches used for the treatment of PD have shown to be largely ineffective in controlling the progression of symptoms in the long term. There is a growing demand for the development of novel therapeutic strategies for PD treatment. Different herbs and supplements have been considered as adjuvant to treat the symptoms of Parkinsonism. The carrot is one of the most consumed vegetable species worldwide, and its root is known for its content of anthocyanins, which possess antioxidant and antiinflammatory properties. This study evaluated the neuroprotective effect of purple carrot extract (CAR) in rats on the reserpine (RES)-induced progressive parkinsonism model. METHODS: Male rats (6-month-old) received orally the CAR (400 mg/kg) or vehicle and subcutaneously RES (0.01 mg/kg) or vehicle for 28 days (Preventive Phase). From the 29th day, rats received CAR or vehicle daily and RES (0.1 mg/kg) or vehicle every other day (for 23 days, Protective phase). Behavioral tests were conducted throughout the treatment. Upon completion, the animals' brain were processed for tyrosine hydroxylase (TH) immunohistochemical assessment. RESULTS: Our results showed that the chronic treatment of CAR protected against motor disabilities, reducing the time of catalepsy behavior and decreasing the frequency of oral movements, possibly by preserving TH levels in the Ventral Tegmental Area (VTA) and SNpc. CONCLUSION: CAR extract is effective to attenuate motor symptoms in rats associated with increased TH+ levels in the Ventral Tegmental Area (VTA) and SNpc, indicating the potential nutraceutical benefits of CAR extract in a progressive parkinsonism model induced by RES.
Assuntos
Daucus carota , Fármacos Neuroprotetores , Extratos Vegetais , Reserpina , Tirosina 3-Mono-Oxigenase , Animais , Reserpina/toxicidade , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Daucus carota/química , Tirosina 3-Mono-Oxigenase/metabolismo , Ratos Wistar , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Modelos Animais de Doenças , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologiaRESUMO
Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated.