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1.
Mov Disord ; 34(6): 821-831, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31002748

RESUMO

BACKGROUND: Prolonged dopaminergic replacement therapy in PD results in pulsatile dopamine receptors stimulation in both dorsal and ventral striatum causing wearing off, motor fluctuations, and nonmotor side effects such as behavioral addictions. Among impulse control disorders, binge eating can be easily modeled in laboratory animals. OBJECTIVES: We hypothesize that manipulation of dopamine levels in a 6-hydroxydopamine-lesioned rats, as a model of PD characterized by a different extent of dopamine denervation between dorsal and ventral striatum, would influence both synaptic plasticity of the nucleus accumbens and binge-like eating behavior. METHODS: Food preference, food intake, and weight gain were monitored in sham-operated and unilaterally lesioned rats, subjected to a modified version of Corwin's limited access protocol, modelling binge eating disorder. Electrophysiological properties and long-term potentiation of GABAergic spiny projection neurons of the nucleus accumbens core were studied through ex vivo intracellular and patch-clamp recordings from corticostriatal slices of naïve and l-dopa-treated rats. RESULTS: Sham-operated animals with intact nucleus accumbens core plasticity reliably developed food-addiction-like behavior when exposed to intermittent access to a highly palatable food. In contrast, parkinsonian rats were unresponsive to such restriction regimens, and also plasticity was lost in ventral spiny neurons. Chronic l-dopa reestablished long-term potentiation and compulsive eating, but with a different temporal dynamic that follows that of drug administration. CONCLUSIONS: Our data indicate that endogenous and exogenous dopamine drive binge-like consumption of a palatable food in healthy and parkinsonian rats with distinct temporal dynamics, providing new insights into the complexity of l-dopa effects on the mesolimbic dopaminergic system. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Dopaminérgicos/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Levodopa/farmacologia , Transtornos Parkinsonianos/fisiopatologia , Animais , Preferências Alimentares/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiopatologia , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Wistar , Aumento de Peso/efeitos dos fármacos
2.
Brain ; 141(2): 505-520, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29281030

RESUMO

Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson's disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson's disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson's disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson's disease, and that might be relevant for other striatal pathologies, such as drug abuse.


Assuntos
Corpo Estriado/citologia , Aprendizagem/fisiologia , Atividade Motora/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Aprendizagem/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Piperazinas/farmacologia , Tempo de Reação/fisiologia , Sinapsinas/genética , Sinapsinas/metabolismo , Sinaptofisina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/farmacologia
3.
Mov Disord ; 32(7): 1035-1046, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28394013

RESUMO

BACKGROUND: Recent studies support the therapeutic utility of repetitive transcranial magnetic stimulation in Parkinson's disease (PD), whose progression is correlated with loss of corticostriatal long-term potentiation and long-term depression. Glial cell activation is also a feature of PD that is gaining increasing attention in the field because astrocytes play a role in chronic neuroinflammatory responses but are also able to manage dopamine (DA) levels. METHODS: Intermittent theta-burst stimulation protocol was applied to study the effect of therapeutic neuromodulation on striatal DA levels measured by means of in vivo microdialysis in 6-hydroxydopamine-hemilesioned rats. Effects on corticostriatal synaptic plasticity were studied through in vitro intracellular and whole-cell patch clamp recordings while stepping test and CatWalk were used to test motor behavior. Immunohistochemical analyses were performed to analyze morphological changes in neurons and glial cells. RESULTS: Acute theta-burst stimulation induced an increase in striatal DA levels in hemiparkinsonian rats, 80 minutes post-treatment, correlated with full recovery of plasticity and amelioration of motor performances. With the same timing, immediate early gene activation was restricted to striatal spiny neurons. Intense astrocytic and microglial responses were also significantly reduced 80 minutes following theta-burst stimulation. CONCLUSION: Taken together, these results provide a first glimpse on physiological adaptations that occur in the parkinsonian striatum following intermittent theta-burst stimulation and may help to disclose the real potential of this technique in treating PD and preventing DA replacement therapy-associated disturbances. © 2017 International Parkinson and Movement Disorder Society.


Assuntos
Astrócitos/fisiologia , Córtex Cerebral , Corpo Estriado , Dopamina/metabolismo , Microglia/fisiologia , Atividade Motora/fisiologia , Plasticidade Neuronal/fisiologia , Transtornos Parkinsonianos/terapia , Estimulação Magnética Transcraniana/métodos , Adrenérgicos/farmacologia , Animais , Comportamento Animal/fisiologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Genes Precoces/fisiologia , Masculino , Microdiálise , Oxidopamina/farmacologia , Transtornos Parkinsonianos/induzido quimicamente , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Ritmo Teta/fisiologia
4.
J Neuroinflammation ; 13(1): 150, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27301743

RESUMO

BACKGROUND: After focal brain injuries occur, in addition to the effects that are attributable to the primary site of damage, the resulting functional impairments depend highly on changes that occur in regions that are remote but functionally connected to the site of injury. Such effects are associated with apoptotic and inflammatory cascades and are considered to be important predictors of outcome. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique that is used to treat various central nervous system (CNS) pathologies and enhance functional recovery after brain damage. OBJECTIVE: This study examined the efficacy of rTMS in mitigating remote degeneration and inflammation and in improving functional recovery in a model of focal brain damage. METHODS: Rats that were undergoing hemicerebellectomy (HCb) were treated with an rTMS protocol for 7 days, and neuronal death indices, glial activation, and functional recovery were assessed. RESULTS: rTMS significantly reduced neuronal death and glial activation in remote regions and improved functional recovery. CONCLUSIONS: Our finding opens up a completely new scenario for exploiting the potential of rTMS as an anti-apoptotic and anti-inflammatory treatment.


Assuntos
Apoptose/efeitos da radiação , Lesões Encefálicas/complicações , Inflamação/etiologia , Inflamação/terapia , Estimulação Magnética Transcraniana , Animais , Lesões Encefálicas/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Citocromos c/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos da radiação , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Neuroglia/metabolismo , Fosfopiruvato Hidratase/metabolismo , RNA Mensageiro , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos da radiação
5.
Neuropharmacology ; 101: 341-50, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26471421

RESUMO

Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca(2+)) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3-10 µM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 µM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 µM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 µM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 µM) and MK801 (10 µM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Memantina/farmacologia , Sinapses/efeitos dos fármacos , Análise de Variância , Animais , Biofísica , Estimulantes do Sistema Nervoso Central/farmacologia , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estimulação Elétrica , Técnicas In Vitro , Masculino , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo
6.
Neurobiol Dis ; 86: 140-53, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26639853

RESUMO

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.


Assuntos
Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Discinesia Induzida por Medicamentos/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Transtornos Parkinsonianos/complicações , Piperazinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Animais , Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Levodopa , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Wistar , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
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