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2.
Mol Cell Neurosci ; 68: 46-55, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25858108

RESUMO

The globus pallidus plays a significant role in motor control under both health and pathological states. Recent studies have revealed that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels occupy a critical position in globus pallidus pacemaking activity. Morphological studies have shown the expression of HCN channels in the globus pallidus. To investigate the in vivo effects of HCN channels in the globus pallidus, extracellular recordings and behavioral tests were performed in the present study. In normal rats, micro-pressure ejection of 0.05mM ZD7288, the selective HCN channel blocker, decreased the frequency of spontaneous firing in 21 out of the 40 pallidal neurons. The average decrease was 50.4±5.4%. Interestingly, in another 18 out of the 40 pallidal neurons, ZD7288 increased the firing rate by 137.1±27.6%. Similar bidirectional modulation on the firing rate was observed by a higher concentration of ZD7288 (0.5mM) as well as another HCN channel blocker, CsCl. Furthermore, activation of HCN channels by 8-Br-cAMP increased the firing rate by 63.0±9.3% in 15 out of the 25 pallidal neurons and decreased the firing rate by 46.9±9.4% in another 8 out of the 25 pallidal neurons. Further experiments revealed that modulation of glutamatergic but not GABAergic transmission may be involved in ZD7288-induced increase in firing rate. Consistent with electrophysiological results, further studies revealed that modulation of HCN channels also had bidirectional effects on behavior. Taken together, the present studies suggest that HCN channels may modulate the activity of pallidal neurons by different pathways in vivo.


Assuntos
Globo Pálido/citologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia , Neurônios/fisiologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cardiotônicos/farmacologia , Césio/farmacologia , Cloretos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Postura/fisiologia , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Núcleo Subtalâmico/lesões , Valina/análogos & derivados , Valina/farmacologia , Vigília
3.
Synapse ; 68(3): 114-26, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24265191

RESUMO

Several studies in rodents have suggested the inactivation of the subthalamic nucleus (STN) as an alternative strategy to Parkinson's disease (PD) treatment. The STN is part of the basal ganglia and plays an important role in the motor function; however, recent data suggest that this structure has a critical role in the cognitive function of the limbic system. The STN receives direct projection from the prefrontal cortex (PFC), structure interconnected with the hippocampus and both structures send excitatory projections to the nucleus accumbens (NAcc). Here, we determined whether and which changes occurred 4 weeks after a STN lesion in the dendritic morphology of pyramidal neurons of the layers 3 and 5 of the PFC and basolateral amygdala, neurons of the ventral hippocampus, and the medium spiny neurons of the NAcc and caudate-putamen. Dendritic morphology was measured using the Golgi-Cox procedure followed by Sholl analysis. We also evaluated the effects of STN lesion on locomotor behavior assessed by an open field test, social interaction, acoustic startle response, prepulse inhibition, and locomotor activity induced by a novel environment and amphetamine. We found that STN damage induced a deficit in locomotion measured by open field test with neuronal hypertrophy in PFC (layer 5) and reduced spinogenesis in CA1 ventral hippocampus and PFC (layer 3). Taken together, these data suggest that the behavioral and morphological effects of STN lesion are, at least partially, mediated by limbic subregions with possible consequences for cognitive-related behaviors observed in PD treatment.


Assuntos
Dendritos/patologia , Hipocampo/patologia , Neurônios/patologia , Córtex Pré-Frontal/patologia , Núcleo Subtalâmico/lesões , Tonsila do Cerebelo/patologia , Animais , Núcleo Caudado/patologia , Espinhas Dendríticas/patologia , Masculino , Atividade Motora , Núcleo Accumbens/patologia , Putamen/patologia , Células Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Filtro Sensorial , Comportamento Social , Núcleo Subtalâmico/patologia , Fatores de Tempo
4.
Stereotact Funct Neurosurg ; 91(5): 323-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23817223

RESUMO

BACKGROUND/AIMS: Operation-induced dyskinesia (OID) occurs in approximately 10% of patients submitted to subthalamotomy. The goal of the authors was to determine the possible causes of this feared complication. METHODS: The 54 patients who underwent unilateral subthalamotomy were divided into two groups: the OID group (OIDG), composed of 6 patients who developed dyskinesia following the operation, and the control group (CG), consisting of 48 patients who did not present this complication. The two groups were compared regarding age; sex; presence of levodopa-induced dyskinesia (LID) and/or stimulation-induced dyskinesia (SID); side of the operation; territories of the subthalamic nucleus (STN) involved by the lesion, and degree of lesion extension towards the zona incerta (ZI). RESULTS: The lesion involved the dorsolateral territory of the STN and was almost completely restricted to this nucleus in all patients of the OIDG, while it spread to the ZI in all but 1 patient of the CG. SID was significantly (p < 0.05) more frequent in the OIDG. There was also a strong trend favoring LID (p = 0.055). CONCLUSIONS: Damage to the dorsolateral territory of the STN and sparing of the ZI seem to be essential for the development of OID. SID and, to a lesser extent, LID are apparently significant risk factors for the development of this complication.


Assuntos
Discinesias/etiologia , Doença de Parkinson/cirurgia , Complicações Pós-Operatórias/etiologia , Núcleo Subtalâmico/cirurgia , Subtálamo/fisiopatologia , Adulto , Idoso , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Discinesias/fisiopatologia , Feminino , Humanos , Levodopa/efeitos adversos , Levodopa/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Complicações Pós-Operatórias/fisiopatologia , Estudos Retrospectivos , Núcleo Subtalâmico/lesões , Núcleo Subtalâmico/patologia , Núcleo Subtalâmico/fisiopatologia , Subtálamo/patologia
5.
Behav Brain Res ; 252: 356-62, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23748197

RESUMO

In Parkinson's disease, global social maladjustment and anxiety are frequent after subthalamic nucleus (STN) stimulation and are generally considered to be linked with sociofamilial alterations induced by the motor effects of stimulation. We hypothesized that the STN is per se involved in these changes and aimed to explore the role of STN in social and anxogenic-like behaviors using an animal model. Nineteen male Wistar rats with bilateral lesions of the STN were compared with 26 sham-lesioned rats by synchronizing an ethological approach based upon direct observation of social behaviors and a standardized approach, the elevated plus maze (EPM). Comparisons between groups were performed by a Mann-Whitney-Wilcoxon test. Lesioned rats showed impairments in their social (P=0.05) and aggressive behaviors with a diminution of attacking (P=0.04) and chasing (P=0.06). In the EPM, concerning the open arms, the percentage of distance, time, inactive time, and entry were significantly decreased in lesioned rats (P=0.02, P=0.01, P=0.04, and P=0.05). The time spent in non-protected head dips was also diminished in the lesioned rats (P=0.01). These results strongly implicate the STN in social behavior and anxogenic-like behavior. In human, as DBS induces changes in the underlying dynamics of the stimulated brain networks, it could create an abnormal brain state in which anxiety and social behavior are altered. These results highlight another level of complexity of the behavioral changes after stimulation.


Assuntos
Ansiedade/etiologia , Ansiedade/patologia , Relações Interpessoais , Núcleo Subtalâmico/fisiologia , Animais , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Elevação dos Membros Posteriores/fisiologia , Elevação dos Membros Posteriores/psicologia , Modelos Lineares , Masculino , Ratos , Ratos Wistar , Núcleo Subtalâmico/lesões
6.
Stereotact Funct Neurosurg ; 91(1): 12-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23154788

RESUMO

BACKGROUND: Microlesion effect (MLE) is a commonly observed phenomenon after electrode insertion into the subthalamic nucleus (STN) for deep brain stimulation (DBS). OBJECTIVES: The aim of this study was to determine the presence of the MLE in the early postoperative period and the relationship between MLE and STN DBS. METHODS: 74 patients with Parkinson's disease were included in this study. Motor symptoms were evaluated preoperatively, within 48 h after electrode implantation and at 6 months with United Parkinson's Disease Rating Scale part III (UPDRS-III). According to the improvement level with MLE, all participants were stratified into three groups: (1) less than 20%; (2) 20-40%, and (3) more than 40% in OFF medication states. The degree of improvement in UPDRS-III with DBS ON for each MLE group was assessed at the 6-month follow-up. Regression analysis was applied for the evaluation of the relationship between MLE and improvement with DBS ON. RESULTS: Mean results in UPDRS-III with the MLE in ON and OFF medication states were 22.1 ± 10.5 and 42.1 ± 14 points, respectively. At the 6-month follow-up, with active stimulation, results tended to further ameliorate to 14.6 (59.4%) points in ON and 20.8 (55.3%) in OFF. Mean improvement in MLE groups were: 33.6% group 1, 47.5% group 2 and 61.4% group 3. Regression analysis revealed a positive correlation between the MLE and results at 6 months with DBS ON. CONCLUSION: Results proved the presence of MLE in the early postoperative period. Furthermore, a positive correlation between MLE and improvement degree with active stimulation was observed.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson/terapia , Núcleo Subtalâmico/fisiopatologia , Antiparkinsonianos/uso terapêutico , Terapia Combinada , Eletrodos Implantados/efeitos adversos , Feminino , Seguimentos , Globo Pálido/lesões , Globo Pálido/fisiopatologia , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Atividade Motora , Doença de Parkinson/tratamento farmacológico , Índice de Gravidade de Doença , Núcleo Subtalâmico/lesões , Resultado do Tratamento
7.
Stereotact Funct Neurosurg ; 91(1): 24-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23154815

RESUMO

BACKGROUND: Deep brain stimulation (DBS) of the caudal zona incerta (cZi) is a relatively unexplored and promising treatment in patients with severe essential tremor (ET). Preliminary data further indicate that the ability to produce language may be slightly affected by the treatment. OBJECTIVE: To evaluate the effects on verbal fluency following cZi DBS in patients with ET. METHOD: Seventeen consecutive patients who had undergone DBS of the cZi for ET were tested regarding verbal fluency before surgery, 3 days after surgery and after 1 year. Ten patients were also evaluated by comparing performance on versus off stimulation after 1 year. RESULTS: The total verbal fluency score decreased slightly, but significantly, from 22.7 (SD = 10.9) before surgery to 18.1 (SD = 7.5) 3 days after surgery (p = 0.036). After 1 year the score was nonsignificantly decreased to 20.1 (SD = 9.7, p = 0.2678). There was no detectable difference between stimulation on and off after 1 year. CONCLUSION: There was a tendency of an immediate and mostly transient postoperative decline in verbal fluency following cZi DBS for ET. In some of the patients this reduction was, however, more pronounced and also sustained over time.


Assuntos
Estimulação Encefálica Profunda/efeitos adversos , Tremor Essencial/terapia , Distúrbios da Fala/etiologia , Núcleo Subtalâmico/fisiopatologia , Idoso , Dominância Cerebral , Eletrodos Implantados/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Distúrbios da Fala/fisiopatologia , Núcleo Subtalâmico/lesões
8.
J Neurosci ; 32(50): 18047-53, 2012 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-23238720

RESUMO

Cellular electrophysiological signatures of Parkinson's disease described in the pharmacological 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease include spontaneous repetitive giant GABAergic currents in a subpopulation of striatal medium spiny neurons (MSNs), and spontaneous rhythmic bursts of spikes generated by subthalamic nucleus (STN) neurons. We investigated whether similar signatures are present in Pink1(-/-) mice, a genetic rodent model of the PARK6 variant of Parkinson's disease. Although 9- to 24-month-old Pink1(-/-) mice show reduced striatal dopamine content and release, and impaired spontaneous locomotion, the relevance of this model to Parkinson's disease has been questioned because mesencephalic dopaminergic neurons do not degenerate during the mouse lifespan. We show that 75% of the MSNs of 5- to 7-month-old Pink1(-/-) mice exhibit giant GABAergic currents, occurring either singly or in bursts (at 40 Hz), rather than the low-frequency (2 Hz), low-amplitude, tonic GABAergic drive common to wild-type MSNs of the same age. STN neurons from 5- to 7-month-old Pink1(-/-) mice spontaneously generated bursts of spikes instead of the control tonic drive. Chronic kainic acid lesion of the STN or chronic levodopa treatment reliably suppressed the giant GABAergic currents of MSNs after 1 month and replaced them with the control tonic activity. The similarity between the in vitro resting states of Pink1 MSNs and those of fully dopamine (DA)-depleted MSNs of 6-OHDA-treated mice, together with the beneficial effect of levodopa treatment, strongly suggest that dysfunction of mesencephalic dopaminergic neurons in Pink1(-/-) mice is more severe than expected. The beneficial effect of the STN lesion also suggests that pathological STN activity strongly influences striatal networks in Pink1(-/-) mice.


Assuntos
Levodopa/farmacologia , Neurônios/efeitos dos fármacos , Transtornos Parkinsonianos/fisiopatologia , Proteínas Quinases/deficiência , Núcleo Subtalâmico/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Antiparkinsonianos/farmacologia , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Condutividade Elétrica , Agonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Imuno-Histoquímica , Ácido Caínico/toxicidade , Masculino , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Transtornos Parkinsonianos/patologia , Técnicas de Patch-Clamp , Proteínas Quinases/genética , Núcleo Subtalâmico/lesões , Núcleo Subtalâmico/patologia , Núcleo Subtalâmico/fisiopatologia
9.
J Clin Neurosci ; 19(11): 1582-3, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22954791

RESUMO

Deep brain stimulation (DBS) can be complicated by adverse events, which are generally classified as surgical-hardware or stimulation-related. Here we report the onset of a painful cervical dystonia probably triggered by the extension wire of a subthalamic nucleus (STN)-DBS device in a woman suffering from advanced Parkinson's disease (PD). Two months after implantation of the STN-DBS device, our patient developed a painful cervical dystonia, which was not responsive to neurostimulation or to medication. No sign of infections or fibrosis was detected. A patch test with the components of the device was performed, revealing no hypersensibility. The patient was referred back to surgery to reposition the pulse generator in the contralateral subclavian region. A deeper channeling of the wire extensions produced a complete remission of the painful dystonia.


Assuntos
Estimulação Encefálica Profunda/efeitos adversos , Estimulação Encefálica Profunda/instrumentação , Eletrodos Implantados/efeitos adversos , Torcicolo/etiologia , Idoso , Falha de Equipamento , Feminino , Humanos , Dor/etiologia , Doença de Parkinson/cirurgia , Doença de Parkinson/terapia , Reoperação , Núcleo Subtalâmico/lesões
10.
Behav Brain Res ; 213(1): 73-81, 2010 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-20434489

RESUMO

Major depression (MD) has been projected to be the first leading cause of disability worldwide. Still, the pathophysiological processes and factors leading to depression remain largely unknown. The present study investigated the differential effects of selective medial prefrontal cortex (mPFC) and subthalamic nucleus (STN) lesions on depression-like and depression-associated behavior in rats, using the following behavioral paradigms: (i) learned helplessness model testing depressive behavior, (ii) elevated plus-maze testing anxious behavior, (iii) 8-arm radial maze testing cognitive performance and (iv) the open-field testing locomotion. Lesion of both, the mPFC or the STN selectively increased depression-like behavior in rats. These effects were not biased by any effects on depression-associated behavior, such as increased anxiety, cognitive impairment or deficits in locomotion. The behavioral data presented in this study support a specific involvement of the mPFC in the pathophysiology of MD and point towards a potent regulatory function of the STN in processing limbic information towards cortical and subcortical regions in the brain pathophysiologically relevant in the manifestation of MD.


Assuntos
Comportamento Animal/fisiologia , Depressão/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Núcleo Subtalâmico/fisiopatologia , Animais , Ansiedade/fisiopatologia , Cognição/fisiologia , Desamparo Aprendido , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Córtex Pré-Frontal/lesões , Ratos , Ratos Wistar , Percepção Espacial/fisiologia , Núcleo Subtalâmico/lesões , Fatores de Tempo
11.
Braz. j. med. biol. res ; 43(1): 85-95, Jan. 2010. ilus
Artigo em Inglês | LILACS | ID: lil-535638

RESUMO

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.


Assuntos
Animais , Masculino , Ratos , Dopamina/fisiologia , Atividade Motora/efeitos dos fármacos , Neurônios/patologia , Doença de Parkinson Secundária/patologia , Substância Negra/citologia , Núcleo Subtalâmico/lesões , Imuno-Histoquímica , Atividade Motora/fisiologia , N-Metilaspartato , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Veículos Farmacêuticos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/fisiopatologia , Distribuição Aleatória , Ratos Wistar , Substância Negra/fisiopatologia , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/patologia , Núcleo Subtalâmico/cirurgia , /metabolismo
12.
Braz J Med Biol Res ; 43(1): 85-95, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19967265

RESUMO

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.


Assuntos
Dopamina/fisiologia , Atividade Motora/efeitos dos fármacos , Neurônios/patologia , Doença de Parkinson Secundária/patologia , Substância Negra/citologia , Núcleo Subtalâmico/lesões , Animais , Imuno-Histoquímica , Masculino , Atividade Motora/fisiologia , N-Metilaspartato , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/fisiopatologia , Veículos Farmacêuticos , Distribuição Aleatória , Ratos , Ratos Wistar , Substância Negra/fisiopatologia , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/patologia , Núcleo Subtalâmico/cirurgia , Tirosina 3-Mono-Oxigenase/metabolismo
13.
Behav Pharmacol ; 20(5-6): 437-46, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19667971

RESUMO

Recent evidence suggests that the subthalamic nucleus (STN) is involved in regulating the incentive value of food reinforcers. The objective of this study was to examine the effect of lesions of the STN on intertemporal choice (choice between reinforcers differing in size and delay). Rats with bilateral quinolinic acid-induced lesions of the STN (n = 15) or sham lesions (n = 14) were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after a delay d(B). d(B) increased across blocks of trials; d(A) was manipulated across phases of the experiment. Indifference delay, d(B(50)) (value of d(B) corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (d(B(50)) vs. d(A)) were derived. The STN-lesioned group showed a flatter slope of the indifference function (implying higher instantaneous reinforcer values) than the sham-lesioned group; the intercepts did not differ between the groups. The results agree with recent evidence for a role of the STN in incentive value. Unlike some earlier studies, these results do not indicate a role of the STN in delay discounting.


Assuntos
Comportamento de Escolha/fisiologia , Preferências Alimentares/fisiologia , Motivação/fisiologia , Reforço Psicológico , Núcleo Subtalâmico/lesões , Núcleo Subtalâmico/fisiopatologia , Animais , Comportamento Animal , Condicionamento Operante/fisiologia , Feminino , Desempenho Psicomotor/fisiologia , Ratos , Ratos Wistar , Esquema de Reforço , Fatores de Tempo
14.
Synapse ; 63(2): 136-46, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19021215

RESUMO

The mechanism by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) achieves its effects in Parkinson's disease (PD) is not known. In animal models of PD, stimulation and lesioning of the STN have some effects which are the same, but others which differ, in reversing cellular and behavioral changes induced by dopamine depletion. We compared the effects of short-term STN stimulation and lesions upon extracellular levels of dopamine and metabolites using in vivo microdialysis of the dorsal striatum of awake, intact and unilateral 6-hydroxydopamine (6OHDA)-lesioned rats. STN stimulation in control rats decreased striatal dopamine levels and caused a relative increase in dopamine metabolism, as expressed by HVA/dopamine and DOPAC/dopamine ratios. This suggests an increase in both vesicular dopamine release (metabolized to HVA), and release from the cytoplasmic dopamine pool (metabolized to DOPAC). STN lesions in control rats increased the HVA/dopamine ratio, also suggesting a relative increase in vesicular dopamine release. These results indicate that STN stimulation and lesioning can affect striatal dopamine metabolism in the intact system. In 6OHDA-lesioned rats at baseline, metabolic ratios were markedly decreased as compared with controls. STN lesions of 6OHDA-lesioned rats did not affect relative metabolic ratios as compared with baseline levels. In 6-OHDA-lesioned rats, STN stimulation decreased extracellular levels of dopamine, and, to a greater extent, metabolites, resulting in a decrease in metabolic ratios. This further decrease in dopamine turnover with STN stimulation would serve to maintain dopamine levels in the dopamine-depleted striatum, and may account for the therapeutic benefit of DBS in Parkinson's disease.


Assuntos
Corpo Estriado/metabolismo , Estimulação Encefálica Profunda , Dopamina/metabolismo , Transtornos Parkinsonianos/metabolismo , Núcleo Subtalâmico/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Imuno-Histoquímica , Masculino , Microdiálise , Ratos , Ratos Sprague-Dawley , Núcleo Subtalâmico/lesões , Núcleo Subtalâmico/cirurgia
16.
J Neurosci ; 28(28): 7209-18, 2008 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-18614691

RESUMO

The subthalamic nucleus (STN) of the basal ganglia is an important element of motor control. This is demonstrated by involuntary movements induced by STN lesions and the successful treatment of Parkinson's disease by STN stimulation. However, it is still unclear how individual STN neurons participate in motor control. Here, we report that the STN has a function in switching from automatic to volitionally controlled eye movement. In the STN of trained macaque monkeys, we found neurons that showed a phasic change in activity specifically before volitionally controlled saccades which were switched from automatic saccades. A majority of switch-related neurons were considered to inhibit no-longer-valid automatic processes, and the inhibition started early enough to enable the animal to switch. We suggest that the STN mediates the control signal originated from the medial frontal cortex and implements the behavioral switching function using its connections with other basal ganglia nuclei and the superior colliculus.


Assuntos
Atenção/fisiologia , Movimentos Oculares/fisiologia , Neurônios/fisiologia , Núcleo Subtalâmico/citologia , Potenciais de Ação/fisiologia , Análise de Variância , Animais , Comportamento Animal , Tomada de Decisões/fisiologia , Lateralidade Funcional , Macaca mulatta , Estimulação Luminosa/métodos , Núcleo Subtalâmico/lesões , Análise e Desempenho de Tarefas
17.
Neuroscience ; 155(3): 603-12, 2008 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-18616989

RESUMO

Stimulation of kappa-opioid receptors in the substantia nigra pars reticulata (SNPR) increases the locomotor activity of young rats: an effect blocked by systemic administration of a D2-like receptor agonist. Based on these initial findings, we proposed that: (a) D2-like receptors in the dorsal striatum are responsible for attenuating kappa-opioid-induced locomotor activity, and (b) the effects of D2-like receptor stimulation are mediated by the indirect pathway, which extends from the dorsal striatum to the SNPR via the globus pallidus (GP) and subthalamic nucleus (STN). To test the first hypothesis, young rats were given a systemic injection (i.p.) of saline or the kappa-opioid receptor agonist (+/-)-trans-U50,488 methanesulfonate salt (U50,488) on postnatal day (PD) 18. Later in the testing session, rats received bilateral infusions of vehicle or the D2-like receptor agonist R(-)-propylnorapomorphine (NPA) into the dorsal striatum, and the ability of NPA to block U50,488-induced locomotor activity was determined. To test the second hypothesis, rats were given sham or bilateral electrolytic lesions of the GP or STN on PD 16. Two days later, saline- and U50,488-induced locomotor activity was measured after systemic (i.p.) administration of vehicle or NPA. As predicted, dorsal striatal infusions of NPA attenuated the U50,488-induced locomotor activity of young rats. Contrary to our expectations, bilateral lesions of the GP or STN did not impair NPA's ability to block U50,488-induced locomotor activity. When considered together, these results suggest that: (a) stimulation of D2-like receptors in the dorsal striatum is sufficient to attenuate the kappa-opioid-mediated locomotor activity of young rats; and (b) the indirect pathway does not mediate the effects of D2-like receptor stimulation in this behavioral model.


Assuntos
Apomorfina/análogos & derivados , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores Opioides kappa/fisiologia , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Analgésicos não Narcóticos/farmacologia , Análise de Variância , Animais , Animais Recém-Nascidos , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/fisiologia , Relação Dose-Resposta a Droga , Globo Pálido/lesões , Globo Pálido/fisiologia , Atividade Motora/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Sprague-Dawley , Núcleo Subtalâmico/lesões , Núcleo Subtalâmico/fisiologia
18.
J Neurosci ; 28(18): 4795-806, 2008 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-18448656

RESUMO

In the subthalamic nucleus (STN) of Parkinson's disease (PD) patients, a pronounced synchronization of oscillatory activity at beta frequencies (15-30 Hz) accompanies movement difficulties. Abnormal beta oscillations and motor symptoms are concomitantly and acutely suppressed by dopaminergic therapies, suggesting that these inappropriate rhythms might also emerge acutely from disrupted dopamine transmission. The neural basis of these abnormal beta oscillations is unclear, and how they might compromise information processing, or how they arise, is unknown. Using a 6-hydroxydopamine-lesioned rodent model of PD, we demonstrate that beta oscillations are inappropriately exaggerated, compared with controls, in a brain-state-dependent manner after chronic dopamine loss. Exaggerated beta oscillations are expressed at the levels of single neurons and small neuronal ensembles, and are focally present and spatially distributed within STN. They are also expressed in synchronous population activities, as evinced by oscillatory local field potentials, in STN and cortex. Excessively synchronized beta oscillations reduce the information coding capacity of STN neuronal ensembles, which may contribute to parkinsonian motor impairment. Acute disruption of dopamine transmission in control animals with antagonists of D(1)/D(2) receptors did not exaggerate STN or cortical beta oscillations. Moreover, beta oscillations were not exaggerated until several days after 6-hydroxydopamine injections. Thus, contrary to predictions, abnormally amplified beta oscillations in cortico-STN circuits do not result simply from an acute absence of dopamine receptor stimulation, but are instead delayed sequelae of chronic dopamine depletion. Targeting the plastic processes underlying the delayed emergence of pathological beta oscillations after continuing dopaminergic dysfunction may offer considerable therapeutic promise.


Assuntos
Ritmo beta , Córtex Cerebral/fisiologia , Dopamina/metabolismo , Núcleo Subtalâmico/fisiologia , Análise de Variância , Animais , Benzazepinas/farmacologia , Ritmo beta/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/lesões , Antagonistas de Dopamina/farmacologia , Masculino , Oxidopamina/toxicidade , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Análise Espectral , Estatísticas não Paramétricas , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/lesões , Simpatolíticos/toxicidade , Fatores de Tempo , Vigília
19.
Eur J Neurosci ; 27(8): 1902-11, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18412611

RESUMO

Different lines of evidence point to dysfunction of basal ganglia-thalamocortical circuits in obsessive-compulsive disorder (OCD). It has been hypothesized that the circuits' dysfunction in OCD may be characterized by a relative under-activity of the indirect compared with the direct pathway within these circuits. The present study tested whether lesions of the subthalamic nucleus (STN), a major node of the indirect pathway, would affect compulsive behavior, using the signal attenuation rat model of OCD. In this model, compulsive lever-pressing is induced by the attenuation of an external signal of reward delivery; an attenuation that is hypothesized to simulate the deficient response feedback suggested to underlie obsessions and compulsions in patients with OCD. Rats sustaining lesions to the STN showed a selective increase in compulsive lever-pressing compared with sham-operated rats. A post mortem biochemical analysis revealed a decrease in serotonin content in the prelimbic and infralimbic cortices, caudate-putamen (but not nucleus accumbens), globus pallidus and substantia nigra-ventral tegmental area, as well as a decrease in dopamine content in the caudate-putamen in STN-lesioned compared with sham rats. A comparison to recent findings that lesions to the orbitofrontal cortex, which also result in a selective increase in compulsive lever-pressing, lead to a decrease in serotonin and dopamine content in the caudate-putamen suggests that there may be a final common pathway by which different brain pathologies may lead to a pro-compulsive state.


Assuntos
Comportamento Compulsivo/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Núcleo Subtalâmico/metabolismo , Animais , Comportamento Animal , Comportamento Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/metabolismo , Transtorno Obsessivo-Compulsivo/fisiopatologia , Ratos , Ratos Sprague-Dawley , Recompensa , Núcleo Subtalâmico/lesões
20.
Neuroscience ; 151(3): 817-23, 2008 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-18164823

RESUMO

The cannabinoid CB1 receptor which is densely located in the basal ganglia is known to participate in the regulation of movement. The present study sought to determine the mechanisms underlying the effect of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) on neurons in the substantia nigra pars compacta (SNpc) using single-unit extracellular recordings in anesthetized rats. Administration of Delta(9)-THC (0.25-2 mg/kg, i.v.) increased the firing rate of SNpc neurons (maximal effect: 33.54+/-6.90%, n=8) without modifying other firing parameters (coefficient of variation and burst firing). This effect was completely blocked by the cannabinoid receptor antagonist rimonabant (0.5 mg/kg, i.v.). In addition, the blockade of excitatory amino acids receptors by kynurenic acid (0.5 microM, i.c.v.) or a chemical lesion of the subthalamic nucleus (STN) with ibotenic acid abolished Delta(9)-THC effect. These results indicate that CB1 receptor activation modulates SNpc neuronal activity by an indirect mechanism involving excitatory amino acids, probably released from STN axon terminals in the SNpc.


Assuntos
Dopamina/metabolismo , Dronabinol/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Psicotrópicos/farmacologia , Núcleo Subtalâmico/fisiologia , Potenciais de Ação/efeitos dos fármacos , Análise de Variância , Animais , Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/efeitos adversos , Ácido Ibotênico/efeitos adversos , Ácido Cinurênico/efeitos adversos , Masculino , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Rimonabanto , Substância Negra/citologia , Núcleo Subtalâmico/lesões
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