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1.
Brain ; 138(Pt 10): 2987-3002, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26220941

RESUMEN

Abnormal dopamine neurotransmission is associated with many different genetic and acquired dystonic disorders. For instance, mutations in genes critical for the synthesis of dopamine, including GCH1 and TH cause l-DOPA-responsive dystonia. Despite evidence that implicates abnormal dopamine neurotransmission in dystonia, the precise nature of the pre- and postsynaptic defects that result in dystonia are not known. To better understand these defects, we generated a knock-in mouse model of l-DOPA-responsive dystonia (DRD) mice that recapitulates the human p.381Q>K TH mutation (c.1141C>A). Mice homozygous for this mutation displayed the core features of the human disorder, including reduced TH activity, dystonia that worsened throughout the course of the active phase, and improvement in the dystonia in response to both l-DOPA and trihexyphenidyl. Although the gross anatomy of the nigrostriatal dopaminergic neurons was normal in DRD mice, the microstructure of striatal synapses was affected whereby the ratio of axo-spinous to axo-dendritic corticostriatal synaptic contacts was reduced. Microinjection of l-DOPA directly into the striatum ameliorated the dystonic movements but cerebellar microinjections of l-DOPA had no effect. Surprisingly, the striatal dopamine concentration was reduced to ∼1% of normal, a concentration more typically associated with akinesia, suggesting that (mal)adaptive postsynaptic responses may also play a role in the development of dystonia. Administration of D1- or D2-like dopamine receptor agonists to enhance dopamine signalling reduced the dystonic movements, whereas administration of D1- or D2-like dopamine receptor antagonists to further reduce dopamine signalling worsened the dystonia, suggesting that both receptors mediate the abnormal movements. Further, D1-dopamine receptors were supersensitive; adenylate cyclase activity, locomotor activity and stereotypy were exaggerated in DRD mice in response to the D1-dopamine receptor agonist SKF 81297. D2-dopamine receptors exhibited a change in the valence in DRD mice with an increase in adenylate cyclase activity and blunted behavioural responses after challenge with the D2-dopamine receptor agonist quinpirole. Together, our findings suggest that the development of dystonia may depend on a reduction in dopamine in combination with specific abnormal receptor responses.


Asunto(s)
Dopaminérgicos/uso terapéutico , Distonía/tratamiento farmacológico , Levodopa/uso terapéutico , Mutación/genética , Tirosina 3-Monooxigenasa/genética , Animales , Benzazepinas/farmacocinética , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Catecolaminas/metabolismo , Modelos Animales de Enfermedad , Antagonistas de Dopamina/farmacocinética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Distonía/diagnóstico por imagen , Distonía/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Cintigrafía , Conducta Estereotipada/fisiología , Tritio/farmacocinética , Tirosina 3-Monooxigenasa/metabolismo
2.
Mol Ther ; 20(3): 544-54, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22008908

RESUMEN

Neurotrophic factors are integrally involved in the development of the nigrostriatal system and in combination with gene therapy, possess great therapeutic potential for Parkinson's disease (PD). Pleiotrophin (PTN) is involved in the development, maintenance, and repair of the nigrostriatal dopamine (DA) system. The present study examined the ability of striatal PTN overexpression, delivered via psueudotyped recombinant adeno-associated virus type 2/1 (rAAV2/1), to provide neuroprotection and functional restoration from 6-hydroxydopamine (6-OHDA). Striatal PTN overexpression led to significant neuroprotection of tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) and THir neurite density in the striatum, with long-term PTN overexpression producing recovery from 6-OHDA-induced deficits in contralateral forelimb use. Transduced striatal PTN levels were increased threefold compared to adult striatal PTN expression and approximated peak endogenous developmental levels (P1). rAAV2/1 vector exclusively transduced neurons within the striatum and SNpc with approximately half the total striatal volume routinely transduced using our injection parameters. Our results indicate that striatal PTN overexpression can provide neuroprotection for the 6-OHDA lesioned nigrostriatal system based upon morphological and functional measures and that striatal PTN levels similar in magnitude to those expressed in the striatum during development are sufficient to provide neuroprotection from Parkinsonian insult.


Asunto(s)
Proteínas Portadoras/genética , Cuerpo Estriado/metabolismo , Citocinas/genética , Trastornos Parkinsonianos/terapia , Animales , Proteínas Portadoras/metabolismo , Citocinas/metabolismo , Dependovirus/genética , Modelos Animales de Enfermedad , Expresión Génica , Orden Génico , Terapia Genética , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Masculino , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/genética , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , Transducción Genética
3.
Physiol Behav ; 96(4-5): 593-601, 2009 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-19162054

RESUMEN

The current study sought to determine whether prenatal 3,4-methylenedioxy-N-methamphetamine (MDMA) exposure from E14-20 in the rat resulted in behavioral sequelae in adult offspring. Prenatal MDMA exposure results in increased dopaminergic fiber density in the prefrontal cortex, striatum and nucleus accumbens of young rats. Since these areas are critical in response to novelty, reward, attention and locomotor activity, we hypothesized that prenatal MDMA exposure would produce significant changes in the performance of tasks that examine such behaviors in adult rats. Adult rats prenatally exposed to MDMA exhibited greater activity and spent more time in the center during a novel open field test as compared to controls. This increased activity was not reflected in normal home cage activity. Prenatal exposure to MDMA did not affect feeding or food reward. It did not alter cocaine self-administration behaviors, nor did it have an effect on the locomotor response to amphetamine challenge. Finally, while prenatal MDMA did not affect performance in the radial arm maze or the Morris water maze (MWM), these animals demonstrated altered performance in a cued MWM paradigm. Prenatal MDMA exposure resulted in perseverative attendance to a hanging cue when the platform in the MWM was removed as compared to controls. Together, these data demonstrate that prenatal exposure to MDMA results in a behavioral phenotype in adult rats characterized by reduced anxiety, a heightened response to novelty, and "hyperattentiveness" to environmental cues during spatial learning.


Asunto(s)
Conducta Animal/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Efectos Tardíos de la Exposición Prenatal , Serotoninérgicos/toxicidad , Conducta Espacial/efectos de los fármacos , Análisis de Varianza , Animales , Aprendizaje por Asociación/efectos de los fármacos , Atención/efectos de los fármacos , Cocaína/farmacología , Período Crítico Psicológico , Inhibidores de Captación de Dopamina/farmacología , Femenino , Edad Gestacional , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo , Actividad Motora/efectos de los fármacos , Embarazo , Distribución Aleatoria , Ratas , Autoadministración , Estadísticas no Paramétricas
4.
Neuropharmacology ; 55(5): 851-9, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18655796

RESUMEN

The current study examined whether modest concentrations of MDMA could increase the survival and/or neurite outgrowth of fetal midbrain dopamine (DA) neurons in vitro since increased DA neurite outgrowth has been previously observed in vivo from prenatal exposure. MDMA concentrations in fetal brain were quantified to determine relevant in vivo concentrations to employ in vitro. A dose response study in vitro demonstrated that MDMA, at concentrations observed in vivo, resulted in increased, DA-specific, neuron survival. Higher doses resulted in non-specific neurotoxicity. MDMA application immediately after culture establishment resulted in greater survival than delayed application, however both were superior to control. MDMA significantly increased the expression of the slc6a3 gene (dopamine transporter; DAT) in culture. Co-application of the DAT reuptake inhibitor methylphenidate (MPH) with MDMA attenuated this effect. Progressive reductions in MPH concentrations restored the MDMA-induced survival effect. This suggests that MDMA's action at DAT mediates the survival effect. Neurite density per neuron was unaffected by MDMA in vitro suggesting that MDMA promotes DA neuron survival but not neurite outgrowth in culture. Finally, animals prenatally exposed to MDMA and examined on postnatal day 35 showed an increase in tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra but not in the ventral tegmental area. These data suggest that during development, MDMA can increase the survival of DA neurons through its action at its transporter. Understanding how MDMA increases DA neuron survival may provide insight into normal DA neuron loss during development.


Asunto(s)
Dopamina/metabolismo , Alucinógenos/farmacología , Mesencéfalo/citología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Neuronas/efectos de los fármacos , Análisis de Varianza , Animales , Animales Recién Nacidos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Masculino , Mesencéfalo/metabolismo , Metilfenidato/metabolismo , Metilfenidato/farmacología , Neuritas/efectos de los fármacos , Neuronas/citología , Neuronas/fisiología , Embarazo , Ratas , Ratas Sprague-Dawley , Tirosina 3-Monooxigenasa/metabolismo
5.
Expert Opin Ther Targets ; 15(12): 1387-403, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22136648

RESUMEN

INTRODUCTION: Dystonia is a neurological disorder associated with twisting motions and abnormal postures, which compromise normal movements and can be both painful and debilitating. It can affect a single body part (focal), several contiguous regions (segmental), or the entire body (generalized), and can arise as a result of numerous causes, both genetic and acquired. Despite the diversity of causes and manifestations, shared clinical features suggest that common mechanisms of pathogenesis may underlie many dystonias. AREAS COVERED: Shared themes in etiologically-diverse dystonias exist at several biological levels. At the cellular level, abnormalities in the dopaminergic system, mitochondrial function and calcium regulation are often present. At the anatomical level, the basal ganglia and the cerebellum are frequently implicated. Global CNS dysfunction, specifically aberrant neuronal plasticity, inhibition and sensorimotor integration, are also observed in a number of dystonias. Using clinical data and data from animal models, this article seeks to highlight shared pathways that may be critical in understanding mechanisms and identifying novel therapeutic strategies in dystonia. EXPERT OPINION: Identifying shared features of pathogenesis can provide insight into the biological processes that underlie etiologically diverse dystonias, and can suggest novel targets for therapeutic intervention that may be effective in a broad group of affected individuals.


Asunto(s)
Distonía/fisiopatología , Animales , Encéfalo/fisiopatología , Calcio/fisiología , Dopamina/fisiología , Humanos , Mitocondrias/fisiología , Plasticidad Neuronal
6.
J Parkinsons Dis ; 1(1): 123-36, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22328911

RESUMEN

The mechanisms underlying the effects of long-term deep brain stimulation of the subthalamic nucleus (STN DBS) as a therapy for Parkinson's disease (PD) remain poorly understood. The present study examined whether functionally effective, long-term STN DBS modulates glial cell line-derived neurotrophic factor (GDNF) and/or brain-derived neurotrophic factor (BDNF) in both unlesioned and unilateral 6-hydroxydopamine lesioned rats. Lesioned rats that received two weeks of continuous unilateral STN DBS exhibited significant improvements in parkinsonian motor behaviors in tests of forelimb akinesia and rearing activity. Unilateral STN DBS did not increase GDNF in the nigrostriatal system, primary motor cortex (M1), or hippocampus of unlesioned rats. In contrast, unilateral STN DBS increased BDNF protein 2-3 fold bilaterally in the nigrostriatal system with the location (substantia nigra vs. striatum) dependent upon lesion status. Further, BDNF protein was bilaterally increased in M1 cortex by as much as 2 fold regardless of lesion status. STN DBS did not impact cortical regions that receive less input from the STN. STN DBS also was associated with bilateral increases in BDNF mRNA in the substantia nigra (SN) and internal globus pallidus (GPi). The increase observed in GPi was completely blocked by pretreatment with 5-Methyl-10,11-dihydro-5 H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), suggesting that the activation of N-methyl-D-aspartate (NMDA) receptors was involved in this phenomenon. The upregulation of BDNF associated with long term STN DBS suggest that this therapy may exert pronounced and underappreciated effects on plasticity in the basal ganglia circuitry that may play a role in the symptomatic effects of this therapy as well as support the neuroprotective effect of stimulation documented in this rat model.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Estimulación Encefálica Profunda , Corteza Motora/metabolismo , Enfermedad de Parkinson/terapia , Sustancia Negra/metabolismo , Núcleo Subtalámico/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica/fisiología , Masculino , Neurotoxinas/toxicidad , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley
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