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1.
CNS Neurosci Ther ; 20(8): 748-53, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24837039

RESUMO

AIM: Natalizumab (NTZ) discontinuation leads to multiple sclerosis (MS) recurrence, but represents the only known strategy to limit the risk of progressive multifocal leukoencephalopathy (PML) in JCV seropositive patients. Here, we compared the clinical and imaging features of three groups of patients who discontinued NTZ treatment. METHODS: We treated 25 patients with subcutaneous INFß-1b (INF group), 40 patients with glatiramer acetate (GA group), and 40 patients with GA plus pulse steroid (GA+CS group). RESULTS: Six of 25 patients (24%) of the INF group were relapse-free 6 months after NTZ suspension. In GA group, a significant higher proportion of patients (26 of 40 patients, 65%) were relapse-free (P<0.05). Far from improving the clinical effects of GA in post-NTZ setting, combination of GA+CS was associated with lower relapse-free rate than GA alone (40% vs. 65%, P=0.04). Also on MRI parameters, combination of GA+CS was associated with worse outcome than GA alone, as 22 of 26 subjects (84.6%) had MRI evidence of disease activity 6 months after NTZ discontinuation. CONCLUSION: Corticosteroids should not be used in combination with GA to prevent post-NTZ disease recurrence.


Assuntos
Corticosteroides/efeitos adversos , Imunossupressores/uso terapêutico , Interferon beta/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Avaliação da Deficiência , Quimioterapia Combinada , Feminino , Acetato de Glatiramer , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Natalizumab , Peptídeos/uso terapêutico , Estudos Retrospectivos
2.
J Neuroinflammation ; 11: 32, 2014 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-24548694

RESUMO

BACKGROUND: Absence of clinical and radiological activity in relapsing-remitting multiple sclerosis (RRMS) is perceived as disease remission. We explored the role of persisting inflammation during remission in disease evolution. METHODS: Cerebrospinal fluid (CSF) levels of interleukin 1ß (IL-1ß), a major proinflammatory cytokine, were measured in 170 RRMS patients at the time of clinical and radiological remission. These patients were then followed up for at least 4 years, and clinical, magnetic resonance imaging (MRI) and optical coherence tomography (OCT) measures of disease progression were recorded. RESULTS: Median follow-up of RRMS patients was 5 years. Detection of CSF IL-1ß levels at the time of remission did not predict earlier relapse or new MRI lesion formation. Detection of IL-1ß in the CSF was instead associated with higher progression index (PI) and Multiple Sclerosis Severity Scale (MSSS) scores at follow-up, and the number of patients with sustained Expanded Disability Status Scale (EDSS) or Multiple Sclerosis Functional Composite worsening at follow-up was higher in individuals with detectable levels of IL-1ß. Patients with undetectable IL-1ß in the CSF had significantly lower PI and MSSS scores and a higher probability of having a benign MS phenotype. Furthermore, patients with undetectable CSF levels of IL-1ß had less retinal nerve fiber layer thickness and macular volume alterations visualized by OCT compared to patients with detectable IL-1ß. CONCLUSIONS: Our results suggest that persistence of a proinflammatory environment in RRMS patients during clinical and radiological remission influences midterm disease progression. Detection of IL-1ß in the CSF at the time of remission appears to be a potential negative prognostic factor in RRMS patients.


Assuntos
Interleucina-1beta/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Adulto , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Itália , Modelos Logísticos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Valor Preditivo dos Testes , Recidiva , Estatísticas não Paramétricas , Tomografia de Coerência Óptica
3.
PLoS One ; 8(6): e67357, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23840674

RESUMO

Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao's brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms.


Assuntos
Córtex Cerebral/fisiopatologia , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Adulto , Córtex Cerebral/metabolismo , Cognição , Progressão da Doença , Feminino , Estudos de Associação Genética , Humanos , Modelos Logísticos , Masculino , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Crônica Progressiva/psicologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Índice de Gravidade de Doença , Adulto Jovem
4.
J Neuroimmune Pharmacol ; 8(3): 651-63, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23370991

RESUMO

Glutamate-mediated excitotoxicity is supposed to induce neurodegeneration in multiple sclerosis (MS). Glatiramer acetate (GA) is an immunomodulatory agent used in MS treatment with potential neuroprotective action. Aim of the present study was to investigate whether GA has effects on glutamate transmission alterations occurring in experimental autoimmune encephalomyelitis (EAE), to disclose a possible mechanism of GA-induced neuroprotection in this mouse model of MS. Single neuron electrophysiological recordings and immunofluorescence analysis of microglia activation were performed in the striatum of EAE mice, treated or not with GA, at different stages of the disease. GA treatment was able to reverse the tumor necrosis factor-α (TNF-α)-induced alterations of striatal glutamate-mediated excitatory postsynaptic currents (EPSCs) of EAE mice. Incubation of striatal slices of control animals with lymphocytes taken from EAE mice treated with GA failed to replicate such an anti-glutamatergic effect, while activated microglial cells stimulated with GA in vitro mimicked the effect of GA treatment of EAE mice. Consistently, EAE mice treated with GA had less microglial activation and less TNF-α expression than untreated EAE animals. Furthermore, direct application of GA to EAE slices replicated the in vivo protective activity of GA. Our results show that GA is neuroprotective against glutamate toxicity independently of its peripheral immunodulatory action, and through direct modulation of microglial activation and TNF-α release in the grey matter of EAE and possibly of MS brains.


Assuntos
Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Imunossupressores/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Peptídeos/uso terapêutico , Sinapses/patologia , Animais , Células Cultivadas , Feminino , Acetato de Glatiramer , Imunossupressores/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Sinapses/efeitos dos fármacos
5.
Mult Scler ; 19(1): 59-68, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22577119

RESUMO

BACKGROUND: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation. OBJECTIVE: To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation. METHODS: Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade. RESULTS: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation. CONCLUSION: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Variação Genética , Fatores Imunológicos/uso terapêutico , Linfocitose/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/genética , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Feminino , Humanos , Masculino , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab , Polimorfismo de Nucleotídeo Único , Recidiva
6.
Mult Scler ; 19(8): 1084-94, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23232603

RESUMO

BACKGROUND: There are two generally accepted strategies for treating multiple sclerosis (MS), preventing central nervous system (CNS) damage indirectly through immunomodulatory interventions and/or repairing CNS damage by promoting remyelination. Both approaches also provide neuroprotection since they can prevent, indirectly or directly, axonal damage. OBJECTIVE: Recent experimental and clinical evidence indicates that the novel immunomodulatory drug laquinimod can exert a neuroprotective role in MS. Whether laquinimod-mediated neuroprotection is exerted directly on neuronal cells or indirectly via peripheral immunomodulation is still unclear. METHODS: C57Bl/6 experimental autoimmune encephalomyelitis (EAE) mice, immunised with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, were treated for 26 days with subcutaneous daily injections of laquinimod (from 1 to 25 mg/kg). Patch clamp electrophysiology was performed on acute brain striatal slices from EAE mice treated with daily (25 mg/kg) laquinimod and on acute brain striatal slices from control mice bathed with laquinimod (1-30 µM). RESULTS: Both preventive and therapeutic laquinimod treatment fully prevented the alterations of GABAergic synapses induced by EAE, the first limiting also glutamatergic synaptic alterations. This dual effect might, in turn, have limited glutamatergic excitotoxicity, a phenomenon previously observed early during EAE and possibly correlated with later axonal damage. Furthermore, laquinimod treatment also preserved cannabinoid CB1 receptor sensitivity, normally lost during EAE. Finally, laquinimod per se was able to regulate synaptic transmission by increasing inhibitory post-synaptic currents and, at the same time, reducing excitatory post-synaptic currents. CONCLUSIONS: Our data suggest a novel neuroprotective mechanism by which laquinimod might in vivo protect from neuronal damage occurring as a consequence of inflammatory immune-mediated demyelination.


Assuntos
Encéfalo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Inflamação/patologia , Fármacos Neuroprotetores/farmacologia , Quinolonas/farmacologia , Sinapses/efeitos dos fármacos , Animais , Encéfalo/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Sinapses/patologia
7.
J Neurosci ; 32(40): 13896-905, 2012 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23035099

RESUMO

Interleukin-1ß (IL-1ß) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1ß-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1ß-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1ß caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1ß-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1ß-CB1R coupling, and TRPV1-/- mice were indeed insensitive to the synaptic and behavioral effects of both IL-1ß and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1ß on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1-/- mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.


Assuntos
Ansiedade/fisiopatologia , Corpo Estriado/fisiopatologia , Endocanabinoides/fisiologia , Interleucina-1beta/fisiologia , Animais , Ansiedade/induzido quimicamente , Colesterol/análise , Corpo Estriado/efeitos dos fármacos , Dominação-Subordinação , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Injeções Intraventriculares , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/administração & dosagem , Interleucina-1beta/farmacologia , Interleucina-1beta/toxicidade , Masculino , Lipídeos de Membrana/análise , Microdomínios da Membrana/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/fisiologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/fisiopatologia , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/fisiologia , Ácido gama-Aminobutírico/fisiologia
8.
Brain ; 135(Pt 11): 3320-35, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23008234

RESUMO

The functional significance of adult neural stem and progenitor cells in hippocampal-dependent learning and memory has been well documented. Although adult neural stem and progenitor cells in the subventricular zone are known to migrate to, maintain and reorganize the olfactory bulb, it is less clear whether they are functionally required for other processes. Using a conditional transgenic mouse model, selective ablation of adult neural stem and progenitor cells in the subventricular zone induced a dramatic increase in morbidity and mortality of central nervous system disorders characterized by excitotoxicity-induced cell death accompanied by reactive inflammation, such as 4-aminopyridine-induced epilepsy and ischaemic stroke. To test the role of subventricular zone adult neural stem and progenitor cells in protecting central nervous system tissue from glutamatergic excitotoxicity, neurophysiological recordings of spontaneous excitatory postsynaptic currents from single medium spiny striatal neurons were measured on acute brain slices. Indeed, lipopolysaccharide-stimulated, but not unstimulated, subventricular zone adult neural stem and progenitor cells reverted the increased frequency and duration of spontaneous excitatory postsynaptic currents by secreting the endocannabinod arachidonoyl ethanolamide, a molecule that regulates glutamatergic tone through type 1 cannabinoid receptor (CB(1)) binding. In vivo restoration of cannabinoid levels, either by administration of the type 1 cannabinoid receptor agonist HU210 or the inhibitor of the principal catabolic enzyme fatty acid amide hydrolase, URB597, completely reverted the increased morbidity and mortality of adult neural stem and progenitor cell-ablated mice suffering from epilepsy and ischaemic stroke. Our results provide the first evidence that adult neural stem and progenitor cells located within the subventricular zone exert an 'innate' homeostatic regulatory role by protecting striatal neurons from glutamate-mediated excitotoxicity.


Assuntos
Corpo Estriado/fisiologia , Ácido Glutâmico/fisiologia , Ventrículos Laterais/fisiologia , Células-Tronco Neurais/fisiologia , Fármacos Neuroprotetores/metabolismo , Células-Tronco/fisiologia , 4-Aminopiridina/antagonistas & inibidores , Amidoidrolases/antagonistas & inibidores , Animais , Ácidos Araquidônicos/biossíntese , Ácidos Araquidônicos/metabolismo , Benzamidas/farmacologia , Carbamatos/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Dronabinol/análogos & derivados , Dronabinol/farmacologia , Endocanabinoides/biossíntese , Endocanabinoides/metabolismo , Epilepsia/metabolismo , Epilepsia/mortalidade , Epilepsia/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ganciclovir , Ácido Glutâmico/farmacologia , Ventrículos Laterais/fisiopatologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/efeitos dos fármacos , Alcamidas Poli-Insaturadas , Células-Tronco/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/fisiopatologia
9.
Exp Neurol ; 237(2): 296-303, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22836148

RESUMO

Multiple sclerosis (MS) causes a variety of motor and sensory deficits and it is also associated with mood disturbances. It is unclear if anxiety and depression in MS entirely reflect a subjective reaction to a chronic disease causing motor disability or rather depend on specific effects of neuroinflammation in neuronal circuits. To answer this question, behavioral, electrophysiological, and immunofluorescence experiments were performed in mice with experimental autoimmune encephalomyelitis (EAE), which models MS in mice. First, we observed high anxiety indexes in EAE mice, preceding the appearance of motor defects. Then, we demonstrated that tumor necrosis factor α (TNF-α) has a crucial role in anxiety associated with neuroinflammation. In fact, intracerebroventricular (icv) administration of etanercept, an inhibitor of TNF-α signaling, resulted in anxiolytic-like effects in EAE-mice. Accordingly, icv injection of TNF-α induced per se overt anxious behavior in control mice. Moreover, we propose the striatum as one of the brain regions potentially involved in EAE anxious behavior. We observed that before disease onset EAE striatum presents elevated TNF-α levels and strong activated microglia, early signs of inflammation associated with alterations of striatal excitatory postsynaptic currents (EPSCs). Interestingly, etanercept corrected the synaptic defects of pre-symptomatic EAE mice while icv injection of TNF-α in non-EAE mice altered EPSCs, thus mimicking the synaptic effects of EAE. In conclusion, anxiety characterizes EAE course since the very early phases of the disease. TNF-α released from activated microglia mediates this effect likely through the modulation of striatal excitatory synaptic transmission.


Assuntos
Ansiedade/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/psicologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Ansiedade/metabolismo , Encefalomielite Autoimune Experimental/fisiopatologia , Ensaio de Imunoadsorção Enzimática , Etanercepte , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Imunofluorescência , Imunoglobulina G/farmacologia , Fatores Imunológicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Esclerose Múltipla/metabolismo , Esclerose Múltipla/psicologia , Técnicas de Patch-Clamp , Receptores do Fator de Necrose Tumoral
10.
Mult Scler ; 18(11): 1633-5, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22419673

RESUMO

Abnormal glutamate-dependent synaptic excitation contributes to neuronal damage in multiple sclerosis (MS). Little is known about the involvement of the GABA system in this disorder. Here we found that cerebrospinal fluid (CSF) from MS patients with enhanced brain lesions on magnetic resonance imaging inhibited GABA transmission in mouse brain slices. Enhanced IL-1ß neuronal action was responsible for this effect, because IL-1ß receptor antagonist blocked, and exogenous IL-1ß mimicked the synaptic effect of inflamed CSF. Our results provide evidence that focal inflammation in MS perturbs the cytokine milieu within the circulating CSF, resulting in diffuse GABAergic alteration in neurons.


Assuntos
Encéfalo/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Esclerose Múltipla/metabolismo , Inibição Neural , Neurônios/metabolismo , Transmissão Sináptica , Ácido gama-Aminobutírico/metabolismo , Adulto , Animais , Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Estudos de Casos e Controles , Citocinas/líquido cefalorraquidiano , Feminino , Humanos , Técnicas In Vitro , Mediadores da Inflamação/líquido cefalorraquidiano , Potenciais Pós-Sinápticos Inibidores , Interleucina-1beta/metabolismo , Imageamento por Ressonância Magnética , Masculino , Camundongos , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Transmissão Sináptica/efeitos dos fármacos , Adulto Jovem
11.
PLoS One ; 7(3): e33260, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22413007

RESUMO

Approach or avoidance behaviors are accompanied by perceptual vigilance for, affective reactivity to and behavioral predisposition towards rewarding or punitive stimuli, respectively. We detected three subpopulations of C57BL/6J mice that responded with avoiding, balancing or approaching behaviors not induced by any experimental manipulation but spontaneously displayed in an approach/avoidance conflict task. Although the detailed neuronal mechanisms underlying the balancing between approach and avoidance are not fully clarified, there is growing evidence that endocannabinoid system (ECS) plays a critical role in the control of these balancing actions. The sensitivity of dorsal striatal synapses to the activation of cannabinoid CB1 receptors was investigated in the subpopulations of spontaneously avoiding, balancing or approaching mice. Avoiding animals displayed decreased control of CB1 receptors on GABAergic striatal transmission and in parallel increase of behavioral inhibition. Conversely, approaching animals exhibited increased control of CB1 receptors and in parallel increase of explorative behavior. Balancing animals reacted with balanced responses between approach and avoidance patterns. Treating avoiding animals with URB597 (fatty acid amide hydrolase inhibitor) or approaching animals with AM251 (CB1 receptor inverse agonist) reverted their respective behavioral and electrophysiological patterns. Therefore, enhanced or reduced CB1-mediated control on dorsal striatal transmission represents the synaptic hallmark of the approach or avoidance behavior, respectively. Thus, the opposite spontaneous responses to conflicting stimuli are modulated by a different involvement of endocannabinoid signaling of dorsal striatal neurons in the range of temperamental traits related to individual differences.


Assuntos
Comportamento Animal/fisiologia , Corpo Estriado/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais , Transmissão Sináptica/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Carbamatos/farmacologia , Corpo Estriado/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Transmissão Sináptica/efeitos dos fármacos
12.
Ann Neurol ; 71(1): 76-83, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22275254

RESUMO

OBJECTIVE: The frequency of inflammatory episodes in the early stages of multiple sclerosis (MS) has been correlated with late neurodegeneration, but the mechanism by which inflammation gives rise to delayed neuronal damage is unknown. Increased activity of the neurotransmitter glutamate is thought to play a role in the inflammation-driven neurodegenerative process of MS, and therefore we tested whether inflammatory cytokines released during acute MS attacks have the property of enhancing glutamate-mediated transmission and excitotoxicity in central neurons. METHODS: We compared the effect of cerebrospinal fluid (CSF) from active and quiescent MS patients on glutamate-mediated excitatory postsynaptic currents (EPSCs) and excitotoxic damage in rodent brain slices. We also measured CSF concentrations of tumor necrosis factor-α, of interleukin-1ß (IL-1ß), and of IL-1 receptor antagonist (IL-1ra), and correlated cytokine levels with cortical excitability assessed in MS patients by means of paired-pulse transcranial magnetic stimulation (TMS). RESULTS: CSF from MS patients with enhanced brain lesions at magnetic resonance imaging was able to increase spontaneous EPSC frequency and glutamate-mediated neuronal swelling in vitro, through a mechanism dependent on enhanced IL-1ß signaling and increased glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor stimulation. Furthermore, IL-1ß/IL-1ra ratio was significantly higher in the CSF of active MS subjects, and correlated with intracortical facilitation, an accredited TMS measure of glutamate transmission. Finally, we identified for the first time transient receptor potential vanilloid 1 channels as essential intermediates for the synaptic action of IL-1ß on central glutamatergic synapses. INTERPRETATION: Our results provide compelling evidence of the synaptic mechanism linking inflammation and excitotoxic neurodegeneration in MS.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Interleucina-1beta/fisiologia , Esclerose Múltipla/fisiopatologia , Transmissão Sináptica/fisiologia , Adulto , Animais , Feminino , Humanos , Interleucina-1beta/efeitos adversos , Interleucina-1beta/líquido cefalorraquidiano , Masculino , Camundongos , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/patologia , Técnicas de Cultura de Órgãos , Sinapses/fisiologia , Estimulação Magnética Transcraniana/métodos , Adulto Jovem
13.
Eur J Neurosci ; 34(9): 1369-77, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22034972

RESUMO

Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD). As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD obtained by triple point-mutation in the dopamine transporter (DAT) gene in mice, making them insensitive to cocaine [DAT cocaine-insensitive (DAT-CI) mice]. DAT-CI mice had a marked hyperactive phenotype, and neurophysiological recordings revealed that the sensitivity of CB1Rs controlling GABA-mediated synaptic currents [CB1Rs((GABA)) ] in the striatum was completely lost. In contrast, CB1Rs modulating glutamate transmission [CB1Rs((Glu)) ], and GABA(B) receptors were not affected in this model of ADHD. In DAT-CI mice, the blockade of CB1R((GABA)) function was complete even after cocaine or environmental manipulations activating the endogenous DA-dependent reward system, which are known to sensitize these receptors in control animals. Conversely, the hedonic property of sucrose was intact in DAT-CI mice, indicating normal sweet perception in these animals. Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/patologia , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Mutação Puntual/genética , Receptor CB1 de Canabinoide/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Cocaína/administração & dosagem , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/administração & dosagem , Dronabinol/análogos & derivados , Dronabinol/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Preferências Alimentares/fisiologia , Regulação da Expressão Gênica/genética , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores/genética , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Receptor CB1 de Canabinoide/genética , Receptores de GABA-B/metabolismo , Sacarose/administração & dosagem
14.
Neurobiol Dis ; 43(3): 669-77, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21672630

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) channels are involved in several inflammatory diseases. However, their action is still controversial, and both pro-inflammatory and anti-inflammatory roles have been described. We used a strain of TRPV1-KO mice to characterize the role of these channels in experimental autoimmune encephalomyelitis (EAE), which models multiple sclerosis (MS) in mice. EAE mice showed higher lethality in the peak phase of the disease and a better recovery of the surviving animals in the chronic stages, compared to their wild-type (WT) counterparts. By means of whole-cell patch clamp experiments in corticostriatal brain slices, we found that the absence of TRPV1 channels exacerbated the defect of glutamate transmission occurring in the peak phase of EAE, and attenuated the alterations of GABA synapses in the chronic phase of EAE, thus paralleling the dual effects of TRPV1-KO on the motor deficits of EAE mice. Furthermore, in slices from non-EAE mice, we found that genetic or pharmacological blockade of TRPV1 channels enhanced the synaptic effects of tumor necrosis factor α (TNF-α) on glutamate-mediated excitatory postsynaptic currents, and prevented the action of interleukin 1ß (IL-1ß) on GABAergic inhibitory postsynaptic currents. Together, our results suggest that TRPV1 channels contrast TNF-α-mediated synaptic deficits in the peak phase of EAE and, in the chronic stages, enhance IL-1ß-induced GABAergic defects. The opposing interplay with the synaptic actions of the two major pro-inflammatory cytokines might explain the bimodal effects of TRPV1 ablation on the motor deficits of EAE, and suggests that the inflammatory milieu determines whether TRPV1 channels exert preferentially aversive or protective effects on neurons during neuroinflammatory diseases.


Assuntos
Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/prevenção & controle , Interleucina-1beta/fisiologia , Sinapses/fisiologia , Canais de Cátion TRPV/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Modelos Animais de Doenças , Regulação para Baixo/genética , Encefalomielite Autoimune Experimental/patologia , Potenciais Pós-Sinápticos Excitadores/genética , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Inflamação/genética , Inflamação/metabolismo , Inflamação/fisiopatologia , Potenciais Pós-Sinápticos Inibidores/genética , Potenciais Pós-Sinápticos Inibidores/fisiologia , Interleucina-1beta/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fármacos Neuroprotetores/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Técnicas de Cultura de Órgãos , Sinapses/genética , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Regulação para Cima/genética
15.
Brain Behav Immun ; 25(6): 1242-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21473912

RESUMO

Cannabinoid CB1 receptors (CB1Rs) regulate the neurodegenerative damage of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R stimulation exerts protective effects is still unclear. Here we show that pharmacological activation of CB1Rs dampens the tumor necrosis factor α (TNFα)-mediated potentiation of striatal spontaneous glutamate-mediated excitatory postsynaptic currents (EPSCs), which is believed to cogently contribute to the inflammation-induced neurodegenerative damage observed in EAE mice. Furthermore, mice lacking CB1Rs showed a more severe clinical course and, in parallel, exacerbated alterations of sEPSC duration after induction of EAE, indicating that endogenous cannabinoids activate CB1Rs and mitigate the synaptotoxic action of TNFα in EAE. Consistently, we found that mice lacking the fatty acid amide hydrolase (FAAH), and thus expressing abnormally high brain levels of the endocannabinoid anandamide, developed a less severe EAE associated with preserved TNFα-induced sEPSC alterations. CB1Rs are important modulators of EAE pathophysiology, and might play a mechanistic role in the neurodegenerative damage of MS patients.


Assuntos
Moduladores de Receptores de Canabinoides/fisiologia , Encefalomielite Autoimune Experimental/fisiopatologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Amidoidrolases/deficiência , Animais , Ácidos Araquidônicos/biossíntese , Ácidos Araquidônicos/fisiologia , Corpo Estriado/fisiopatologia , Maleato de Dizocilpina/farmacologia , Dronabinol/análogos & derivados , Dronabinol/farmacologia , Endocanabinoides , Etanercepte , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Ácido Glutâmico/fisiologia , Imunoglobulina G/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural , Neurônios/fisiologia , Alcamidas Poli-Insaturadas , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/farmacologia
16.
Brain Behav Immun ; 25(5): 947-56, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20940040

RESUMO

Synaptic dysfunction triggers neuronal damage in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). While excessive glutamate signaling has been reported in the striatum of EAE, it is still uncertain whether GABA synapses are altered. Electrophysiological recordings showed a reduction of spontaneous GABAergic synaptic currents (sIPSCs) recorded from striatal projection neurons of mice with MOG((35-55))-induced EAE. GABAergic sIPSC deficits started in the acute phase of the disease (20-25days post immunization, dpi), and were exacerbated at later time-points (35, 50, 70 and 90dpi). Of note, in slices they were independent of microglial activation and of release of TNF-α. Indeed, sIPSC inhibition likely involved synaptic inputs arising from GABAergic interneurons, because EAE preferentially reduced sIPSCs of high amplitude, and was associated with a selective loss of striatal parvalbumin (PV)-positive GABAergic interneurons, which contact striatal projection neurons in their somatic region, giving rise to more efficient synaptic inhibition. Furthermore, we found also that the chronic persistence of pro-inflammatory cytokines were able, per se, to produce profound alterations of electrophysiological network properties, that were reverted by GABA administration. The results of the present investigation indicate defective GABA transmission in MS models depending from alteration of PV cells number and, in part, deriving from the effects of a chronic inflammation, and suggest that pharmacological agents potentiating GABA signaling might be considered to limit neuronal damage in MS patients.


Assuntos
Corpo Estriado/fisiopatologia , Encefalomielite Autoimune Experimental/fisiopatologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Western Blotting , Células Cultivadas , Corpo Estriado/metabolismo , Citocinas/fisiologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/fisiologia
17.
Mult Scler ; 17(3): 281-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21148019

RESUMO

BACKGROUND: Genetic and pharmacological inactivation of cannabinoid CB(1) receptors (CB(1)Rs) exacerbates disease course in experimental autoimmune encephalomyelitis, suggesting that CB(1)Rs might play a role in the neurodegenerative damage associated with multiple sclerosis (MS). OBJECTIVES: To see whether CNR1 gene polymorphism could influence disease progression in relapsing-remitting MS. METHODS: The genotype of 350 patients for the number of AAT repeats was characterized and correlation studies were performed with measures of disease severity and progression. RESULTS: MS patients with the homozygous genotype for long AAT repeats in the CNR1 gene had more severe disease and higher risk of progression. These subjects had significantly higher scores on both the progression index and the MS severity scale. Furthermore, the percentage of patients with MS functional composite score progression or Bayesian Risk Estimate for MS (BREMS) score ≥ 2 (considered at very high risk of secondary progression) was significantly higher in the AAT long group than in the short group, while the frequency of patients with BREMS score ≤-0.63 (very likely to remain progression-free) was not significantly different between the two groups, although lower in the long group. Finally, the frequency of patients prescribed a second-line treatment was significantly higher among subjects of the AAT long group, providing a further, indirect indication of higher disease severity. CONCLUSIONS: The results of the present investigation point to CB(1)R as an important modulator of disease severity in relapsing MS subjects.


Assuntos
Esclerose Múltipla Recidivante-Remitente/genética , Polimorfismo Genético , Receptor CB1 de Canabinoide/genética , Repetições de Trinucleotídeos , Adulto , Distribuição de Qui-Quadrado , Avaliação da Deficiência , Progressão da Doença , Feminino , Frequência do Gene , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Imunossupressores/uso terapêutico , Itália , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fenótipo , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
18.
Neurobiol Dis ; 42(1): 9-20, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21182946

RESUMO

Cerebellar compensation is a reliable model of lesion-induced plasticity occurring through profound synaptic and neurochemical modifications in cortical and sub-cortical regions. As the recovery from cerebellar deficits progresses, the firstly enhanced glutamate striatal transmission is then normalized. The time course of cerebellar compensation and the concomitant striatal modifications might be influenced by protocols of environmental enrichment (EE) differently timed in respect to cerebellar lesion. In the present study, we analyzed the effects of different EE protocols on postural and locomotor behaviors (by means of a neurological rating scale), and on striatal synaptic activity (by means of recordings of spontaneous glutamate-mediated excitatory postsynaptic currents (sEPSCs)) and on morphological correlates (by means of density and dendritic length of Fast Spiking (FS) interneurons) following hemicerebellectomy (HCb) in rats. Cerebellar motor deficits were reduced faster in the enriched animals in comparison to standard housed HCbed rats. The beneficial influence of EE was higher in the animals enriched before the HCb than in rats enriched only after the lesion. In parallel, the HCb-induced increase in striatal sEPSCs was not observed in rats enriched before HCb and attenuated in rats enriched after HCb. Furthermore, the EE prevented the shrinkage of dendritic arborization of FS striatal interneurons. Also this effect was more marked in animals enriched before than after the HCb. The exposure to EE exerted either neuro-protective or therapeutic actions on the cerebellar deficits. The experience-dependent changes of the synaptic and neuronal connectivity observed in the striatal neurons may represent one of the mechanisms through which the enrichment facilitates functional compensation following the cerebellar damage.


Assuntos
Lesões Encefálicas/fisiopatologia , Doenças Cerebelares/patologia , Doenças Cerebelares/fisiopatologia , Ambiente Controlado , Meio Ambiente , Atividade Motora/fisiologia , Transmissão Sináptica/fisiologia , Animais , Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Doenças Cerebelares/terapia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar
19.
Brain Behav Immun ; 24(8): 1379-85, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20647042

RESUMO

It is increasingly accepted that excessive glutamate release plays a key role in the pathophysiology of grey matter damage in multiple sclerosis (MS). The mechanisms causing abnormal glutamate transmission in this disorder are however largely unexplored. By means of electrophysiological recordings from single striatal neurons in slices, we found that the presymptomatic and acute phases of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, are associated with enhanced synaptic release of glutamate. The reverse mode of action of axonal Na(+)/Ca(++) exchanger, secondary to abnormal functioning of voltage-dependent Na(+) channels, was identified as a major cause of this alteration. In fact, inhibition of the Na(+)/Ca(++) exchanger with bepridil or with KB-R7943, which selectively blocks the reverse mode of the exchanger, reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from striatal neurons in EAE mice but not in control animals. In the presence of tetrodotoxin (TTX), a blocker of voltage-dependent Na(+) channels, the effect of bepridil was normalized in acute (25 days post-immunization) EAE mice, indicating that axonal accumulation of Na(+) ions flowing through voltage-dependent Na(+) channels plays a role in the abnormal activity of the Na(+)/Ca(++) exchanger in EAE. Our data reveal an important role of Na(+)/Ca(++) exchanger and of voltage-dependent Na(+) channels in the pathological process of EAE, and provide a rationale for the use of neuroprotective strategies since the very early stages of MS.


Assuntos
Encefalomielite Autoimune Experimental/fisiopatologia , Ácido Glutâmico/fisiologia , Trocador de Sódio e Cálcio/metabolismo , Transmissão Sináptica/fisiologia , Anestésicos Locais/farmacologia , Animais , Corpo Estriado/citologia , Corpo Estriado/fisiologia , Fenômenos Eletrofisiológicos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Cinética , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Neurônios/fisiologia , Técnicas de Patch-Clamp , Desempenho Psicomotor/fisiologia , Receptores Pré-Sinápticos/fisiologia , Trocador de Sódio e Cálcio/antagonistas & inibidores , Tetrodotoxina/farmacologia
20.
J Neurosci ; 30(24): 8127-37, 2010 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-20554863

RESUMO

The role of brain-derived neurotrophic factor (BDNF) in emotional processes suggests an interaction with the endocannabinoid system. Here, we addressed the functional interplay between BDNF and cannabinoid CB(1) receptors (CB(1)Rs) in the striatum, a brain area in which both BDNF and CB(1)s play a role in the emotional consequences of stress and of rewarding experiences. BDNF potently inhibited CB(1)R function in the striatum, through a mechanism mediated by altered cholesterol metabolism and membrane lipid raft function. The effect of BDNF was restricted to CB(1)Rs controlling GABA-mediated IPSCs (CB(1)R(GABA)), whereas CB(1)Rs modulating glutamate transmission and GABA(B) receptors were not affected. The action of BDNF on CB(1)R(GABA) function was tyrosine kinase dependent and was complete even after receptor sensitization with cocaine or environmental manipulations activating the dopamine (DA)-dependent reward system. In mice lacking one copy of the BDNF gene (BDNF(+/-)), CB(1)R(GABA) responses were potentiated and were preserved from the action of haloperidol, a DA D(2) receptor (D(2)R) antagonist able to fully abolish CB(1)R(GABA) function in rewarded animals. Haloperidol also enhanced BDNF levels in the striatum, suggesting that this neurotrophin may act as a downstream effector of D(2)Rs in the modulation of cannabinoid signaling. Accordingly, 5 d cocaine exposure both reduced striatal BDNF levels and increased CB(1)R(GABA) activity, through a mechanism dependent on D(2)Rs. The present study identifies a novel mechanism of CB(1)R regulation mediated by BDNF and cholesterol metabolism and provides some evidence that DA D(2)R-dependent modulation of striatal CB(1)R activity is mediated by this neurotrophin.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/deficiência , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colesterol/metabolismo , Cocaína/farmacologia , Corpo Estriado/citologia , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Dronabinol/análogos & derivados , Dronabinol/farmacologia , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , GABAérgicos/farmacologia , Haloperidol/farmacologia , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp/métodos , Fenóis/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Recompensa , beta-Ciclodextrinas/farmacologia
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