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1.
Cereb Cortex ; 28(1): 307-322, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29121220

RESUMO

The vast majority of neurons within the striatum are GABAergic medium spiny neurons (MSNs), which receive glutamatergic input from the cortex and thalamus, and form two major efferent pathways: the direct pathway, expressing dopamine D1 receptor (D1R-MSNs), and the indirect pathway, expressing dopamine D2 receptor (D2R-MSNs). While molecular mechanisms of MSN degeneration have been identified in animal models of striatal damage, the molecular factors that dictate a selective vulnerability of D1R-MSNs or D2R-MSNs remain unknown. Here, we combined genetic, chemogenetic, and pharmacological strategies with behavioral and neurochemical analyses, and show that the pool of cannabinoid CB1 receptor (CB1R) located on corticostriatal terminals efficiently safeguards D1R-MSNs, but not D2R-MSNs, from different insults. This cell-specific response relies on the regulation of glutamatergic signaling, and is independent from the CB1R-dependent control of astroglial activity in the striatum. These findings define cortical CB1R as a pivotal synaptic player in dictating a differential vulnerability of D1R-MSNs versus D2R-MSNs, and increase our understanding of the role of coordinated cannabinergic-glutamatergic signaling in establishing corticostriatal circuits and its dysregulation in neurodegenerative diseases.


Assuntos
Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Neurônios/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Vetores Genéticos , Ácido Glutâmico/metabolismo , Humanos , Proteína Huntingtina/administração & dosagem , Proteína Huntingtina/genética , Proteína Huntingtina/toxicidade , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Masculino , Camundongos Transgênicos , Vias Neurais/citologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Receptor CB1 de Canabinoide/genética , Transmissão Sináptica/fisiologia
2.
J Neurosci ; 36(41): 10611-10624, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27733612

RESUMO

The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. The functionality of striatal neurons is tightly controlled by various metabotropic receptors. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain poorly understood. Here, using different experimental approaches, especially designer receptor exclusively activated by designer drug (DREADD) chemogenetic technology, we found that sustained activation of Gq-protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca2+/proline-rich tyrosine kinase 2/cJun N-terminal kinase pathway. Moreover, engagement of this intracellular signaling route was functionally active in the mouse dorsal striatum in vivo, as proven by the disruption of neuronal integrity and behavioral tasks. To analyze this effect anatomically, we manipulated Gq-protein-dependent signaling selectively in neurons belonging to the direct or indirect striatal pathway. Acute Gq-protein activation in direct-pathway or indirect-pathway neurons produced an enhancement or a decrease, respectively, of activity-dependent parameters. In contrast, sustained Gq-protein activation impaired the functionality of direct-pathway and indirect-pathway neurons and disrupted the behavioral performance and electroencephalography-related activity tasks controlled by either anatomical framework. Collectively, these findings define the molecular mechanism and functional relevance of Gq-protein-driven signals in striatal circuits under normal and overactivated states. SIGNIFICANCE STATEMENT: The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain unclear. Here, we show that striatal circuits can be "turned on" by acute Gq-protein signaling or "turned off" by sustained Gq-protein signaling. Specifically, sustained Gq-protein signaling inactivates striatal neurons by an intracellular pathway that relies on cJun N-terminal kinase. Overall, this study sheds new light onto the molecular mechanism and functional relevance of Gq-protein-driven signals in striatal circuits under normal and overactivated states.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Neostriado/fisiologia , Vias Neurais/fisiologia , Transdução de Sinais/fisiologia , Animais , Comportamento Animal/fisiologia , Sinalização do Cálcio/fisiologia , Eletroencefalografia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Desempenho Psicomotor/fisiologia , Percepção Espacial/fisiologia , Fosfolipases Tipo C/fisiologia
3.
Proc Natl Acad Sci U S A ; 111(22): 8257-62, 2014 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-24843137

RESUMO

The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.


Assuntos
Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Neurônios/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Idoso , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Córtex Cerebral/citologia , Corpo Estriado/citologia , Endocanabinoides/metabolismo , Endocanabinoides/fisiologia , Endocanabinoides/uso terapêutico , Feminino , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Ácido Glutâmico/metabolismo , Humanos , Integrases/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Neurotoxinas/metabolismo , Técnicas de Cultura de Órgãos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptores de GABA-A/metabolismo , Sinaptossomos/fisiologia
4.
Brain ; 134(Pt 1): 119-36, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20929960

RESUMO

Endocannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 cannabinoid receptors. These receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 cannabinoid receptors has been documented in the basal ganglia of patients with Huntington's disease and animal models. However, the pathophysiological impact of this loss of receptors in Huntington's disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the cannabinoid Δ(9)-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the receptors involves the control of the type 1 cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington's disease. Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington's disease, and suggest that activation of these receptors in patients with Huntington's disease may attenuate disease progression.


Assuntos
Corpo Estriado/metabolismo , Doença de Huntington/genética , Neurônios/metabolismo , Receptor CB1 de Canabinoide/genética , Análise de Variância , Animais , Western Blotting , Sobrevivência Celular , Dronabinol/farmacologia , Hormônio Liberador de Hormônio do Crescimento/análogos & derivados , Doença de Huntington/metabolismo , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Teste de Desempenho do Rota-Rod
5.
Elife ; 92020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32513388

RESUMO

Early Huntington's disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Doença de Huntington/metabolismo , Receptores de Dopamina D1 , Receptores Histamínicos H3 , Animais , Células Cultivadas , Feminino , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Piperidinas/farmacologia , Receptores de Dopamina D1/química , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores Histamínicos H3/química , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Córtex Visual/citologia
6.
Neuropsychopharmacology ; 43(5): 964-977, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28102227

RESUMO

The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A2A receptor (A2AR) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A2AR and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A2AR-CB1R heteromeric complexes. However, the specific location and properties of these heteromers have remained largely unknown. Here, by using techniques that allowed a precise visualization of the heteromers in situ in combination with sophisticated genetically modified animal models, together with biochemical and pharmacological approaches, we provide a high-resolution expression map and a detailed functional characterization of A2AR-CB1R heteromers in the dorsal striatum. Specifically, our data unveil that the A2AR-CB1R heteromer (i) is essentially absent from corticostriatal projections and striatonigral neurons, and, instead, is largely present in striatopallidal neurons, (ii) displays a striking G protein-coupled signaling profile, where co-stimulation of both receptors leads to strongly reduced downstream signaling, and (iii) undergoes an unprecedented dysfunction in Huntington's disease, an archetypal disease that affects striatal neurons. Altogether, our findings may open a new conceptual framework to understand the role of coordinated adenosine-endocannabinoid signaling in the indirect striatal pathway, which may be relevant in motor function and neurodegenerative diseases.


Assuntos
Corpo Estriado/metabolismo , Estrutura Quaternária de Proteína , Receptor A2A de Adenosina/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais , Animais , Humanos , Doença de Huntington/metabolismo , Camundongos , Vias Neurais/metabolismo , Subunidades Proteicas/biossíntese
7.
Life Sci ; 81(6): 468-79, 2007 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-17673260

RESUMO

Anorexia, nausea/emesis and peripheral sensorial neuropathy are frequent adverse effects associated with chemotherapy. Cannabinoids have been proposed to alleviate these effects, but their preventive properties in long-term experimental models have not been tested. This study was conducted to determine whether or not a cannabinoid agonist (WIN-55,212-2) can prevent anorexia, pica (an indirect marker of nausea in non-vomiting species, consisting of the ingestion of non-nutritive substances such as kaolin) and mechanical allodynia (a marker of peripheral neuropathy) induced by the antineoplastic drug cisplatin chronically administered. Isolated rats with free access to food and kaolin received either saline, cannabinoid vehicle, WIN-55,212-2 (1-2 mg kg(-1)), cisplatin (1-2 mg kg(-1)), or both drugs once per week for five consecutive weeks. Modifications in temperature, body weight gain, food and kaolin intake, and the threshold for mechanical allodynia were recorded. Additionally, the acute psychoactive effects of the cannabinoid (hypomotility, hypothermia, analgesia and catalepsia) were assayed by means of the cannabinoid tetrad. WIN 55,212-2 prevented the development of mechanical allodynia but not anorexia, pica and reduction in weight gain induced by chronic cisplatin. The effect of WIN 55,212-2 was evident even at a dose lacking activity in the cannabinoid tetrad. The preventive effect on cisplatin-induced mechanical allodynia exerted by the cannabinoid could be due to a neuroprotective role, as has been suggested for other conditions. The present results support the interest in the evaluation of cannabinoids for treatment of patients suffering or likely to suffer neuropathic pain.


Assuntos
Analgésicos/farmacologia , Antineoplásicos/toxicidade , Benzoxazinas/farmacologia , Cisplatino/toxicidade , Comportamento Alimentar/efeitos dos fármacos , Morfolinas/farmacologia , Naftalenos/farmacologia , Dor/tratamento farmacológico , Animais , Antidiarreicos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Caulim/farmacologia , Masculino , Dor/psicologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/psicologia , Pica/prevenção & controle , Pica/psicologia , Ratos , Ratos Wistar
8.
Auton Neurosci ; 126-127: 81-92, 2006 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-16567130

RESUMO

In animals without the emetic reflex, several emetogenic stimuli induce pica, an altered feeding behaviour consisting of the ingestion of non-nutritive substances. The development of pica in response to an emetogenic stimulus has been proposed to be useful as an indirect marker of nausea in the rat. In fact, like nausea and emesis in humans, it is accompanied by serotonin release from the enterochromaffin cells, increased c-fos labelling in the area postrema and the nucleus tractus solitarius, and a delay in gastric emptying. Furthermore, pica, measured as kaolin intake, is reduced by anti-emetic drugs. Pica has been demonstrated after single doses of cisplatin, the most emetogenic chemotherapeutic drug. However, cisplatin, as other antineoplastic drugs, is generally given in cycles, where conventional anti-emetics tend to lose efficiency. The aim of this work was to evaluate the pica induced by long-term treatment with cisplatin. Saline or cisplatin was administered once a week for 5 consecutive weeks, and temperature, body weight, food ingestion and kaolin intake were measured on a daily basis. The influence of isolation (pica is necessarily studied in isolated animals) and exposure to kaolin (basal kaolin intake could modify pica itself and other parameters) on temperature, body weight and daily food ingestion was negligible in saline-treated rats. Cisplatin administered at 3 mg/kg/week was too toxic: it produced hypothermia, weight drop and anorexia in both grouped and isolated rats, and 50% mortality in isolated animals. Toxicity associated with cisplatin administered at 1 mg/kg/week was acceptable, with a slower rate of weight gain being the major effect. In these rats, each cisplatin injection produced both acute anorexia and rebound hyperphagic responses. In addition, each administration induced both acute pica and an increase in basal kaolin intake, resembling the development of nausea in humans. This model could be useful for studying both the mechanisms leading to nausea associated with a long-term antineoplastic treatment and the efficiency of new anti-emetic drugs.


Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Esquema de Medicação , Caulim/administração & dosagem , Masculino , Ratos , Ratos Wistar , Isolamento Social , Fatores de Tempo
9.
Neuropharmacology ; 108: 345-52, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27179908

RESUMO

Cannabinoid CB1 receptor, the molecular target of endocannabinoids and cannabis active components, is one of the most abundant metabotropic receptors in the brain. Cannabis is widely used for both recreational and medicinal purposes. Despite the ever-growing fundamental roles of microRNAs in the brain, the possible molecular connections between the CB1 receptor and microRNAs are surprisingly unknown. Here, by using reporter gene constructs that express interaction sequences for microRNAs in human SH-SY5Y neuroblastoma cells, we show that CB1 receptor activation enhances the expression of several microRNAs, including let-7d. This was confirmed by measuring hsa-let-7d expression levels. Accordingly, knocking-down CB1 receptor in zebrafish reduced dre-let-7d levels, and knocking-out CB1 receptor in mice decreased mmu-let-7d levels in the cortex, striatum and hippocampus. Conversely, knocking-down let-7d increased CB1 receptor mRNA expression in zebrafish, SH-SY5Y cells and primary striatal neurons. Likewise, in primary striatal neurons chronically exposed to a cannabinoid or opioid agonist, a let-7d-inhibiting sequence facilitated not only cannabinoid or opioid signaling but also cannabinoid/opioid cross-signaling. Taken together, these findings provide the first evidence for a bidirectional link between the CB1 receptor and a microRNA, namely let-7d, and thus unveil a new player in the complex process of cannabinoid action.


Assuntos
Canabinoides/biossíntese , MicroRNAs/biossíntese , Receptor CB1 de Canabinoide/biossíntese , Animais , Canfanos/farmacologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Peixe-Zebra
10.
Nat Neurosci ; 17(3): 407-15, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24509429

RESUMO

Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Ingestão de Alimentos/fisiologia , Endocanabinoides/fisiologia , Comportamento Alimentar/fisiologia , Condutos Olfatórios/fisiologia , Percepção Olfatória/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Transmissão Sináptica/fisiologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Endocanabinoides/metabolismo , Retroalimentação Fisiológica/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Bulbo Olfatório/fisiologia , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/metabolismo , Percepção Olfatória/efeitos dos fármacos , Receptor CB1 de Canabinoide/genética , Transmissão Sináptica/efeitos dos fármacos
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