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1.
J Psychiatry Neurosci ; 46(1): E1-E13, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-32559027

RESUMO

Background: Glutamate transmission is implicated in drug-induced behavioural sensitization and the associated long-lasting increases in mesolimbic output. Metabotropic glutamate type 5 (mGlu5) receptors might be particularly important, but most details are poorly understood. Methods: We first assessed in mice (n = 51, all male) the effects of repeated dextroamphetamine administration (2.0 mg/kg, i.p.) on locomotor activity and binding of the mGlu5 ligand [3H]ABP688. In a parallel study, in 19 stimulant-drug-naïve healthy human volunteers (14 female) we administered 3 doses of dextroamphetamine (0.3 mg/kg, p.o.) or placebo, followed by a fourth dose 2 weeks later. We measured [11C]ABP688 binding using positron emission tomography before and after the induction phase. We assessed psychomotor and behavioural sensitization using speech rate, eye blink rate and self-report. We measured the localization of mGlu5 relative to synaptic markers in mouse striatum using immunofluorescence. Results: We observed amphetamine-induced psychomotor sensitization in mice and humans. We did not see group differences in mGlu5 availability following 3 pre-challenge amphetamine doses, but group differences did develop in mice administered 5 doses. In mice and humans, individual differences in mGlu5 binding after repeated amphetamine administration were negatively correlated with the extent of behavioural sensitization. In drug-naïve mice, mGlu5 was expressed at 67% of excitatory synapses on dendrites of striatal medium spiny neur. Limitations: Correlational results should be interpreted as suggestive because of the limited sample size. We did not assess sex differences. Conclusion: Together, these results suggest that changes in mGlu5 availability are not part of the earliest neural adaptations in stimulant-induced behavioural sensitization, but low mGlu5 binding might identify a higher propensity for sensitization.


Assuntos
Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado , Dextroanfetamina/farmacologia , Locomoção/efeitos dos fármacos , Córtex Pré-Frontal , Desempenho Psicomotor/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5/metabolismo , Adulto , Animais , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dextroanfetamina/administração & dosagem , Feminino , Imunofluorescência , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Oximas/farmacocinética , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores
2.
J Neurochem ; 148(6): 779-795, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30556914

RESUMO

Several subtypes of modulatory neurons co-express vesicular glutamate transporters (VGLUTs) in addition to their cognate vesicular transporters. These neurons are believed to establish new forms of neuronal communication. The atypical VGLUT3 is of particular interest since in the striatum this subtype is found in tonically active cholinergic interneurons (TANs) and in a subset of 5-HT fibers. The striatum plays a major role in psychomotor effects induced by amphetamine. Whether and how VGLUT3-operated glutamate/ACh or glutamate/5HT co-transmissions modulates psychostimulants-induced maladaptive behaviors is still unknown. Here, we investigate the involvement of VGLUT3 and glutamate co-transmission in amphetamine-induced psychomotor effects and stereotypies. Taking advantage of constitutive and cell-type specific VGLUT3-deficient mouse lines, we tackled the hypothesis that VGLUT3 could gate psychomotor effects (locomotor activity and stereotypies) induced by acute or chronic administration of amphetamine. Interestingly, VGLUT3-null mice demonstrated blunted amphetamine-induced stereotypies as well as reduced striatal ∆FosB expression. VGLUT3-positive varicosities within the striatum arise in part from 5HT neurons. We tested the involvement of VGLUT3 deletion in serotoninergic neurons in amphetamine-induced stereotypies. Mice lacking VGLUT3 specifically in 5HT fibers showed no alteration to amphetamine sensitivity. In contrast, specific deletion of VGLUT3 in cholinergic neurons partially phenocopied the effects observed in the constitutive knock-out mice. Our results show that constitutive deletion of VGLUT3 modulates acute and chronic locomotor effects induced by amphetamine. They point to the fact that the expression of VGLUT3 in multiple brain areas is pivotal in gating amphetamine-induced psychomotor adaptations. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Anfetamina/farmacologia , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Locomoção/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
J Neurosci ; 36(10): 3016-23, 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26961955

RESUMO

The medial septum and diagonal band of Broca (MS-DBB) has an essential role for theta rhythm generation in the hippocampus and is critical for learning and memory. The MS-DBB contains cholinergic, GABAergic, and recently described glutamatergic neurons, but their specific contribution to theta generation is poorly understood. Here, we examined the role of MS-DBB glutamatergic neurons in theta rhythm using optogenetic activation and electrophysiological recordings performed in in vitro preparations and in freely behaving mice. The experiments in slices suggest that MS-DBB glutamatergic neurons provide prominent excitatory inputs to a majority of local GABAergic and a minority of septal cholinergic neurons. In contrast, activation of MS-DBB glutamatergic fiber terminals in hippocampal slices elicited weak postsynaptic responses in hippocampal neurons. In the in vitro septo-hippocampal preparation, activation of MS-DBB glutamatergic neurons did increase the rhythmicity of hippocampal theta oscillations, whereas stimulation of septo-hippocampal glutamatergic fibers in the fornix did not have an effect. In freely behaving mice, activation of these neurons in the MS-DBB strongly synchronized hippocampal theta rhythms over a wide range of frequencies, whereas activation of their projections to the hippocampus through fornix stimulations had no effect on theta rhythms, suggesting that MS-DBB glutamatergic neurons played a role in theta generation through local modulation of septal neurons. Together, these results provide the first evidence that MS-DBB glutamatergic neurons modulate local septal circuits, which in turn contribute to theta rhythms in the hippocampus.


Assuntos
Glutamatos/metabolismo , Hipocampo/fisiologia , Neurônios/fisiologia , Optogenética , Núcleos Septais/citologia , Ritmo Teta/fisiologia , Animais , Animais Recém-Nascidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Channelrhodopsins , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Feixe Diagonal de Broca/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Potenciais da Membrana/genética , Camundongos , Vias Neurais/fisiologia , Quinoxalinas/farmacologia , Sinapsinas/genética , Sinapsinas/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
4.
Nat Neurosci ; 27(9): 1783-1793, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38965445

RESUMO

The role of the striatum in motor control is commonly assumed to be mediated by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing dopamine (DA) D1 receptors or D2 receptors (D1-SPNs and D2-SPNs, respectively), without regard to SPNs coexpressing both receptors (D1/D2-SPNs). Here we developed an approach to target these hybrid SPNs in mice and demonstrate that, although these SPNs are less abundant, they have a major role in guiding the motor function of the other two populations. D1/D2-SPNs project exclusively to the external globus pallidus and have specific electrophysiological features with distinctive integration of DA signals. Gain- and loss-of-function experiments indicate that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this population of D1/D2-coexpressing neurons in orchestrating the fine-tuning of DA regulation in thalamo-cortico-striatal loops.


Assuntos
Corpo Estriado , Neurônios , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Animais , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Corpo Estriado/metabolismo , Camundongos , Neurônios/metabolismo , Masculino , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Atividade Motora/efeitos dos fármacos , Vias Neurais/fisiologia , Vias Neurais/metabolismo , Feminino , Globo Pálido/metabolismo
5.
J Physiol ; 590(20): 5183-98, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22890712

RESUMO

Neonates respond to hypoxia initially by increasing ventilation, and then by markedly decreasing both ventilation (hypoxic ventilatory decline) and oxygen consumption (hypoxic hypometabolism). This latter process, which vanishes with age, reflects a tight coupling between ventilatory and thermogenic responses to hypoxia. The neurological substrate of hypoxic hypometabolism is unclear, but it is known to be centrally mediated, with a strong involvement of the 5-hydroxytryptamine (5-HT, serotonin) system. To clarify this issue, we investigated the possible role of VGLUT3, the third subtype of vesicular glutamate transporter. VGLUT3 contributes to glutamate signalling by 5-HT neurons, facilitates 5-HT transmission and is expressed in strategic regions for respiratory and thermogenic control. We therefore assumed that VGLUT3 might significantly contribute to the response to hypoxia. To test this possibility, we analysed this response in newborn mice lacking VGLUT3 using anatomical, biochemical, electrophysiological and integrative physiology approaches. We found that the lack of VGLUT3 did not affect the histological organization of brainstem respiratory networks or respiratory activity under basal conditions. However, it impaired respiratory responses to 5-HT and anoxia, showing a marked alteration of central respiratory control. These impairments were associated with altered 5-HT turnover at the brainstem level. Furthermore, under cold conditions, the lack of VGLUT3 disrupted the metabolic rate, body temperature, baseline breathing and the ventilatory response to hypoxia. We conclude that VGLUT3 expression is dispensable under basal conditions but is required for optimal response to hypoxic stress in neonates.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/fisiologia , Hipóxia/fisiopatologia , Animais , Animais Recém-Nascidos , Tronco Encefálico/anatomia & histologia , Tronco Encefálico/fisiologia , Camundongos , Camundongos Transgênicos , Respiração , Serotonina/fisiologia , Estresse Fisiológico
6.
Nat Commun ; 13(1): 886, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35173173

RESUMO

Early-onset familial Alzheimer's disease (AD) is marked by an aggressive buildup of amyloid beta (Aß) proteins, yet the neural circuit operations impacted during the initial stages of Aß pathogenesis remain elusive. Here, we report a coding impairment of the medial entorhinal cortex (MEC) grid cell network in the J20 transgenic mouse model of familial AD that over-expresses Aß throughout the hippocampus and entorhinal cortex. Grid cells showed reduced spatial periodicity, spatial stability, and synchrony with interneurons and head-direction cells. In contrast, the spatial coding of non-grid cells within the MEC, and place cells within the hippocampus, remained intact. Grid cell deficits emerged at the earliest incidence of Aß fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread Aß-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Córtex Entorrinal/patologia , Células de Grade/patologia , Hipocampo/patologia , Potenciais de Ação/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais , Memória Espacial/fisiologia
7.
Bioorg Med Chem Lett ; 21(3): 1041-6, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21215624

RESUMO

Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.


Assuntos
Amidas/química , Indóis/química , Naftalenos/química , Quinolinas/química , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Compostos de Sulfonilureia/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/síntese química , Indóis/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacocinética
8.
J Clin Invest ; 130(12): 6616-6630, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33164988

RESUMO

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.


Assuntos
Acetilcolina/metabolismo , Corpo Estriado , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Ácido Glutâmico/metabolismo , Interneurônios/metabolismo , Adulto , Animais , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Donepezila/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Feminino , Humanos , Levodopa/farmacologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
9.
Bioorg Med Chem Lett ; 18(6): 2048-54, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18291643

RESUMO

A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.


Assuntos
Artrite Experimental/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Cães , Cobaias , Humanos , Macaca mulatta , Estrutura Molecular , Quinolinas/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética
10.
Front Cell Neurosci ; 11: 140, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28559797

RESUMO

Hippocampal interneurons release the inhibitory transmitter GABA to regulate excitation, rhythm generation and synaptic plasticity. A subpopulation of GABAergic basket cells co-expresses the GABA/glycine vesicular transporters (VIAAT) and the atypical type III vesicular glutamate transporter (VGLUT3); therefore, these cells have the ability to signal with both GABA and glutamate. GABAergic transmission by basket cells has been extensively characterized but nothing is known about the functional implications of VGLUT3-dependent glutamate released by these cells. Here, using VGLUT3-null mice we observed that the loss of VGLUT3 results in a metaplastic shift in synaptic plasticity at Shaeffer's collaterals - CA1 synapses and an altered theta oscillation. These changes were paralleled by the loss of a VGLUT3-dependent inhibition of GABAergic current in CA1 pyramidal layer. Therefore presynaptic type III metabotropic could be activated by glutamate released from VGLUT3-positive interneurons. This putative presynaptic heterologous feedback mechanism inhibits local GABAergic tone and regulates the hippocampal neuronal network.

11.
Front Neuroanat ; 10: 39, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27147980

RESUMO

A subset of monoamine neurons releases glutamate as a cotransmitter due to presence of the vesicular glutamate transporters VGLUT2 or VGLUT3. In addition to mediating vesicular loading of glutamate, it has been proposed that VGLUT3 enhances serotonin (5-HT) vesicular loading by the vesicular monoamine transporter (VMAT2) in 5-HT neurons. In dopamine (DA) neurons, glutamate appears to be released from specialized subsets of terminals and it may play a developmental role, promoting neuronal growth and survival. The hypothesis of a similar developmental role and axonal localization of glutamate co-release in 5-HT neurons has not been directly examined. Using postnatal mouse raphe neurons in culture, we first observed that in contrast to 5-HT itself, other phenotypic markers of 5-HT axon terminals such as the 5-HT reuptake transporter (SERT) show a more restricted localization in the axonal arborization. Interestingly, only a subset of SERT- and 5-HT-positive axonal varicosities expressed VGLUT3, with SERT and VGLUT3 being mostly segregated. Using VGLUT3 knockout mice, we found that deletion of this transporter leads to reduced survival of 5-HT neurons in vitro and also decreased the density of 5-HT-immunoreactivity in terminals in the dorsal striatum and dorsal part of the hippocampus in the intact brain. Our results demonstrate that raphe 5-HT neurons express SERT and VGLUT3 mainly in segregated axon terminals and that VGLUT3 regulates the vulnerability of these neurons and the neurochemical identity of their axonal domain, offering new perspectives on the functional connectivity of a cell population involved in anxiety disorders and depression.

12.
Neurobiol Aging ; 36(3): 1471-82, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25556161

RESUMO

In humans, memory capacities are generally affected with aging, even without any reported neurologic disorders. The mechanisms behind cognitive decline are not well understood. We studied here whether postsynaptic glutamate receptor and presynaptic vesicular glutamate transporters (VGLUTs) levels may change in the course of aging and be related to cognitive abilities using various age-impaired (AI) or age-unimpaired rat strains. Twenty-four-month-old Long-Evans (LE) rats with intact spatial memory maintained postsynaptic ionotropic glutamate receptor levels in the hippocampal-adjacent cortex similar to those of young animals. In contrast, AI rats showed significantly reduced expression of ionotropic glutamate receptor GluR2, NR2A and NR2B subunits. In AI LE rats, VGLUT1 and VGLUT2 levels were increased and negatively correlated with receptor levels as shown by principal component analysis and correlation matrices. We also investigated whether glutamatergic receptors and VGLUT levels were altered in the obesity-resistant LOU/C/Jall (LOU) rat strain which is characterized by intact memory despite aging. No difference was observed between 24-month-old LOU rats and their young counterparts. Taken together, the unaltered spatial memory performance of 24-month-old age-unimpaired LE and LOU rats suggests that intact coordination of the presynaptic and postsynaptic hippocampal-adjacent cortex glutamatergic networks may be important for successful cognitive aging. Accordingly, altered expression of presynaptic and postsynaptic glutamatergic components, such as in AI LE rats, could be considered a marker of age-related cognitive deficits.


Assuntos
Envelhecimento/psicologia , Expressão Gênica/genética , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Memória Espacial/fisiologia , Proteína Vesicular 1 de Transporte de Glutamato/genética , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Animais , Biomarcadores/metabolismo , Córtex Cerebral/metabolismo , Transtornos Cognitivos/diagnóstico , Feminino , Hipocampo/metabolismo , Masculino , Modelos Animais , Ratos Endogâmicos , Ratos Long-Evans
13.
Front Neuroanat ; 9: 23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25798091

RESUMO

Glutamate is the major excitatory transmitter in the brain. Vesicular glutamate transporters (VGLUT1-3) are responsible for uploading glutamate into synaptic vesicles. VGLUT1 and VGLUT2 are considered as specific markers of canonical glutamatergic neurons, while VGLUT3 is found in neurons previously shown to use other neurotransmitters than glutamate. Although there exists a rich literature on the localization of these glutamatergic markers in the rodent brain, little is currently known about the distribution of VGLUT1-3 in the human brain. In the present study, using subtype specific probes and antisera, we examined the localization of the three vesicular glutamate transporters in the human brain by in situ hybridization, immunoautoradiography and immunohistochemistry. We found that the VGLUT1 transcript was highly expressed in the cerebral cortex, hippocampus and cerebellum, whereas VGLUT2 mRNA was mainly found in the thalamus and brainstem. VGLUT3 mRNA was localized in scarce neurons within the cerebral cortex, hippocampus, striatum and raphe nuclei. Following immunoautoradiographic labeling, intense VGLUT1- and VGLUT2-immunoreactivities were observed in all regions investigated (cerebral cortex, hippocampus, caudate-putamen, cerebellum, thalamus, amygdala, substantia nigra, raphe) while VGLUT3 was absent from the thalamus and cerebellum. This extensive mapping of VGLUT1-3 in human brain reveals distributions that correspond for the most part to those previously described in rodent brains.

14.
Nat Med ; 20(7): 764-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24908571

RESUMO

Major depressive disorder (MDD) is a prevalent mood disorder that is associated with differential prefrontal brain expression patterns. Treatment of MDD includes a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for depressive episodes, and they are among the most prescribed medications in North America. Although antidepressants are clearly effective, particularly for moderate to severe depressive episodes, there is variability in how individuals respond to antidepressant treatment. Failure to respond has individual, economic and social consequences for patients and their families. Several lines of evidence demonstrate that genes are regulated through the activity of microRNAs (miRNAs), which act as fine-tuners and on-off switches of gene expression. Here we report on complementary studies using postmortem human brain samples, cellular assays and samples from clinical trials of patients with depression and show that miR-1202, a miRNA specific to primates and enriched in the human brain, is differentially expressed in individuals with depression. Additionally, miR-1202 regulates expression of the gene encoding metabotropic glutamate receptor-4 (GRM4) and predicts antidepressant response at baseline. These results suggest that miR-1202 is associated with the pathophysiology of depression and is a potential target for new antidepressant treatments.


Assuntos
Antidepressivos/uso terapêutico , Encéfalo/metabolismo , Transtorno Depressivo Maior/genética , MicroRNAs/fisiologia , Linhagem Celular , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , MicroRNAs/metabolismo
15.
PLoS One ; 5(10): e13644, 2010 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-21048979

RESUMO

BACKGROUND: To secure pH homeostasis, the central respiratory network must permanently adapt its rhythmic motor drive to environment and behaviour. In neonates, it is commonly admitted that the retrotrapezoid/parafacial respiratory group of neurons of the ventral medulla plays the primary role in the respiratory response to acidosis, although the serotonergic system may also contribute to this response. METHODOLOGY/PRINCIPAL FINDINGS: Using en bloc medullary preparations from neonatal mice, we have shown for the first time that the respiratory response to acidosis is abolished after pre-treatment with the serotonin-transporter blocker fluoxetine (25-50 µM, 20 min), a commonly used antidepressant. Using mRNA in situ hybridization and immunohistology, we have also shown the expression of the serotonin transporter mRNA and serotonin-containing neurons in the vicinity of the RTN/pFRG of neonatal mice. CONCLUSIONS: These results reveal that the serotonergic system plays a pivotal role in pH homeostasis. Although obtained in vitro in neonatal mice, they suggest that drugs targeting the serotonergic system should be used with caution in infants, pregnant women and breastfeeding mothers.


Assuntos
Acidose/fisiopatologia , Fluoxetina/farmacologia , Respiração/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Animais Recém-Nascidos , Sequência de Bases , Primers do DNA , Hibridização In Situ , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
16.
Mol Cell Biol ; 30(24): 5752-63, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20956558

RESUMO

Erk4 and Erk3 are atypical members of the mitogen-activated protein (MAP) kinase family. The high sequence identity of Erk4 and Erk3 proteins and the similar organization of their genes imply that the two protein kinases are paralogs. Recently, we have shown that Erk3 function is essential for neonatal survival and critical for the establishment of fetal growth potential and pulmonary function. To investigate the specific functions of Erk4, we have generated mice with a targeted disruption of the Mapk4 gene. We show that Erk4-deficient mice are viable and fertile and exhibit no gross morphological or physiological anomalies. Loss of Erk4 is not compensated by changes in Erk3 expression or activity during embryogenesis or in adult tissues. We further demonstrate that additional loss of Erk4 does not exacerbate the fetal growth restriction and pulmonary immaturity phenotypes of Erk3(-/-) mice and does not compromise the viability of Erk3(+/-) neonates. Interestingly, behavioral phenotyping revealed that Erk4-deficient mice manifest depression-like behavior in the forced-swimming test. Our analysis indicates that the MAP kinase Erk4 is dispensable for mouse embryonic development and reveals that Erk3 and Erk4 have acquired specialized functions through evolutionary diversification.


Assuntos
Isoenzimas/metabolismo , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Animais , Comportamento Animal/fisiologia , Células Cultivadas , Embrião de Mamíferos/anatomia & histologia , Embrião de Mamíferos/fisiologia , Fibroblastos/citologia , Fibroblastos/fisiologia , Genótipo , Isoenzimas/genética , Camundongos , Camundongos Knockout , Proteína Quinase 6 Ativada por Mitógeno/genética , Proteína Quinase 7 Ativada por Mitógeno/genética , Neurogênese/fisiologia , Testes Neuropsicológicos , Distribuição Tecidual
17.
J Med Chem ; 53(5): 2227-38, 2010 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-20163116

RESUMO

The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.


Assuntos
Analgésicos/síntese química , Benzoatos/síntese química , Ciclopropanos/síntese química , Antagonistas de Prostaglandina/síntese química , Receptores de Prostaglandina E/metabolismo , Tiofenos/síntese química , Analgésicos/química , Analgésicos/farmacocinética , Animais , Benzoatos/química , Benzoatos/farmacocinética , Ciclopropanos/química , Ciclopropanos/farmacocinética , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Dor/tratamento farmacológico , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/antagonistas & inibidores , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacocinética
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