Publicações

Veja, abaixo, os mais recentes artigos publicados pelos pesquisadores do INNT (em inglês).

Archives of Oral Biology

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Human dental follicle cells express embryonic, mesenchymal and neural stem cells markers

Rodrigo Lopes de Lima, Rosenilde Carvalho de Holanda Afonso, Vivaldo Moura Neto, Ana Maria Bolognese, Marcos Fabio Henriques dos Santos, Margareth Maria Gomes de Souza

Objective: This study was conducted to identify and characterize dental follicle stem cells (DFSCs) by analyzing expression of embryonic, mesenchymal and neural stem cells surface markers. Design Dental follicle cells (DFCs) were evaluated by immunocytochemistry using embryonic stem cells markers (OCT4 and SOX2), mesenchmal stem cells (MSCs) markers (Notch1, active Notch1, STRO, CD44, HLA-ABC, CD90), neural stem cells markers (Nestin and b-III-tubulin), neural crest stem cells (NCSCs) markers (p75 and HNK1) and a glial cells marker (GFAP). RT-PCR was performed to identify the expression of OCT4 and NANOG in DFCs and dental follicle tissue. Results: Immunocytochemistry and RT-PCR analysis revealed that a significant proportion of the DFCs evaluated expressed human embryonic stem cells marker OCT4 (75%) whereas NANOG was weakly expressed. A considerable amount of MSCs (90%) expressed Notch1, STRO, CD44 and HLA-ABC. However, they were weakly positive for CD90. Moreover, it was possible to demonstrate that dental follicle contains a significant proportion of neural stem/progenitors cells, expressing b-III-tubulin (90%) and nestin (70%). Interestingly, immunocytochemistry showed DFCs positive for p75 (50%), HNK1 (<10%) and a small proportion (<20%) of GFAP-positive cells. This is the first study reporting the presence of NCSCs and glial-like cells in the dental follicle. Conclusions: The results of the present study suggest the occurrence of heterogeneous populations of stem cells, particularly neural stem/progenitor cells, in the dental follicle, Therefore, the human dental follicle might be a promising source of adult stem cells for regenerative purposes.

KEYWORDS: Dental stem cells, Human dental follicle, Mesenchymal stem cells, Neural stem cells, Regenerative medicine

Acta Neuropathol

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A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma

Elias A. El‐Habr, Luiz G. Dubois, Fanny Burel‐Vandenbos, Alexandra Bogeas, Joanna Lipecka, Laurent Turchi, François‐Xavier Lejeune, Paulo Lucas Cerqueira Coehlo, Tomohiro Yamaki, Bryan M. Wittmann, Mohamed Fareh, Emna Mahfoudhi, Maxime Janin, Ashwin Narayanan, Ghislaine Morvan‐Dubois, Charlotte Schmitt, Maité Verreault, Lisa Oliver, Ariane Sharif, Johan Pallud, Bertrand Devaux1, Stéphanie Puget, Penelope Korkolopoulou, Pascale Varlet, Chris Ottolenghi, Isabelle Plo, Vivaldo Moura‐Neto, Thierry Virolle, Hervé Chneiweiss, Marie‐Pierre Junier

Cell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting α-ketoglutarate-dependent Ten–eleven Trans-locations (TET) activity, resulting indecreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/α-ketoglutarate ratios, and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. Our findings support an active participation of metabolic variations in the genesis of tumor heterogeneity.

Cognitive and Behavioral Neurology

Hemispheric Dominance for Stereognosis in a Patient With an Infarct of the Left Postcentral Sensory Hand Area.

Moll J, de Oliveira-Souza R.

The concept of left hemispheric dominance for praxis, speech, and language has been one of the pillars of neurology since the mid-19th century. In 1906, Hermann Oppenheim reported a patient with bilateral stereoagnosia (astereognosis) caused by a left parietal lobe tumor and proposed that the left hemisphere was also dominant for stereognosis. Surprisingly, few cases of bilateral stereoagnosia caused by a unilateral cerebral lesion have been documented in the literature since then. Here we report a 75-year-old right-handed man who developed bilateral stereoagnosia after suffering a small infarct in the crown of the left postcentral gyrus. He could not recognize objects with either hand, but retained the ability to localize stimuli applied to the palm of his left (ipsilesional) hand. He was severely disabled in ordinary activities requiring the use of his hands. The lesion corresponded to Brodmann area 1, where probabilistic anatomic, functional, and electrophysiologic studies have located one of the multiple somatosensory representations of the hand. The lesion was in a strategic position to interrupt both the processing of afferent tactile information issuing from the primary somatosensory cortex (areas 3a and 3b) and the forward higher-order processing in area 2, the secondary sensory cortex, and the contralateral area 1. The lesion also deprived the motor hand area of its afferent regulation from the sensory hand area (grasping), while leaving intact the visuomotor projections from the occipital cortex (reaching). Our patient supports Oppenheim’s proposal that the left postcentral gyrus of some individuals is dominant for stereognosis.

Link para acessar: https://www.ncbi.nlm.nih.gov/pubmed/28926418

Advances in Experimental Medicine and Biology

Microglia in Cancer: For Good or for Bad?

da Fonseca AC, Amaral R, Garcia C, Geraldo LH, Matias D, Lima FR

Glioblastoma is a malignant tumor of astrocytic origin that is highly invasive, proliferative and angiogenic. Despite current advances in multimodal therapies, such as surgery, radio- and chemotherapy, the outcome for patients with glioblastoma is nearly always fatal. The glioblastoma microenvironment has a tremendous influence over the tumor growth and spread. Microglia and macrophages are abundant cells in the tumor mass. Increasing evidence indicates that glioblastoma recruits these cell populations and signals in a way that microglia and macrophages are subverted to promote tumor progression. In this chapter, we discuss some aspects of the interaction between microglia and glioblastoma, consequences of this interaction for tumor progression and the possibility of microglial cells being used as therapeutic vectors, which opens up new alternatives for the development of GBM therapies targeting microglia.

KEYWORDS: Central nervous system; Glioblastoma; Microglia; Therapy

Link para acessarhttps://www.ncbi.nlm.nih.gov/pubmed/27714693

Molecular Biology of the Cell

Neuroprotective astrocyte-derived insulin/insulin-like growth factor 1 stimulates endocytic processing and extracellular release of neuron-bound Aβ oligomers

Pitt J, Wilcox KC, Tortelli V, Diniz LP, Oliveira MS, Dobbins C, Yu XW, Nandamuri S, Gomes FCA, DiNunno N, Viola KL, De Felice FG, Ferreira ST, Klein WL

Synaptopathy underlying memory deficits in Alzheimer’s disease (AD) is increasingly thought to be instigated by toxic oligomers of the amyloid beta peptide (AβOs). Given the long latency and incomplete penetrance of AD dementia with respect to Aβ pathology, we hypothesized that factors present in the CNS may physiologically protect neurons from the deleterious impact of AβOs. Here we employed physically separated neuron-astrocyte cocultures to investigate potential non-cell autonomous neuroprotective factors influencing AβO toxicity. Neurons cultivated in the absence of an astrocyte feeder layer showed abundant AβO binding to dendritic processes and associated synapse deterioration. In contrast, neurons in the presence of astrocytes showed markedly reduced AβO binding and synaptopathy. Results identified the protective factors released by astrocytes as insulin and insulin-like growth factor-1 (IGF1). The protective mechanism involved release of newly bound AβOs into the extracellular medium dependent upon trafficking that was sensitive to exosome pathway inhibitors. Delaying insulin treatment led to AβO binding that was no longer releasable. The neuroprotective potential of astrocytes was itself sensitive to chronic AβO exposure, which reduced insulin/IGF1 expression. Our findings support the idea that physiological protection against synaptotoxic AβOs can be mediated by astrocyte-derived insulin/IGF1, but that this protection itself is vulnerable to AβO buildup.

Link para acessar: https://www.ncbi.nlm.nih.gov/pubmed/28963439

Current Pharmaceutical Design

Role of pharmacogenomics in antiepileptic drug therapy: current status and future perspectives.

Gambardella A, Labate A, Mumoli L, Lopes-Cendes I, Cendes F

BACKGROUND:
Growing evidence indicates that pharmacogenomics will positively impact treatment for patients with epilepsy in the near future, leading to the implementation of a precision-based use of antiepileptic drug (AED) therapy, thereby providing a cornerstone for precision medicine.
OBJECTIVE:
In this review, we briefly summarize the studies of pharmacogenomics in epilepsy, recent advances, and how it may progress in the future.
METHODS:
We subdivided the review into two main sections: genetic variants that may modulate response to AEDs through pharmacokinetics or pharmacodynamics mechanisms; and gene variants that may affect tolerability and safety of AEDs.
RESULTS:
Results from most studies have been contradictory, due to several flaws, including small sample sizes, inaccurate phenotyping, and genotyping strategies. However, even with these limitations, very recent developments indicate that the goal of incorporating genetic data into clinical practice may be attainable in the near future. In addition, recent pharmacogenomic studies of hypersensitivity reactions to AEDs have also made important strides, as its prevention appears attainable with the identification of HLA-A genotypes for patients at high risk of carbamazepine hypersensitivity.
CONCLUSION:
To better clarify the relationship between genetic factors and AEDs, future studies will require more precise epilepsy phenotypes, larger sample sizes, and astute use of new genotyping strategies. Reasonably, this will lead to novel therapeutic approaches in drug targeting and antiepileptogenesis.

KEYWORDS: AEDs; adverse drug reactions ; drug resistance; drug response; epilepsy; pharmacodynamics; pharmacogenomics; pharmacokinetics; precision medicine

Link para acessar: https://www.ncbi.nlm.nih.gov/pubmed/28891449

Frontiers in Neurology

Fish Oil Supplementation Reduces Heart Levels of Interleukin-6 in Rats with Chronic Inflammation due to Epilepsy

Nejm MB, Haidar AA, Hirata AE, Oyama LM, de Almeida AG, Cysneiros RM, Cavalheiro EA, Scorza CA, Scorza FA

Sudden unexpected death in epilepsy (SUDEP) is a major cause of premature death related to epilepsy. The causes of SUDEP remain unknown, but cardiac arrhythmias and asphyxia have been suggested as a major mechanism of this event. Inflammation has been implicated in the pathogenesis of both epilepsy and ventricular arrhythmia, with interleukin-6 (IL-6) being recognized as a crucial orchestrator of inflammatory states. Our group previously reported that levels of IL-6 were increased in the hearts of epileptic rats. In this scenario, anti-inflammatory actions are among the beneficial effects of fish oil dietary supplementation. This investigation revealed that elevated levels of IL-6 in the heart were markedly reduced in epileptic rats that were treated in the long-term with fish oil, suggesting protective anti-inflammatory actions against dangerously high levels of IL-6. Based on these findings, our results suggest beneficial effects of long-term intake of fish oil in reducing the inflammation associated with chronic epilepsy.

KEYWORDS: epilepsy; fish oil; heart; inflammation; interleukin-6; sudden unexpected death in epilepsy

Link para acessarhttps://www.ncbi.nlm.nih.gov/pubmed/28649227

Experimental Eye Research

Retinal exposure to high glucose condition modifies the GABAergic system: Regulation by nitric oxide

R.Carpi-Santos, R.S.Maggesissi, M.P.von Seehausen, K.C.Calaza

Diabetic retinopathy is a severe retinal complication that diabetic patients are susceptible to present. Although this disease is currently characterized as a microvascular disease, there is growing evidence that neural changes occur and maybe precede vascular impairments. Using chicken retina, an avascular tissue with no direct contact with blood vessels and neural retina, this study aimed to evaluate the influence of acute exposure to high glucose concentration in the retinal GABAergic system, and the role of nitric oxide (NO) in this modulation. Therefore, in ex vivo experiments, retinas were incubated in control (10 mM glucose) or high glucose condition (35 mM) for 30 min. By using DAF-FM to evaluate NO production, it was possible to show that high glucose (HG) significantly increased NO levels in the outer nuclear layer, inner nuclear layer (outer and inner portion), and inner plexiform layer. It was also observed that HG increased GABA immunoreactivity (IR) in amacrine and horizontal cells. HG did not change glutamic acid decarboxylase-IR, whereas it decreased GABA Transporter (GAT) 1-IR and increased GAT-3-IR. The co-treatment with 7-NI, an inhibitor of neuronal nitric oxide synthase (nNOS), blocked all changes stimulated by HG exposure. The concomitant exposure with SNAP-5114, a GAT-2/3 inhibitor, blocked the increase in GABA-IR caused by HG incubation. Therefore, our data suggest that hyperglycemia induces GABA accumulation in the cytosol by modulating GABA transporters. This response is dependent on NO production and signaling.

KEYWORDKS: Retina; Avascular; Diabetes; Diabetic retinopathy; GABA; Neuronal nitric oxide synthase

Link para acessar: http://www.sciencedirect.com/science/article/pii/S001448351730297X

Annals of Clinical and Translational Neurology

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Elevated glutamate and lactate predict brain death after severe head trauma

Marco A. Stefani, Rafael Modkovski, Gisele Hansel, Eduardo R. Zimmer, Afonso Kopczynski, Alexandre P. Muller, Nathan R. Strogulski, Marcelo S. Rodolphi, Randhall K. Carteri, Andre P. Schmidt, Jean P. Oses, Douglas H. Smith & Luis V. Portela

Laboratory of Neuroanatomy, Department of Morphological Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

Laboratory of Neurotrauma, Department of Biochemistry, Post-graduation Program in Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil

Laboratory of Exercise, Biochemistry and Physiology, University of Southern Santa Catarina (UNESC), Criciuma, Santa Catarina, Brazil

Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, Brazil

Penn Center for Brain Injury and Repair and Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Objective: Clinical neurological assessment is challenging for severe traumatic brain injury (TBI) patients in the acute setting. Waves of neurochemical abnormalities that follow TBI may serve as fluid biomarkers of neurological status. We assessed the cerebrospinal fluid (CSF) levels of glutamate, lactate, BDNF, and GDNF, to identify potential prognostic biomarkers of neurological outcome. Methods: This cross-sectional study was carried out in a total of 20 consecutive patients (mean [SD] age, 29 [13] years; M/F, 9:1) with severe TBI Glasgow Coma Scale ≤ 8 and abnormal computed tomography scan on admission. Patients were submitted to ventricular drainage and had CSF collected between 2 and 4 h after hospital admission. Patients were then stratified according to two clinical outcomes: deterioration to brain death (nonsurvival, n = 6) or survival (survival, n = 14), within 3 days after hospital admission. Received: 23 February 2017; Accepted: 31 March 2017 CSF levels of brain-derived substances were compared between nonsurvival and survival groups. Clinical and neurological parameters were also assessed. doi: 10.1002/acn3.416 Results: Glutamate and lactate are significantly increased in nonsurvival relative to survival patients. We tested the accuracy of both biomarkers to discriminate patient outcome. Setting a cutoff of >57.75, glutamate provides 80.0% of sensitivity and 84.62% of specificity (AUC: 0.8214, 95% CL: 54.55–98.08%; and a cutoff of >4.65, lactate has 100% of sensitivity and 85.71% of specificity (AUC: 0.8810, 95% CL: 54.55–98.08%). BDNF and GDNF did not discriminate poor outcome. Interpretation: This early study suggests that glutamate and lactate concentrations at hospital admission accurately predict death within 3 days after severe TBI.

Neurobiology of Learning and Memory

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Modulation of the consolidation and reconsolidation of fear memory by three different serotonin receptors in hippocampus

S.D. Schmidt, C.R.G. Furini, C.G. Zinn, L.E. Cavalcante, F.F. Ferreira, J.A.K. Behling, J.C. Myskiw, I. Izquierdo

Memory Center, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 – 2ndfloor, 90610-000 Porto Alegre, RS, Brazil

National Institute of Translational Neuroscience (INNT), National Research Council of Brazil, Brazil

The process of memory formation is complex and highly dynamic. During learning, the newly acquired information is found in a fragile and labile state. Through a process known as consolidation, which requires specific mechanisms such as protein synthesis, the memory trace is stored and stabilized. It is known that when a consolidated memory is recalled, it again becomes labile and sensitive to disruption. To be maintained, this memory must undergo an additional process of restabilization called reconsolidation, which requires another phase of protein synthesis. Memory consolidation has been studied for more than a century, while the molecular mechanisms underlying the memory reconsolidation are starting to be elucidated. For this, is essential compare the participation of important neurotransmitters and its receptors in both processes in brain regions that play a central role in the fear response learning. With focus on serotonin (5-HT), a well characterized neurotransmitter that has been strongly implicated in learning and memory, we investigated, in the CA1 region of the dorsal hippocampus, whether the latest discovered serotonergic receptors, 5-HT5A, 5-HT6 and 5-HT7, are involved in the consolidation and reconsolidation of contextual fear conditioning (CFC) memory. For this, male rats with cannulae implanted in the CA1 region received immediately after the training or reactivation session, or 3 h post-reactivation of the CFC, infusions of agonists or antagonists of the 5-HT5A, 5-HT6 and 5-HT7 receptors. After 24 h, animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of the hippocampus the 5-HT5A, 5-HT6 and 5-HT7 serotonin receptors participate in the reconsolidation of the CFC memory 3 h post-reactivation. Additionally, the results suggest that the 5-HT6 and 5-HT7 receptors also participate in the consolidation of the CFC memory.

KEYWORDS: Consolidation, Reconsolidation, Serotoninergic receptors, Contextual fear conditioning

Behavioural Brain Research

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Extinction memory is facilitated by methylphenidate and regulated by dopamine and noradrenaline receptors

Cristiane R.G. Furini, Jonny A.K. Behling, Carolina G. Zinn, Mara Lise Zanini, Eduardo Assis Brasil, Luiza Doro Pereira, Ivan Izquierdo, Jociane de Carvalho Myskiw

Memory Center, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690–2nd Floor, 90610-000, Porto Alegre, RS, Brazil

National Institute of Translational Neuroscience (INNT), National Research Council of Brazil, Brazil

College of Chemistry, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681, 90619-900. Porto Alegre, RS, Brazil

Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH)is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However,the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region ofthe hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5 g/side) 20 min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally,the administration of MPH + Timolol(1 g/side) or MPH + SCH23390 (1.5 g/side)intra-CA1 20 min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both -adrenergic and D1/D5 dopaminergic receptors.

KEYWORDS: Extinction memory, Methylphenidate, Dopamine receptors, Noradrenaline receptors, Contextual fear conditioning, Hippocampus

Diabetes Journals

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Getting a “GRiP” on Hypothalamic Endoplasmic Reticulum Stress to Combat Obesity

Fernanda G. De Felice and Sergio T. Ferreira

Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Department of Biomedical and Molecular Sciences, Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada

Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

The endoplasmic reticulum (ER) coordinates the synthesis, folding, and sorting of proteins for retention in the cell or for entry into the secretory pathway. Certain conditions (e.g., calcium dyshomeostasis, lipotoxicity, abnormally elevated protein synthesis) may result in protein misfolding and aberrant accumulation in the ER. This process, known as ER stress, activates the adaptive unfolded protein response (UPR), a conserved set of molecular pathways that leads to decreased protein synthesis and misfolding and to increased protein degradation and autophagy, overall aiming to restore cellular homeostasis (1,2). However, persistent activation of the UPR triggers cell death pathways. ER stress and the UPR thus play crucial roles in protein folding and cell survival. Several studies further indicate that they have broader functions in the regulation of cell physiology, including growth, differentiation, and cellular metabolism.

The Journal of Biological Chemistry

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Interaction of amyloid β oligomers (AβOs) with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice

Jordano Brito-Moreira, Mychael V. Lourenco, Mauricio M. Oliveira, Felipe C. Ribeiro, José Henrique Ledo, Luan P. Diniz, Juliana F. S. Vital, Margaret H. Magdesian, Helen M. Melo, Fernanda Barros-Aragão, Jorge M. de Souza, Soniza V. Alves-Leon, Flavia C. A. Gomes, Julia R. Clarke, Cláudia P. Figueiredo, Fernanda G. De Felice, and Sergio T. Ferreira

Institute of Medical Biochemistry Leopoldo de Meis, Institute of Biophysics Carlos Chagas Filho, Institute of Biomedical Sciences, Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, and **School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil, and

Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada

Brain accumulation of the amyloid β protein (Aβ) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). Aβ oligomers (AβOs) are synaptotoxins that build up in the brains of patients and are thought to contribute to memory impairment in AD. Thus, identification of novel synaptic components that are targeted by AβOs may contribute to the elucidation of disease-relevant mechanisms. Trans-synaptic interactions between neurexins (Nrxs) and neuroligins (NLs) are essential for synapse structure, stability, and function, and reduced NL levels have been associated recently with AD. Here we investigated whether the interaction of AβOs with Nrxs or NLs mediates synapse damage and cognitive impairment in AD models.Wefound that AβOs interact with different isoforms of Nrx and NL, including Nrx2α and NL1. Anti-Nrx2α and anti- NL1 antibodies reduced AβO binding to hippocampal neurons and prevented AβO-induced neuronal oxidative stress and synapse loss. Anti-Nrx2α and anti-NL1 antibodies further blocked memory impairment induced by AβOs in mice. The results indicate that Nrx2α and NL1 are targets of AβOs and that prevention of this interaction reduces the deleterious impact of AβOs on synapses and cognition. Identification of Nrx2α and NL1 as synaptic components that interact with AβOs may pave the way for development of novel approaches aimed at halting synapse failure and cognitive loss in AD.

The Journal of Neuroscience

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Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer’s Amyloid-β Oligomers in Mice

Jose Henrique Ledo, Estefania P. Azevedo, Danielle Beckman, Felipe C. Ribeiro, Luis E. Santos, Daniela S. Razolli, Grasielle C. Kincheski, Helen M. Melo, Maria Bellio, Antonio L. Teixeira, Licio A. Velloso, Debora Foguel, Fernanda G. De Felice, and Sergio T. Ferreira

Institute of Medical Biochemistry Leopoldo de Meis, Institute of Biophysics Carlos Chagas Filho, and Institute of Microbiology Prof. Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-902 Brazil,

Faculty of Medical Sciences, University of Campinas, Campinas, 13083-887 Brazil,

Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, 30130-100 Brazil, and

Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, K7L3N6 Canada

Considerable clinical and epidemiological evidence links Alzheimer’s disease (AD) and depression. However,the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble Aβ oligomers (AβOs), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves AβO-induced microglial activation, aberrant TNFα-signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNFα- and abolished depressive-like behavior induced by AβOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AβOs failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that AβOs trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD.

KEYWORDS: Alzheimer’s; depression; inflammation; microglia; serotonin

Science Direct

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Relationship between seizure frequency and number of neuronal and non-neuronal cells in the hippocampus throughout the life of rats with epilepsy

Glauber Menezes Lopim, Diego Vannucci Campos, Sérgio Gomes da Silva, Alexandre Aparecido de Almeida, Roberto Lent, Esper Abrão Cavalheiro, Ricardo Mario Arida

Departamento de Fisiologia, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu 862, Ed. Ciências Biomédicas, 51 andar. Vila Clementino, CEP: 04023-900 São Paulo, SP, Brazil

Instituto do Cérebro (INCE), Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil

Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil

Universidade de Mogi das Cruzes, SP, Brazil

The relationship between seizure frequency and cell death has been a subject of controversy. To tackle this issue, we determined the frequency of seizures and the total number of hippocampal cells throughout the life of rats with epilepsy using the pilocarpine model. Seizure frequency varied in animals with epilepsy according to which period of life they were in, with a progressive increase in the number of seizures until 180 days (sixth months) of epileptic life followed by a decrease (330 days-eleventh month) and subsequently stabilization of seizures. Cell counts by means of isotropic fractionation showed a reduction in the number of hippocampal neuronal cells following 30, 90, 180 and 360 days of spontaneous recurrent seizures (SRS) in rats compared to their controls (about 25%–30% of neuronal cell reduction). In addition, animals with 360 days of SRS showed a reduction in the number of neuronal cells when compared with animals with 90 and 180 days of seizures. The total number of hippocampal non-neuronal cells was reduced in rats with epilepsy after 30 days of SRS, but no significant alteration was observed on the 90th, 180th and 360th days. The total number of neuronal cells was negatively correlated with seizure frequency, indicating an association between occurrence of epileptic seizures throughout life and neuronal loss. In sum, our results add novel data to the literature concerning the time-course of SRS and hippocampal cell number throughout epileptic life.

KEYWORDS: Epilepsy, Seizure frequency, Hippocampus, Neuronal cell, Non-neuronal cell

PNAS

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Structural and functional brain rewiring clarifies preserved interhemispheric transfer in humans born without the corpus callosum

Fernanda Tovar-Moll, Myriam Monteiro, Juliana Andrade, Ivanei E. Bramati, Rodrigo Vianna-Barbosa, Theo Marins, Erika Rodrigues, Natalia Dantas, Timothy E. J. Behrens, Ricardo de Oliveira-Souza, Jorge Moll and Roberto Lent

D’Or Institute for Research and Education (IDOR), 22281-032, Rio de Janeiro, Brazil;

Institute of Biomedical Sciences (ICB) and National Center of Structural Biology and Bioimaging (CENABIO), Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil;

National Institute for Translational Neuroscience (INNT), Ministry of Science and Technology, Brazil;

Augusto Motta University (Unisuam), 21041-020, Rio de Janeiro, Brazil;

Centre for Functional Magnetic Resonance Imaging of the Brain, Oxford University, Oxford OX3 9DU, United Kingdom

Why do humans born without the corpus callosum, the major interhemispheric commissure, lack the disconnection syndrome classically described in callosotomized patients? This paradox was discovered by Nobel laureate Roger Sperry in 1968, and has remained unsolved since then. To tackle the hypothesis that alternative neural pathways could explain this puzzle, we investigated patients with callosal dysgenesis using structural and functional neuroimaging, as well as neuropsychological assessments. We identified two anomalous white-matter tracts by deterministic and probabilistic tractography, and provide supporting resting-state functional neuroimaging and neuropsychological evidence for their functional role in preserved interhemispheric transfer of complex tactile information, such as object recognition. These compensatory pathways connect the homotopic posterior parietal cortical areas (Brodmann areas 39 and surroundings) via the posterior and anterior commissures. We propose that anomalous brain circuitry of callosal dysgenesis is determined by long-distance plasticity, a set of hardware changes occurring in the developing brain after pathological interference. So far unknown, these pathological changes somehow divert growing axons away from the dorsal midline, creating alternative tracts through the ventral forebrain and the dorsal midbrain midline, with partial compensatory effects to the interhemispheric transfer of cortical function.

KEYWORDS: callosal agenesis, callosal plasticity, human connectome

Brain Structure and Function

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Do age and sex impact on the absolute cell numbers of human brain regions?

Ana V. Oliveira-Pinto, Carlos H. Andrade-Moraes, Lays M. Oliveira, Danielle R. Parente-Bruno, Raquel M. Santos, Renan A. Coutinho, Ana T. L. Alho, Renata E. P. Leite, Claudia K. Suemoto, Lea T. Grinberg, Carlos A. Pasqualucci, Wilson Jacob-Filho, Roberto Lent

Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Brazilian Aging Brain Study Group, LIM 22, University of São Paulo Medical School, São Paulo, Brazil

Department of Neurology and Pathology, University of California, San Francisco, USA

National Institute of Translational Neuroscience, Ministry of Science and Technology, São Paulo, Brazil

Discipline of Geriatrics, University of São Paulo Medical School, São Paulo, SP, Brazil

Hospital Israelita Albert Einstein, Brain Institute, São Paulo, SP, Brazil

Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas 373, Sl. F1-31, Ilha do Fundão, Rio de Janeiro CEP 21941-902, Brazil

What is the influence of sex and age on the quantitative cell composition of the human brain? By using the isotropic fractionator to estimate absolute cell numbers in selected brain regions, we looked for sex- and age-related differences in 32 medial temporal lobes (comprised basically by the hippocampal formation, amygdala and parahippocampal gyrus), sixteen male (29–92 years) and sixteen female (25–82); and 31 cerebella, seventeen male (29–92 years) and fourteen female (25–82). These regions were dissected from the brain, fixed and homogenized, and then labeled with a DNA-marker (to count all nuclei) and with a neuron-specific nuclear marker (to estimate neuron number). Total number of cells in the medial temporal lobe was found to be 1.91 billion in men, and 1.47 billion in women, a difference of 23 %. This region showed 34 % more neurons in men than in women: 525.1 million against 347.4 million. In contrast, no sex differences were found in the cerebellum. Regarding the influence of age, a quadratic correlation was found between neuronal numbers and age in the female medial temporal lobe, suggesting an early increase followed by slight decline after age 50. The cerebellum showed numerical stability along aging for both neurons and non-neuronal cells. In sum, results indicate a sex-related regional difference in total and neuronal cell numbers in the medial temporal lobe, but not in the cerebellum. On the other hand, aging was found to impact on cell numbers in the medial temporal lobe, while the cerebellum proved resilient to neuronal losses in the course of life.

KEYWORDS: Brain cellularity,  Aging,  Sexual dimorphism,  Isotropic fractionator

Prospects

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The various forms of neuroplasticity: Biological bases of learning and teaching

Fernanda Tovar-Moll, Roberto Lent

Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Av. Carlos Chagas 273, Ilha do Fundão, Rio de Janeiro CEP 21941-902, Brazil

D’Or Institute of Research and Education, Rio de Janeiro, Brazil

Education is a socially structured form of learning. It involves the brains of different players – students, teachers, family members, and others – in permanent interaction. The biological set of mechanisms by which these brains receive, encode, store, and retrieve mutually exchanged information is called ‘‘neuroplasticity’’. This is the ability that enables developing and adult brains to react and adapt at different coexisting levels – from molecules to neurons, circuits, networks, persons, and societies. This article aims to discuss the major current concepts of neuroplasticity research to help policymakers, researchers, and educators bridge them to learning and teaching models and practices.

KEYWORDS: Synaptic plasticity,  Developmental plasticity,  Neuroeducation, Synaptogenesis, Long-distance plasticity, Circuit plasticity, Network plasticity

Frontiers in Neurology

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Effects of Soccer Heading on Brain Structure and Function

Ana Carolina Rodrigues, Rodrigo Pace Lasmar and Paulo Caramelli

Pró-Reitoria de Graduação, Reitoria da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Grupo de Pesquisa em Neurologia Cognitiva e do Comportamento, Departamento de Clínica Médica, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Faculdade de Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Soccer is the most popular sport in the world, with more than 265 million players worldwide, including professional and amateur ones. Soccer is unique in comparison to other sports, as it is the only sport in which participants purposely use their head to hit the ball. Heading is considered as an offensive or defensive move whereby the player’s unprotected head is used to deliberately impact the ball and direct it during play. A soccer player can be subjected to an average of 6–12 incidents of heading the ball per competitive game, where the ball reaches high velocities. Moreover, in practice sessions, heading training, which involves heading the ball repeatedly at low velocities, is common. Although the scientific community, as well as the media, has focused on the effects of concussions in contact sports, the role of subconcussive impacts, as it can occur during heading, has recently gained attention, considering that it may represent an additional mechanism of cumulative brain injury. The purpose of this study is to review the existing literature regarding the effects of soccer heading on brain structure and function. Only in the last years, some investigations have addressed the impact of heading on brain structure, by using neuroimaging techniques. Similarly, there have been some recent studies investigating biochemical markers of brain injury in soccer players. There is evidence of association between heading and abnormal brain structure, but the data are still preliminary. Also, some studies have suggested that subconcussive head impacts, as heading, could cause cognitive impairment, whereas others have not corroborated this finding. Questions persist as to whether or not heading is deleterious to cognitive functioning. Further studies, especially with longitudinal designs, are needed to clarify the clinical significance of heading as a cause of brain injury and to identify risk factors. Such investigations might contribute to the establishment of safety guidelines that could help to minimize the risk of possible adverse effects of soccer on brain structure and function.

KEYWORDS: sports, soccer, heading, injury, brain, cognition

Journal of Alzheimer’s Disease

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Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms

Luís F.J.R. Miranda, Karina B. Gomes, Pedro A.L. Tito, Josianne N. Silveira, Gerson A. Pianetti, Ricardo M.D. Byrro, Patrícia R.H. Peles, Fernando H. Pereira, Thiago R. Santos, Arthur G. Assini, Valeria V. Ribeiro, Edgar N. Moraes and Paulo Caramelli

Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brasil

Faculdade de Farmácia da Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brasil

Serviço de Neurologia do Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brasil

Instituto de Ciências Exatas da Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brasil

Instituto de Ciências Biológicas da Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brasil

Serviço de Geriatria do Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brasil

The clinical response to donepezil in patients with mild and moderate dementia was investigated in relation to the drug plasma concentration and APOE and CYP2D6 polymorphisms. In a prospective naturalistic observational study, 42 patients with Alzheimer’s disease (AD) and AD with cerebrovascular disease who took donepezil (10 mg) for 12 months were evaluated. Their DNA was genotyped, and the donepezil plasma concentrations were measured after 3, 6, and 12 months. Good responders scored ≥–1 on the Mini-Mental State Examination at 12 months in comparison to the baseline score. The study results indicated the good response pattern was influenced by the concentration of donepezil, but not by APOE and CYP2D6 polymorphisms.

KEYWORDS: Alzheimer’s disease, APOE, CYP2D6, donepezil, genetics, naturalistic study

Neuroscience

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Partial lesion of dopamine neurons of rat substantia nigra impairs conditioned place aversion but spares conditioned place preference

BERNARDO F. C. LIMA, DANIELE C. RAMOS, JANAÍNA K. BARBIERO, LAURA PULIDO, PETER REDGRAVE, DONITA L. ROBINSON, ALEXANDER GÓMEZ-A AND CLAUDIO DA CUNHA

Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba 81.530-980, PR, Brazil

Department of Psychology, University of Sheffield, UK

Department of Psychiatry and Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599-7178, USA

Midbrain dopamine neurons play critical roles in reward- and aversion- driven associative learning. However, it is not clear whether they do this by a common mechanism or by separate mechanisms that can be dissociated. In the present study we addressed this question by testing whether a partial lesion of the dopamine neurons of the rat SNc has comparable effects on conditioned place preference (CPP) learning and conditioned place aversion (CPA) learning. Partial lesions of dopamine neurons in the rat substantia nigra pars compacta (SNc) induced by bilateral intranigral infusion of 6-hydroxydopamine (6-OHDA, 3 lg/side) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 200 lg/side) impaired learning of conditioned place aversion (CPA) without affecting conditioned place preference (CPP) learning. Control experiments demonstrated that these lesions did not impair motor performance and did not alter the hedonic value of the sucrose and quinine. The number of dopamine neurons in the caudal part of the SNc positively correlated with the CPP scores of the 6-OHDA rats and negatively correlated with CPA scores of the SHAM rats. In addition, the CPA scores of the 6-OHDA rats positively correlated with the tissue content of striatal dopamine. Insomuch as reward-driven learning depends on an increase in dopamine release by nigral neurons, these findings show that this mechanism is functional even in rats with a partial lesion of the SNc. On the other hand, if aversion-driven learning depends on a reduction of extracellular dopamine in the striatum, the present study suggests that this mechanism is no longer functional after the partial SNc lesion. 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: basal ganglia, dopaminergic neurons, procedural memory, incentive salience, motivation, mesolimbic dopamine.

Science Signaling

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Caveolin-1–mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype

Camila C. Portugal, Renato Socodato, Teresa Canedo, Cátia M. Silva, Tânia Martins, Vivian S. M. Coreixas, Erick C. Loiola, Burkhard Gess, Dominik Röhr, Ana R. Santiago, Peter Young, Richard D. Minshall, Roberto Paes-de-Carvalho, António F. Ambrósio, João B. Relvas

Vitamin C is essential for the development and function of the central nervous system (CNS). The plasma membrane sodium–vitamin C cotransporter 2 (SVCT2) is the primary mediator of vitamin C uptake in neurons. SVCT2 specifically transports ascorbate, the reduced form of vitamin C, which acts as a reducing agent. We demonstrated that ascorbate uptake through SVCT2 was critical for the homeostasis of microglia, the resident myeloid cells of the CNS that are essential for proper functioning of the nervous tissue. We found that depletion of SVCT2 from the plasma membrane triggered a proinflammatory phenotype in microglia and resulted in microglia activation. Src-mediated phosphorylation of caveolin-1 on Tyr14 in microglia induced the internalization of SVCT2. Ascorbate treatment, SVCT2 overexpression, or blocking SVCT2 internalization prevented the activation of microglia. Overall, our work demonstrates the importance of the ascorbate transport system for microglial homeostasis and hints that dysregulation of ascorbate transport might play a role in neurological disorders.

Scientific Reports

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Dopamine promotes NMDA receptor hypofunction in the retina through D1 receptor-mediated Csk activation, Src inhibition and decrease of GluN2B phosphorylation

Renato Socodato, Felipe N. Santiago, CamilaC. Portugal, Ivan Domith, ThaísaG. Encarnação, ErickC. Loiola, Ana L. M.Ventura, Marcelo Cossenza, João B. Relvas, NewtonG. Castro & Roberto Paes-de-Carvalho

Dopamine and glutamate are critical neurotransmitters involved in light-induced synaptic activity in the retina. In brain neurons, dopamine D1 receptors (D1Rs) and the cytosolic protein tyrosine kinase Src can, independently, modulate the behavior of NMDA-type glutamate receptors (NMDARs). Here we studied the interplay between D1Rs, Src and NMDARs in retinal neurons. We reveal that dopamine-mediated D1R stimulation provoked NMDAR hypofunction in retinal neurons by attenuating NMDA-gated currents, by preventing NMDA-elicited calcium mobilization and by decreasing the phosphorylation of NMDAR subunit GluN2B. This dopamine effect was dependent on upregulation of the canonical D1R/ adenylyl cyclase/cAMP/PKA pathway, of PKA-induced activation of C-terminal Src kinase (Csk) and of Src inhibition. Accordingly, knocking down Csk or overexpressing a Csk phosphoresistant Src mutant abrogated the dopamine-induced NMDAR hypofunction. Overall, the interplay between dopamine and NMDAR hypofunction, through the D1R/Csk/Src/GluN2B pathway, might impact on light-regulated synaptic activity in retinal neurons.

Experimental Eye Research

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Cannabinoid receptors and TRPA1 on neuroprotection in a model of retinal ischemia

D.S.M. Araújo, V.S. Miya-Coreixas, P. Pandolfo, K.C. Calaza

Laboratory of Neurobiology of the Retina, Department of Neurobiology and Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niteroi, RJ, Brazil

Laboratory of Neurobiology of Animal Behavior, Department of Neurobiology and Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niteroi, RJ, Brazil

Retinal ischemia is a pathological event present in several retinopathies such as diabetic retinopathy and glaucoma, leading to partial or full blindness with no effective treatment available. Since synthetic and endogenous cannabinoids have been studied as modulators of ischemic events in the central nervous system (CNS), the present study aimed to investigate the involvement of cannabinoid system in the cell death induced by ischemia in an avascular (chick) retina. We observed that chick retinal treatment with a combination of WIN 55212-2 and cannabinoid receptor antagonists (either AM251/O-2050 or AM630) decreased the release of lactate dehydrogenase (LDH) induced by retinal ischemia in an oxygen and glucose deprivation (OGD) model. Further, the increased availability of endocannabinoids together with cannabinoid receptor antagonists also had a neuroprotective effect. Surprisingly, retinal exposure to any of these drugs alone did not prevent the release of LDH stimulated by OGD. Since cannabinoids may also activate transient receptor potential (TRP) channels, we investigated the involvement of TRPA1 receptors (TRPA1) in retinal cell death induced by ischemic events. We demonstrated the presence of TRPA1 in the chick retina, and observed an increase in TRPA1 content after OGD, both by western blot and immunohistochemistry. In addition, the selective activation of TRPA1 by mustard oil (MO) did not worsen retinal LDH release induced by OGD, whereas the blockage of TRPA1 completely prevented the extravasation of cellular LDH in ischemic condition. Hence, these results show that during the ischemic event there is an augment of TRPA1, and activation of this receptor is important in cell death induction. The data also indicate that metabotropic cannabinoid receptors, both type 1 and 2, are not involved with the cell death found in the early stages of ischemia. Therefore, the study points to a potential role of TRPA1 as a target for neuroprotective approaches in retinal ischemia.

KEYWORDS: Endocannabinoid, TRP channel, Oxygen glucose deprivation, TRPA1, Retina, Chick

ACS Chemical Neuroscience

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Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine

Alexander Gomez-A, Amanda M. Fiorenza, Suelen L. Boschen, Adam H. Sugi, Danielle Beckman, Sergio T. Ferreira, Kendall Lee, Charles D. Blaha, and Claudio Da Cunha

Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba 81.530-980, PR, Brazil

Institute of Biophysics Carlos Chagas Filho and Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota 55905, United States

Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fastscan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.

KEYWORDS: Dopaminergic neurons, Electrochemistry, Ventral tegmental area, Nucleus accumbens core, GABA, Anxiolytic, Anticonvulsant