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The National Institutes of Health (NIH) recognizes that, despite HIV scientific advances, stigma and discrimination continue to be critical barriers to the uptake of evidence-based HIV interventions. Achieving the Ending the HIV Epidemic: A Plan for America (EHE) goals will require eliminating HIV-related stigma. NIH has a significant history of supporting HIV stigma research across its Institutes, Centers, and Offices (ICOs) as a research priority. This article provides an overview of NIH HIV stigma research efforts. Each ICO articulates how their mission shapes their interest in HIV stigma research and provides a summary of ICO-relevant scientific findings. Research gaps and/or future opportunities are identified throughout, with key research themes and approaches noted. Taken together, the collective actions on the part of the NIH, in tandem with a whole of government and whole of society approach, will contribute to achieving EHE's milestones.
RESUMEN: Los Institutos de Salud Nacional (NIH, siglas en inglés) reconocen que, a pesar de los avances en la prevención y el tratamiento, el estigma y la discriminación continúan siendo barreras críticas a la adopción de la prevención y el cuido basados en la evidencia. Las metas de Logrando el Fin de la Epidemia de VIH: Plan para América (EHE, siglas en inglés) requerirán la eliminación del estigma relacionado al VIH. Los NIH tienen una historia significativa apoyando la investigación del estigma relacionado al VIH a través de sus Institutos, Centros, y Oficinas (ICOs, siglas en inglés). Esta investigación es una prioridad fundamental y entrelazada para los ICOs. En este artículo, los autores de los NIH proveen una reseña sobre la investigación del estigma relacionado al VIH a través de los ICOs selectos. Cada ICO articula como su misión y prioridad dan forma a su interés en la investigación del estigma al VIH y provee una breve reseña de los hallazgos científicos pertinentes al ICO. Lagunas en la investigación relacionada a la misión, prioridades, y/o áreas de investigación futuras se identifican a través del artículo. También se apuntan en el resumen los temas de investigación claves y sus estrategias. En conjunto, las acciones colectivas de parte de los NIH, junto a la estrategia necesaria de parte del gobierno en su totalidad y de la sociedad en su totalidad, contribuirán al logro de las metas del EHE.
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Infecções por HIV , Infecções por HIV/prevenção & controle , Humanos , National Institutes of Health (U.S.) , Estigma Social , Estados UnidosRESUMO
The transactivator of transcription protein, HIV-1 Tat, is linked to neuroAIDS, where degeneration of dopamine neurons occurs. Using a mouse model expressing GFAP-driven Tat protein under doxycycline (Dox) regulation, we investigated microglial-neuronal interactions in the rostral substantia nigra pars compacta (SNc). Immunohistochemistry for microglia and tyrosine hydroxylase (TH) showed that the ratio of microglia to dopamine neurons is smaller in the SNc than in the ventral tegmental area (VTA) and that this difference is maintained following 7-day Dox exposure in wild type animals. Administration of Dox to wild types had no effect on microglial densities. In addressing the sensitivity of neurons to potentially adverse effects of HIV-1 Tat, we found that HIV-1 Tat exposure in vivo selectively decreased TH immunoreactivity in the SNc but not in the VTA, while levels of TH mRNA in the SNc remained unchanged. HIV-1 Tat induction in vivo did not alter the total number of neurons in these brain regions. Application of Tat (5 ng) into dopamine neurons with whole-cell patch pipette decreased spontaneous firing activity. Tat induction also produced a decline in microglial cell numbers, but no microglial activation. Thus, disappearance of dopaminergic phenotype is due to a loss of TH immunoreactivity rather than to neuronal death, which would have triggered microglial activation. We conclude that adverse effects of HIV-1 Tat produce a hypodopamine state by decreasing TH immunoreactivity and firing activity of dopamine neurons. Reduced microglial numbers after Tat exposure in vivo suggest impaired microglial functions and altered bidirectional interactions between dopamine neurons and microglia.
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Encéfalo/metabolismo , Neurônios Dopaminérgicos/metabolismo , Microglia/metabolismo , Transmissão Sináptica/fisiologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Encéfalo/patologia , Encéfalo/virologia , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA , Dopamina/metabolismo , Neurônios Dopaminérgicos/virologia , HIV-1 , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Microglia/patologia , Microglia/virologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , RNA Mensageiro/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Human Immunodeficiency Virus (HIV) is a progressive infection that targets the immune system, affecting more than 37 million people around the world. While combinatorial antiretroviral therapy (cART) has lowered mortality rates and improved quality of life in infected individuals, the prevalence of HIV associated neurocognitive disorders is increasing and HIV associated cognitive decline remains prevalent. Recent research has suggested that HIV accessory proteins may be involved in this decline, and several studies have indicated that the HIV protein transactivator of transcription (Tat) can disrupt normal neuronal and glial function. Specifically, data indicate that Tat may directly impact dopaminergic neurotransmission, by modulating the function of the dopamine transporter and specifically damaging dopamine-rich regions of the CNS. HIV infection of the CNS has long been associated with dopaminergic dysfunction, but the mechanisms remain undefined. The specific effect(s) of Tat on dopaminergic neurotransmission may be, at least partially, a mechanism by which HIV infection directly or indirectly induces dopaminergic dysfunction. Therefore, precisely defining the specific effects of Tat on the dopaminergic system will help to elucidate the mechanisms by which HIV infection of the CNS induces neuropsychiatric, neurocognitive and neurological disorders that involve dopaminergic neurotransmission. Further, this will provide a discussion of the experiments needed to further these investigations, and may help to identify or develop new therapeutic approaches for the prevention or treatment of these disorders in HIV-infected individuals.
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Transtornos Cognitivos , Dopamina/metabolismo , Infecções por HIV , Doenças do Sistema Nervoso , Transmissão Sináptica/fisiologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/virologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/virologiaRESUMO
OBJECTIVES: The All of Us Research Program is a precision medicine initiative aimed at establishing a vast, diverse biomedical database accessible through a cloud-based data analysis platform, the Researcher Workbench (RW). Our goal was to empower the research community by co-designing the implementation of SAS in the RW alongside researchers to enable broader use of All of Us data. MATERIALS AND METHODS: Researchers from various fields and with different SAS experience levels participated in co-designing the SAS implementation through user experience interviews. RESULTS: Feedback and lessons learned from user testing informed the final design of the SAS application. DISCUSSION: The co-design approach is critical for reducing technical barriers, broadening All of Us data use, and enhancing the user experience for data analysis on the RW. CONCLUSION: Our co-design approach successfully tailored the implementation of the SAS application to researchers' needs. This approach may inform future software implementations on the RW.
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Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment. Whether this is due to long-term deficits in short-term memory and/or hippocampal plasticity remains unclear. Recently, we reported that METH increases baseline synaptic transmission and reduces LTP in an ex vivo preparation of the hippocampal CA1 region from young mice. In the current study, we tested the hypothesis that a repeated neurotoxic regimen of METH exposure in adolescent mice decreases hippocampal synaptic plasticity and produces a deficit in short-term memory. Contrary to our prediction, there was no change in the hippocampal plasticity or short-term memory when measured after 14 days of METH exposure. However, we found that at 7, 14, and 21 days of drug abstinence, METH-exposed mice exhibited a deficit in spatial memory, which was accompanied by a decrease in hippocampal plasticity. Our results support the interpretation that the deleterious cognitive consequences of neurotoxic levels of METH exposure may manifest and persist after drug abstinence. Therefore, therapeutic strategies should consider short-term as well as long-term consequences of methamphetamine exposure.
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Dopaminérgicos/toxicidade , Memória de Curto Prazo/efeitos dos fármacos , Metanfetamina/toxicidade , Fatores Etários , Animais , Hipocampo/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de TempoRESUMO
HIV testing rates vary by race and ethnicity. Whether social capital indicators are related to HIV testing and whether these associations differ by race or ethnicity is unknown. Multivariable analysis was used to examine whether social capital (collective engagement and civic and social participation), including social cohesion (trust in neighbors, neighbors willing to help, feelings of belongingness) were associated with testing for HIV in the past 12 months. Participants were white, Black or African American, and Hispanic/Latino adults ages 18 to 44 (N = 2823) from the general population, in Philadelphia, PA who participated in the Southeastern Pennsylvania Household Health Surveys 2010 and 2012. Overall HIV testing in this sample was 42%, and was higher among women, and Black compared to white people. Mean social capital scores were significantly highest among whites. Greater trust in neighbors was associated with lower odds of testing for HIV (adjusted Odds Ratio[aOR]:0.61, 95% CI = 0.49-0.74), and this relationship varied by race/ethnicity, with stronger inverse associations among Hispanic/Latino (aOR = 0.43, p < 0.001) and white adults (aOR = 0.50, p < -0.001) than among Black adults (aOR = 0.75, p < 0.05). Greater neighborhood belongingness (aOR = 1.31, 95% CI = 1.11-1.54) and working together to improve the neighborhood (aOR = 1.33, 95%CI = 1.03-1.73) were associated with higher odds of testing for HIV. Different indicators of social capital were associated with higher as well as lower odds of testing for HIV. These patterns did not vary statistically by race or ethnicity. HIV testing prevention interventions will need to address social capital in design and implementation strategies.
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Dysregulation of dopamine (DA) homeostasis is implicated in neurodegenerative diseases, drug addiction, and neuropsychiatric disorders. The neuronal plasma membrane dopamine transporter (DAT) is essential for the maintenance of DA homeostasis in the brain. α-Synuclein is a 140-amino acid protein that forms a stable complex with DAT and is linked to the pathogenesis of neurodegenerative disease. To elucidate the potential functional consequences of DAT/α-synuclein interaction, we explored α-synuclein modulation of DAT activity in midbrain dopaminergic neurons obtained from TH::RFP mice, immortalized DA neurons, and a heterologous system expressing DAT. We used dual pipette whole cell patch clamp recording to measure the DAT-mediated current before and after dialysis of recombinant α-synuclein into immortalized DA neurons. Our data suggest that intracellular α-synuclein induces a Na+ independent but Cl--sensitive inward current in DAT-expressing cells. This current is blocked by DAT blocker GBR12935 and is absent when heat-inactivated α-synuclein is dialyzed into these cells. The functional consequence of this interaction on DAT activity was further examined with real-time monitoring of transport function using a fluorescent substrate of DAT, 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+). Overexpression of α-synuclein in DAT-positive immortalized DA neurons and CHO cells expressing DAT decreased the magnitude and rate of DAT-mediated substrate uptake without a decrease in the initial binding of the substrate at the plasma membrane. Taken together our findings are consistent with the interpretation that DAT/α-synuclein interaction at the cell surface results in a DAT-dependent, Na+-insensitive, Cl-sensitive inward current with a decrease in substrate uptake, suggesting that DAT/α-synuclein interaction can modulate dopamine transmission and thus neuronal function.
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Cloretos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Dopamina/metabolismo , Corantes Fluorescentes/farmacologia , Humanos , Camundongos , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Técnicas de Patch-ClampRESUMO
Biotechnology offers vast benefits to the environment, animals, and human health, and contributes to improving socioeconomic conditions for the public. However, biotechnology innovations continue to trigger public concern and opposition over their potential social, health, and ecological risks. There is an opportunity to increase knowledge and acceptance of biotechnology through engagement, education, and community participation. In this perspective, we highlight crucial factors that shape the public perception of biotechnology and present opportunities for scientists to effectively communicate their ideas while engaging with local and global communities. Initiatives that seek to involve communities in design, development, and adoption processes are crucial for the successful implementation of biotechnology-based solutions.
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The sudden increase in alcohol use in the young adult population during the COVID-19 pandemic may be partially explained by social isolation and stress due to restricted stay-at-home orders. The goal of this study was to assess specific psychological factors (e.g., anxiety, depressive symptoms, sleep disturbances, and alcohol cravings) and COVID-19 diagnoses and their association with increased alcohol use and misuse during the COVID-19 pandemic among New York residents 18-35 years of age. Survey data were collected via Qualtrics between July 2020-October 2020. Path analyses tests were employed to test alcohol use cravings as a mediator. Among the total sample (N=575), mean age was 27.94±4.12; a majority were White non-Hispanic (66%), female (55%) and had completed a 4-year college or university degree (n = 249; 43.5%). Results revealed that alcohol use cravings was a significant mediator between sleep disturbances, having a COVID-19 diagnoses, and having mental health symptoms on increased alcohol use. Our findings underscore the importance of providing alcohol use prevention and treatment resources in this unprecedented COVID-19 era. Policymakers, public health professionals, and clinicians have a significant role in curbing the COVID-19-induced substance use epidemic.
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Pathophysiological changes in dopamine neurons precede their demise and contribute to the early phases of Parkinson's disease (PD). Intracellular pathological inclusions of the protein α-synuclein within dopaminergic neurons are a cardinal feature of PD, but the mechanisms by which α-synuclein contributes to dopaminergic neuron vulnerability remain unknown. The inaccessibility to diseased tissue has been a limitation in studying progression of pathophysiology prior to degeneration of dopamine neurons. To address these issues, we differentiated induced pluripotent stem cells (iPSCs) from a PD patient carrying the α-synuclein triplication mutation (AST) and an unaffected first-degree relative (NAS) into dopaminergic neurons. In human-like dopamine neurons α-synuclein overexpression reduced the functional availability of D2 receptors, resulting in a stark dysregulation in firing activity, dopamine release, and neuronal morphology. We back-translated these findings into primary mouse neurons overexpressing α-synuclein and found a similar phenotype, supporting the causal role for α-synuclein. Importantly, application of D2 receptor agonist, quinpirole, restored the altered firing activity of AST-derived dopaminergic neurons to normal levels. These results provide novel insights into the pre-degenerative pathophysiological neuro-phenotype induced by α-synuclein overexpression and introduce a potential mechanism for the long-established clinical efficacy of D2 receptor agonists in the treatment of PD.
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Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Doença de Parkinson/fisiopatologia , Receptores de Dopamina D2/metabolismo , alfa-Sinucleína/genética , Animais , Células Cultivadas , Humanos , Camundongos , Mutação , Doença de Parkinson/etiologia , alfa-Sinucleína/metabolismoRESUMO
Cardiovascular disease (CVD), including hypertensive disorders of pregnancy (HDP) and peripartum cardiomyopathy, is a leading cause of pregnancy-related death in the United States. Women who are African American or American Indian/Alaskan Native, have HDP, are medically underserved, are older, or are obese have a major risk for the onset and/or progression of CVD during and after pregnancy. Paradoxically, women with no preexisting chronic conditions or risk factors also experience significant pregnancy-related cardiovascular (CV) complications. The question remains whether substantial physiologic stress on the CV system during pregnancy reflected in hemodynamic, hematological, and metabolic changes uncovers subclinical prepregnancy CVD in these otherwise healthy women. Equally important and similarly understudied is the concept that women's long-term CV health could be detrimentally affected by adverse pregnancy outcomes, such as preeclampsia, gestational hypertension, and diabetes, and preterm birth. Thus, a critical life span perspective in the assessment of women's CV risk factors is needed to help women and health care providers recognize and appreciate not only optimal CV health but also risk factors present before, during, and after pregnancy. In this review article, we highlight new advancements in understanding adverse, pregnancy-related CV conditions and will discuss promising strategies or interventions for their prevention, diagnosis, and treatment.
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Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez , Fatores de RiscoRESUMO
Antiretroviral therapy (ART) prevented premature mortality and improved the quality of life among people living with the human immunodeficiency virus (PLWH), such that now more than half of PLWH in the United States are 50 years of age and older. Increased longevity among PLWH has resulted in a significant rise in chronic, comorbid diseases. However, the implementation of guideline-based interventions for preventing, treating, and managing such age-related, chronic conditions among the HIV population is lacking. The PRECluDE consortium supported by the Center for Translation Research and Implementation Science at the National Heart, Lung, and Blood Institute catalyzes implementation research on proven-effective interventions for co-occurring heart, lung, blood, and sleep diseases and conditions among PLWH. These collaborative research studies use novel implementation frameworks with HIV, mental health, cardiovascular, and pulmonary care to advance comprehensive HIV and chronic disease healthcare in a variety of settings and among diverse populations.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Sobreviventes de Longo Prazo ao HIV , Ciência da Implementação , Doenças não Transmissíveis/prevenção & controle , Serviços Preventivos de Saúde , Pesquisa Translacional Biomédica , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Doença Crônica , Comorbidade , Difusão de Inovações , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Comportamentos Relacionados com a Saúde , Nível de Saúde , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doenças não Transmissíveis/epidemiologia , Fatores de Proteção , Terapia Respiratória , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Carga Viral , Adulto JovemRESUMO
Alzheimer's disease (AD) is the main cause of dementia in the elderly. The discovery of new targets of therapeutic intervention is fundamental to the development of new drugs against AD pathology. Upregulation of cRaf-1 has been found post-mortem in the brains of AD patients. cRaf-1 is a cytosolic protein kinase that regulates neuronal survival and senescence. In this study, we investigated cRaf-1 in the brains of aged APPswe mice presenting AD-like pathology and whether Raf inhibitors protected cultured cortical cells against amyloid beta toxicity (Abeta). We found a dysregulation of cRaf-1 in the cortex of APPswe mice, which showed a 147% increase in the active form phosphorylated at serine 338 and a 40% decrease in the levels of the inactive form of cRaf-1, phospho-cRaf-1[Ser259]. Furthermore, treatment of primary cortical neurons with the cRaf-1 inhibitors, GW5074 or ZM336372, and the nuclear factor kappa B (NFkappaB) inhibitor SN50, protected cortical neurons against Abeta toxicity. Since Raf stimulates NFkappaB, we studied the effect of Raf inhibition on its activation by studying changes in NFkappaB phosphorylation at serine 276. Our results suggest that Raf inhibition with GW5074 is neuroprotective against Abeta toxicity through a mechanism that involves NFkappaB inhibition.
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Peptídeos beta-Amiloides/toxicidade , Córtex Cerebral/citologia , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/farmacologia , Camundongos , Camundongos Transgênicos , Peptídeos/farmacologia , Fenóis/farmacologia , Ratos , Fatores de TempoRESUMO
Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice. We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation. Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.
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Comportamento Animal/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , CamundongosRESUMO
Pharmacologic augmentation of endogenous cannabinoid (eCB) signaling is an emerging therapeutic approach for the treatment of a broad range of pathophysiological conditions. Thus far, pharmacological approaches have focused on inhibition of the canonical eCB inactivation pathways - fatty acid amide hydrolase (FAAH) for anandamide and monoacylglycerol lipase (MAGL) for 2-arachidonoylglycerol. We review here the experimental evidence that cyclooxygenase-2 (COX-2)-mediated eCB oxygenation represents a third mechanism for terminating eCB action at cannabinoid receptors. We describe the development, molecular mechanisms, and in vivo validation of 'substrate-selective' COX-2 inhibitors (SSCIs) that prevent eCB inactivation by COX-2 without affecting prostaglandin (PG) generation from arachidonic acid (AA). Lastly, we review recent data on the potential therapeutic applications of SSCIs with a focus on neuropsychiatric disorders.
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Canabinoides/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Especificidade por SubstratoRESUMO
The central amygdala (CeA) is a key structure at the limbic-motor interface regulating stress responses and emotional learning. Endocannabinoid (eCB) signaling is heavily implicated in the regulation of stress-response physiology and emotional learning processes; however, the role of eCBs in the modulation of synaptic efficacy in the CeA is not well understood. Here we describe the subcellular localization of CB1 cannabinoid receptors and eCB synthetic machinery at glutamatergic synapses in the CeA and find that CeA neurons exhibit multiple mechanistically and temporally distinct modes of postsynaptic eCB mobilization. These data identify a prominent role for eCBs in the modulation of excitatory drive to CeA neurons and provide insight into the mechanisms by which eCB signaling and exogenous cannabinoids could regulate stress responses and emotional learning.
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Tonsila do Cerebelo/metabolismo , Endocanabinoides/metabolismo , Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Sinapses/metabolismo , Tonsila do Cerebelo/citologia , Animais , Cálcio/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Quinase 2 de Receptor Acoplado a Proteína G , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Muscarínicos/metabolismo , Transdução de Sinais/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
RATIONALE: Central CB1 cannabinoid receptors regulate anxiety-like and appetitive consummatory behaviors. Pharmacological antagonism/inverse-agonism of CB1 receptors increases anxiety and decreases appetitive behaviors; however, neither well-defined dose nor context dependence of these effects has been simultaneously assessed in one behavioral assay. OBJECTIVES: We sought to determine the context and dose dependence of the effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in a model that allowed for simultaneous detection of anxiety-like and consummatory-related behaviors. METHODS: We determined the effects of the CB1 receptor antagonist/inverse-agonist, rimonabant, in the novelty-induced hypophagia (NIH) assay in juvenile male ICR mice. RESULTS: Rimonabant dose-dependently decreased consumption of a palatable reward solution completely independent of contextual novelty. Grooming and scratching behavior was also increased by rimonabant in a context-independent manner. In contrast, rimonabant increased feeding latency, a measure of anxiety-like behaviors, only in a novel, mildly anxiogenic context. The effects of rimonabant were specific since no effects of rimonabant on despair-like behavior were observed in the tail suspension assay. Blockade of CB2 receptors had no effect on novelty-induced increases in feeding latency or palatable food consumption. CONCLUSIONS: Our findings indicate that CB1 receptor blockade decreases the hedonic value of palatable food irrespective of environmental novelty, whereas the anxiogenic-like effects are highly context-dependent. Blockade of CB2 receptors does not regulate either anxiety-like or consummatory behaviors in the NIH assay. These findings suggest that rimonabant modulates distinct and dissociable neural processes regulating anxiety and consummatory behavior to sculpt complex and context-dependent behavioral repertories.
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Ansiedade/metabolismo , Antagonistas de Receptores de Canabinoides/farmacologia , Comportamento Consumatório/efeitos dos fármacos , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Estresse Psicológico/complicações , Animais , Ansiedade/etiologia , Ansiedade/psicologia , Antagonistas de Receptores de Canabinoides/administração & dosagem , Relação Dose-Resposta a Droga , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Elevação dos Membros Posteriores , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Rimonabanto , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologiaRESUMO
Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.