Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Neurosci Res ; 99(4): 1099-1107, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33368537

RESUMO

The effects of social isolation on an individual's behavior is an important field of research, especially as public health officials encourage social distancing to prevent the spread of pandemic disease. In this study we evaluate the effects of social isolation on physical activity in mice. Utilizing a pixel-based tracking system, we continuously monitored the movement of isolated mice compared with paired cage mates in the home cage environment. We demonstrate that mice that are socially isolated dramatically decrease their movement when separated from their cage mate, and especially in the dark cycle, when mice are normally most active. When isolated mice are re-paired with their original cage mate, this effect is reversed, and mice return to their prior levels of activity. These findings suggest a close link between social isolation and physical activity, and are of particular interest in the wake of coronavirus disease 2019, when many are forced into isolation. Social isolation may affect an individual's overall activity levels in humans too, which may have unintended effects on health that deserve further consideration.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32974615

RESUMO

Multiple and diverse psychotherapeutic or psychopharmacologic treatments effectively reduce symptoms for many patients with anxiety disorders, but the trajectory and magnitude of response vary considerably. This heterogeneity of treatment response has invigorated the search for biomarkers of treatment response in anxiety disorders, across the lifespan. In this review, we summarize evidence for biomarkers of treatment response in children, adolescents and adults with generalized, separation and social anxiety disorders as well as panic disorder. We then discuss the relationship between these biomarkers of treatment response and the pathophysiology of anxiety disorders. Finally, we provide context for treatment response biomarkers of the future, including neuronally-derived extracellular vesicles in anxiety disorders and discuss challenges that must be overcome prior to the debut of treatment response biomarkers in the clinic. A number of promising treatment response biomarkers have been identified, although there is an urgent need to replicate findings and to identify which biomarkers might guide clinicians in selecting from available treatments rather than just simply identifying patients who may be less likely to respond to a given intervention.

3.
Front Cell Neurosci ; 14: 207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742260

RESUMO

A recurrent and devastating feature of addiction to a drug of abuse is its persistence, which is mediated by maladaptive long-term memories of the highly pleasurable experience initially associated with the consumption of the drug. We have recently found that members of the CPEB family of proteins (Cytoplasmic Polyadenylation Element-Binding Proteins) are involved in the maintenance of spatial memory. However, their possible role in the maintenance of memories that sustain addictive behavior has yet to be explored. Little is known about any of the mechanisms for maintaining memories for addictive behavior. To address the mechanisms whereby addictive behavior is maintained over time, we utilized a conditional transgenic mouse model expressing a dominant-negative version of CPEB1 that abolishes the activity in the forebrain of two of the four CPEB isoforms (CPEB1 and CPEB3). We found that, following cocaine administration, these dominant-negative (DN) CPEB mice showed a significant decrease, when compared to wild type (WT) mice, in both locomotor sensitizations and conditioned place preference (CPP), two indices of addictive behavior. Supporting these behavioral results, we also found a difference between WT and DN-CPEB1-3 mice in the cocaine-induced synaptic depression in the core of the Nucleus Accumbens (NAc). Finally, we found that (1) CPEB is reduced in transgenic mice following cocaine injections and that (2) FosB, known for its contribution to establishing the addictive phenotype, when its expression in the striatum is increased by drug administration, is a novel target of CPEBs molecules. Thus, our study highlights how CPEB1 and CPEB3 act on target mRNAs to build the neuroadaptative implicit memory responses that lead to the development of the cocaine addictive phenotypes in mammals.

4.
J Child Adolesc Psychopharmacol ; 30(10): 606-616, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32721213

RESUMO

Objectives: Placebo response is one of the most significant barriers to detecting treatment effects in pediatric (and adult) clinical trials focusing on affective and anxiety disorders. We sought to identify neurofunctional predictors of placebo response in adolescents with generalized anxiety disorder (GAD) by examining dynamic and static functional brain connectivity. Methods: Before randomization to blinded placebo, adolescents, aged 12-17 years, with GAD (N = 25) underwent resting state functional magnetic resonance imaging. Whole brain voxelwise correlation analyses were used to determine the relationship between change in anxiety symptoms from baseline to week 8 and seed-based dynamic and static functional connectivity maps of regions in the salience and ventral attention networks (amygdala, dorsal anterior cingulate cortex [dACC], and ventrolateral prefrontal cortex [VLPFC]). Results: Greater dynamic functional connectivity variability in amygdala, dACC, VLPFC, and regions within salience, default mode, and frontoparietal networks was associated with greater placebo response. Lower static functional connectivity between amygdala and dorsolateral prefrontal cortex, amygdala and medial prefrontal cortex, dACC and posterior cingulate cortex and greater static functional connectivity between VLPFC and inferior parietal lobule were associated with greater placebo response. Conclusion: Placebo response is associated with a distinct dynamic and static connectivity fingerprint characterized by "variable" dynamic but "weak" static connectivity in the salience, default mode, frontoparietal, and ventral attention networks. These data provide granular evidence of how circuit-based biotypes mechanistically relate to placebo response. Finding biosignatures that predict placebo response is critically important in clinical psychopharmacology and to improve our ability to detect medication-placebo differences in clinical trials.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32500537

RESUMO

BACKGROUND: Anxiety disorders first emerge during the critical developmental periods of childhood and adolescence. This review synthesizes recent findings on the prevalence, risk factors, and course of the anxiety disorders; and their neurobiology and treatment. METHODS: For this review, searches were conducted using PubMed, PsycINFO, and clinicaltrials.gov. Findings related to the epidemiology, neurobiology, risk factors, and treatment of pediatric anxiety disorders were then summarized. FINDINGS: Anxiety disorders are high prevalence, and early-onset conditions associated with multiple risk factors including early inhibited temperament, environment stress, and structural and functional abnormalities in the prefrontal-amygdala circuitry as well as the default mode and salience networks. The anxiety disorders are effectively treated with cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). CONCLUSIONS: Anxiety disorders are high prevalence, early-onset conditions associated with a distinct neurobiological fingerprint, and are consistently responsive to treatment. Questions remain regarding who is at risk of developing anxiety disorders as well as the way in which neurobiology predicts treatment response.

6.
Aging Cell ; 18(6): e13047, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31576648

RESUMO

Cellular mechanisms that act in concert to maintain protein homeostasis (proteostasis) are vital for organismal functionality and survival. Nevertheless, subsets of aggregation-prone proteins form toxic aggregates (proteotoxicity) that in some cases, underlie the development of neurodegenerative diseases. Proteotoxic aggregates are often deposited in the vicinity of the nucleus, a process that is cytoskeleton-dependent. Accordingly, cytoskeletal dysfunction contributes to pathological hallmarks of various neurodegenerative diseases. Here, we asked whether the linker of nucleoskeleton and cytoskeleton (LINC) complex, which bridges these filaments across the nuclear envelope, is needed for the maintenance of proteostasis. Employing model nematodes, we discovered that knocking down LINC components impairs the ability of the worm to cope with proteotoxicity. Knocking down anc-1, which encodes a key component of the LINC complex, modulates the expression of transcription factors and E3 ubiquitin ligases, thereby affecting the rates of protein ubiquitination and impairing proteasome-mediated protein degradation. Our results establish a link between the LINC complex, protein degradation, and neurodegeneration-associated proteotoxicity.


Assuntos
Caenorhabditis elegans/genética , Citoesqueleto/genética , Regulação da Expressão Gênica , Matriz Nuclear/genética , Complexo de Endopeptidases do Proteassoma/genética , Proteostase/genética , Animais , Caenorhabditis elegans/metabolismo , Citoesqueleto/metabolismo , Perfilação da Expressão Gênica , Matriz Nuclear/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Análise de Sequência de RNA
7.
Expert Opin Pharmacother ; 19(10): 1057-1070, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30056792

RESUMO

INTRODUCTION: Generalized anxiety disorder (GAD) often begins during adolescence or early adulthood and persists throughout the lifespan. Randomized controlled trials support the efficacy of selective serotonin and selective serotonin norepinephrine reuptake inhibitors (SSRIs and SNRIs, respectively), as well as benzodiazepines, azapirones, anti-adrenergic medications, melatonin analogs, second-generation antipsychotics, kava, and lavender oil in GAD. However, psychopharmacologic treatment selection requires clinicians to consider multiple factors, including age, co-morbidity, and prior treatment. Areas covered: The authors review the literature concerning pharmacotherapy for pediatric and adult patients with GAD with specific commentary on the efficacy and tolerability of selected agents in these age groups. The authors describe an algorithmic approach to the pediatric and adult patient with GAD and highlight considerations for the use of selected medications in these patients. Expert opinion: In adults with GAD, SSRIs and SNRIs represent the first-line psychopharmacologic treatment while second-line pharmacotherapies include buspirone, benzodiazepines, SGAs, and pregabalin. In pediatric patients with GAD, SSRIs should be considered the first line pharmacotherapy and psychotherapy enhances antidepressant response.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Adulto , Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtornos de Ansiedade/patologia , Criança , Prática Clínica Baseada em Evidências , Humanos , Inibidores da Monoaminoxidase/uso terapêutico
8.
PLoS One ; 13(3): e0194780, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29579097

RESUMO

S-allylmercapto-N-acetylcysteine (ASSNAC) was shown in our previous study to activate Nrf2-mediated processes and increase glutathione level and resistance to oxidative stress in cultured endothelial cells. In this study, we explored the antioxidant protective effect of ASSNAC in Caenorhabditis elegans (C. elegans). Treatment of gst-4 reporter strain (CL2166) with increasing concentrations of ASSNAC (0.2 to 20 mM) for 24 hours and with ASSNAC (10 mM) for various time periods demonstrated a significant concentration- and time-dependent increase in Glutathione S-transferase (GST) gene expression (up to 60-fold at 20 mM after 24 hours). In addition, ASSNAC (2 mM; 24 hours) treatment of C. elegans strains N2 (wild type strain), gst-4 reporter (CL2166) and temperature sensitive sterile strain (CF512) significantly increased GST enzyme activity by 1.9-, 1.5- and 1.8-fold, respectively. ASSNAC (2.0 mM; 24 hours) increased the reduced glutathione content in N2 and CF512 strains by 5.9- and 4.9-fold, respectively. Exposure of C. elegans (N2 strain) to a lethal concentration of H2O2 (3.5 mM; 120 min) resulted in death of 88% of the nematodes while pretreatment with ASSNAC (24 hours) reduced nematodes death in a concentration-dependent manner down to 8% at 2.0 mM. C. elegans nematodes (strain CF512) cultured on agar plates containing ASSNAC (0.5 to 5.0 mM) demonstrated a significant increase in lifespan compared to control (mean lifespan 26.45 ± 0.64 versus 22.90 ± 0.59 days; log-rank p ≤ 0.001 at 2.0 mM) with a maximal lifespan of 40 versus 36 days. In conclusion, ASSNAC up-regulates the GST gene expression and enzyme activity as well as the glutathione content in C. elegans nematodes and thereby increases their resistance to oxidative stress and extends their lifespan.


Assuntos
Acetilcisteína/análogos & derivados , Compostos Alílicos/farmacologia , Caenorhabditis elegans/fisiologia , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/farmacologia , Animais , Antioxidantes/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/metabolismo , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Peróxido de Hidrogênio/toxicidade , Substâncias Protetoras/farmacologia , Temperatura , Regulação para Cima/efeitos dos fármacos
9.
BMC Biol ; 16(1): 8, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29338709

RESUMO

BACKGROUND: Caenorhabditis elegans nematodes are powerful model organisms, yet quantification of visible phenotypes is still often labor-intensive, biased, and error-prone. We developed WorMachine, a three-step MATLAB-based image analysis software that allows (1) automated identification of C. elegans worms, (2) extraction of morphological features and quantification of fluorescent signals, and (3) machine learning techniques for high-level analysis. RESULTS: We examined the power of WorMachine using five separate representative assays: supervised classification of binary-sex phenotype, scoring continuous-sexual phenotypes, quantifying the effects of two different RNA interference treatments, and measuring intracellular protein aggregation. CONCLUSIONS: WorMachine is suitable for analysis of a variety of biological questions and provides an accurate and reproducible analysis tool for measuring diverse phenotypes. It serves as a "quick and easy," convenient, high-throughput, and automated solution for nematode research.


Assuntos
Caenorhabditis elegans/genética , Testes Genéticos/métodos , Aprendizado de Máquina , Imagem Óptica/métodos , Fenótipo , Animais , Caenorhabditis elegans/anatomia & histologia , Feminino , Testes Genéticos/tendências , Aprendizado de Máquina/tendências , Masculino , Imagem Óptica/tendências
10.
BMC Biol ; 15(1): 29, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28385158

RESUMO

BACKGROUND: Animals exhibit astonishingly complex behaviors. Studying the subtle features of these behaviors requires quantitative, high-throughput, and accurate systems that can cope with the often rich perplexing data. RESULTS: Here, we present a Multi-Animal Tracker (MAT) that provides a user-friendly, end-to-end solution for imaging, tracking, and analyzing complex behaviors of multiple animals simultaneously. At the core of the tracker is a machine learning algorithm that provides immense flexibility to image various animals (e.g., worms, flies, zebrafish, etc.) under different experimental setups and conditions. Focusing on C. elegans worms, we demonstrate the vast advantages of using this MAT in studying complex behaviors. Beginning with chemotaxis, we show that approximately 100 animals can be tracked simultaneously, providing rich behavioral data. Interestingly, we reveal that worms' directional changes are biased, rather than random - a strategy that significantly enhances chemotaxis performance. Next, we show that worms can integrate environmental information and that directional changes mediate the enhanced chemotaxis towards richer environments. Finally, offering high-throughput and accurate tracking, we show that the system is highly suitable for longitudinal studies of aging- and proteotoxicity-associated locomotion deficits, enabling large-scale drug and genetic screens. CONCLUSIONS: Together, our tracker provides a powerful and simple system to study complex behaviors in a quantitative, high-throughput, and accurate manner.


Assuntos
Comportamento Animal , Caenorhabditis elegans/fisiologia , Etologia/métodos , Envelhecimento/fisiologia , Algoritmos , Animais , Quimiotaxia , Aprendizado de Máquina , Degeneração Neural/patologia , Proteínas/toxicidade , Software , Fatores de Tempo , Gravação em Vídeo
11.
J Am Acad Child Adolesc Psychiatry ; 56(3): 214-225, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28219487

RESUMO

OBJECTIVE: This review of the scientific literature examines the potential adult sequelae of exposure to cannabis and related synthetic cannabinoids in adolescence. We examine the four neuropsychiatric outcomes that are likely most vulnerable to alteration by early cannabinoid use, as identified within both the clinical and preclinical research: cognition, emotional functioning, risk for psychosis, and addiction. METHOD: A literature search was conducted through PubMed, PsychInfo, and Google Scholar with no publication date restrictions. The search terms used were "adolescent" and "adult," and either "cannabis," "marijuana," "delta-9-tetra-hydrocannabinol," or "cannabinoid," which was then crossed with one or more of the following terms: "deficit," "impairment," "alteration," "long-term," "persistent," "development," "maturation," and "pubescent." RESULTS: The majority of the clinical and preclinical data point to a strong correlation between adolescent cannabinoid exposure and persistent, adverse neuropsychiatric outcomes in adulthood. Although the literature supports the hypothesis that adolescent cannabis use is connected to impaired cognition and mental health in adults, it does not conclusively demonstrate that cannabis consumption alone is sufficient to cause these deficits in humans. The animal literature, however, clearly indicates that adolescent-onset exposure to cannabinoids can catalyze molecular processes that lead to persistent functional deficits in adulthood, deficits that are not found to follow adult-onset exposure and that model some of the adverse outcomes reported in humans among adult populations of early-onset cannabis users. CONCLUSION: Based on the data in the current literature, a strong association is found between early, frequent, and heavy adolescent cannabis exposure and poor cognitive and psychiatric outcomes in adulthood, yet definite conclusions cannot yet be made as to whether cannabis use alone has a negative impact on the human adolescent brain. Future research will require animal models and longitudinal studies to be carefully designed with a focus on integrating assessments of molecular, structural, and behavioral outcomes in order to elucidate the full range of potential adverse and long-term consequences of cannabinoid exposure in adolescence.


Assuntos
Sintomas Afetivos/etiologia , Canabinoides/efeitos adversos , Disfunção Cognitiva/etiologia , Uso da Maconha/efeitos adversos , Transtornos Psicóticos/etiologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Adolescente , Adulto , Sintomas Afetivos/induzido quimicamente , Animais , Disfunção Cognitiva/induzido quimicamente , Humanos
12.
PLoS One ; 11(9): e0163077, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27632422

RESUMO

Epidemiological findings suggest that social involvement plays a major role in establishing resilience to adversity, however, the neurobiology by which social involvement confers protection is not well understood. Hypothesizing that social involvement confers resilience by changing the way adverse life events are encoded, we designed a series of behavioral tests in mice that utilize the presence or absence of conspecific cage mates in measuring response to novel and adverse events. We found that the presence of cage mates increased movement after exposure to a novel environment, increased time spent in the open arms of the elevated plus maze, and decreased freezing time after a foot shock as well as expedited fear extinction, therefore significantly changing the response to adversity. This is a first description of a mouse model for the effects of social involvement on adverse life events. Understanding how social involvement provides resilience to adversity may contribute to the future treatment and prevention of mental and physical illness.


Assuntos
Comportamento Animal , Comportamento Social , Animais , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL
13.
Neuropharmacology ; 105: 308-317, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26808314

RESUMO

Adolescence represents a unique developmental period associated with increased risk-taking behavior and experimentation with drugs of abuse, in particular nicotine. We hypothesized that exposure to nicotine during early adolescence might increase the risk for drug reward in adulthood. To test this hypothesis, male ICR mice were treated with a subchronic regimen of nicotine or saline during adolescence, and their preference for cocaine, morphine and amphetamine was examined using the conditioned place preference (CPP) test in adulthood. Long-term behavioral changes induced by nicotine suggested a possible role of altered gene transcription. Thus, immunoblot for ΔFosB, a member of the Fos family of transcription factors, was conducted in the nucleus accumbens of these mice. Mice treated with nicotine during early but not late adolescence showed an increase in CPP for cocaine, morphine and amphetamine later in adulthood. This effect was not seen in mice pretreated with a subchronic regimen of nicotine as adults, suggesting that exposure to nicotine specifically during early adolescence increases the rewarding effects of other drugs in adulthood. However, adolescent nicotine exposure did not alter highly palatable food conditioning in mice. The enhancement of cocaine CPP by nicotine was strain-dependent and was blocked by pretreatment with nicotinic antagonists. In addition, nicotine exposure during early adolescence induced ΔFosB expression to a greater extent than identical nicotine exposure in adulthood, and enhanced cocaine-induced locomotor sensitization later in adulthood. These results suggest that nicotine exposure during early adolescence increases drug-induced reward in adulthood through mechanisms that may involve the induction of ΔFosB.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Recompensa , Envelhecimento/psicologia , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Operante , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética
15.
J Neurosci ; 35(1): 386-95, 2015 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-25568130

RESUMO

Basic region leucine zipper (bZIP) transcription factors regulate gene expression critical for long-term synaptic plasticity or neuronal excitability contributing to learning and memory. At sensorimotor synapses of Aplysia, changes in activation or expression of CREB1 and CREB2 in sensory neurons are required for long-term synaptic plasticity. However, it is unknown whether concomitant stimulus-induced changes in expression and activation of bZIP transcription factors in the postsynaptic motor neuron also contribute to persistent long-term facilitation (P-LTF). We overexpressed various forms of CREB1, CREB2, or cJun in the postsynaptic motor neuron L7 in cell culture to examine whether these factors contribute to P-LTF. P-LTF is evoked by 2 consecutive days of 5-HT applications (2 5-HT), while a transient form of LTF is produced by 1 day of 5-HT applications (1 5-HT). Significant increases in the expression of both cJun and CREB2 mRNA in L7 accompany P-LTF. Overexpressing each bZIP factor in L7 did not alter basal synapse strength, while coexpressing cJun and CREB2 in L7 evoked persistent increases in basal synapse strength. In contrast, overexpressing cJun and CREB2 in sensory neurons evoked persistent decreases in basal synapse strength. Overexpressing wild-type cJun or CREB2, but not CREB1, in L7 can replace the second day of 5-HT applications in producing P-LTF. Reducing cJun activity in L7 blocked P-LTF evoked by 2 5-HT. These results suggest that expression and activation of different bZIP factors in both presynaptic and postsynaptic neurons contribute to persistent change in synapse strength including stimulus-dependent long-term synaptic plasticity.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Potenciação de Longa Duração/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas Repressoras/biossíntese , Células Receptoras Sensoriais/metabolismo , Sinapses/metabolismo , Potenciais Sinápticos/fisiologia , Animais , Aplysia , Células Cultivadas
16.
Learn Mem ; 21(3): 153-60, 2014 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-24549570

RESUMO

The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.


Assuntos
Cocaína/farmacologia , Giro Denteado/efeitos dos fármacos , Histonas/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Nicotina/farmacologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/metabolismo , Animais , Giro Denteado/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histonas/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D5/antagonistas & inibidores , Vorinostat
17.
Neuropharmacology ; 74: 126-34, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23597510

RESUMO

In human populations, there is a well-defined sequence of involvement in drugs of abuse, in which the use of nicotine or alcohol precedes the use of marijuana, which in turn, precedes the use of cocaine. The term "Gateway Hypothesis" describes this developmental sequence of drug involvement. In prior work, we have developed a mouse model to study the underlying metaplastic behavioral, cellular and molecular mechanisms by which exposure to one drug, namely nicotine, affects the response to another drug, namely cocaine. We found that nicotine enhances significantly the changes in synaptic plasticity in the striatum induced by cocaine (Levine et al., 2011). Here we ask: does the metaplastic effect of nicotine on cocaine also apply in the amygdala, a brain region that is involved in the orchestration of emotions and in drug addiction? We find that pretreatment with nicotine enhances long-term synaptic potentiation (LTP) in response to cocaine in the amygdala. Both short-term (1 day) and long-term (7 days) pre-exposure to nicotine facilitate the induction of LTP by cocaine. The effect of nicotine on LTP is unidirectional; exposure to nicotine following treatment with cocaine is ineffective. This metaplastic effect of nicotine on cocaine is long lasting but reversible. The facilitation of LTP can be obtained for 24 but not 40 days after cessation of nicotine. As is the case in the striatum, pretreatment with Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, simulates the priming effect of nicotine. These results provide further evidence that the priming effect of nicotine may be achieved, at least partially, by the inhibition of histone acetylation and indicate that the amygdala appears to be an important brain structure for the processing of the metaplastic effect of nicotine on cocaine. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Cocaína/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Nicotina/farmacologia , Aconitina/análogos & derivados , Aconitina/farmacologia , Tonsila do Cerebelo/fisiologia , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Di-Hidro-beta-Eritroidina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Compostos de Espiro/farmacologia , Fatores de Tempo , Vorinostat , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Receptor Nicotínico de Acetilcolina alfa7/fisiologia
18.
Soc Work Public Health ; 27(6): 604-15, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22963160

RESUMO

This article explores the evolutionary course that the social problem of alcohol use has taken in the United States since the Colonial Era. This article utilizes a range of theoretical models to analyze the evolving nature of alcohol use from an unrecognized to a perceived social problem. The models used include critical constructionism (Heiner, 2002), top-down policy model (Dye, 2001) and Mauss'(1975) understanding of social problems and movements. These theoretical constructs exhibit the relative nature of alcohol use as a social problem in regards to a specific time, place, and social context as well as the powerful and influential role that social elites have in defining alcohol asa social problem. Studies regarding the development of alcohol policy formation are discussed to illuminate the different powers, constituents, and factors that play a role in alcohol policy formation.Finally, implications for future study are discussed [corrected].


Assuntos
Alcoolismo/epidemiologia , Política de Saúde , Problemas Sociais , Empirismo , Relativismo Ético , Humanos , Teoria da Construção Pessoal , Estados Unidos/epidemiologia
19.
Neurobiol Dis ; 45(1): 488-98, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21964251

RESUMO

Early life stress can elicit long-lasting changes in gene expression and behavior. Recent studies on rodents suggest that these lasting effects depend on the genetic background. Whether epigenetic factors also play a role remains to be investigated. Here we exposed the stress-susceptible mouse strain Balb/c and the more resilient strain C57Bl/6 to a powerful early life stress paradigm, infant maternal separation. In Balb/c mice, infant maternal separation led to decreased expression of mRNA encoding the histone deacetylases (HDACs) 1, 3, 7, 8, and 10 in the forebrain neocortex in adulthood, an effect accompanied by increased expression of acetylated histone H4 proteins, especially acetylated H4K12 protein. These changes in HDAC expression and histone modifications were not detected in C57Bl/6 mice exposed to early life stress. Moreover, a reversal of the H4K12 hyperacetylation detected in infant maternally separated Balb/c mice (achieved with chronic adolescent treatment with a low dose of theophylline that only activates HDACs) worsened the abnormal emotional phenotype resulting from this early life stress exposure. In contrast, fluoxetine, a drug with potent antidepressant efficacy in infant maternally separated Balb/c mice, potentiated all histone modifications triggered by early life stress. Moreover, in non-stressed Balb/c mice, co-administration of an HDAC inhibitor and fluoxetine, but not fluoxetine alone, elicited antidepressant effects and also triggered changes in histone H4 expression that were similar to those provoked by fluoxetine treatment of mice exposed to early life stress. These results suggest that Balb/c mice develop epigenetic modifications after early life stress exposure that, in terms of the emotive phenotype, are of adaptive nature, and that enhance the efficacy of antidepressant drugs.


Assuntos
Antidepressivos/farmacologia , Fluoxetina/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Privação Materna , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Histona Desacetilases/genética , Histonas/genética , Camundongos , Neocórtex/efeitos dos fármacos , Neocórtex/metabolismo , Fenótipo , Estresse Psicológico/genética
20.
Sci Transl Med ; 3(107): 107ra109, 2011 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-22049069

RESUMO

In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine, or other illicit substances. To understand the biological basis of the gateway sequence of drug use, we developed an animal model in mice and used it to study the effects of nicotine on subsequent responses to cocaine. We found that pretreatment of mice with nicotine increased the response to cocaine, as assessed by addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward. Locomotor sensitization was increased by 98%, conditioned place preference was increased by 78%, and cocaine-induced reduction in long-term potentiation (LTP) was enhanced by 24%. The responses to cocaine were altered only when nicotine was administered first, and nicotine and cocaine were then administered concurrently. Reversing the order of drug administration was ineffective; cocaine had no effect on nicotine-induced behaviors and synaptic plasticity. Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibition of histone deacetylase, which caused global histone acetylation in the striatum. We tested this conclusion further and found that a histone deacetylase inhibitor simulated the actions of nicotine by priming the response to cocaine and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect by infusing a low dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These results from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking and while actively still smoking, and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data from mice. If our findings in mice apply to humans, a decrease in smoking rates in young people would be expected to lead to a decrease in cocaine addiction.


Assuntos
Cocaína/toxicidade , Epigênese Genética/efeitos dos fármacos , Nicotina/toxicidade , Animais , Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Epigênese Genética/genética , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Teofilina/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA