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1.
Neurology ; 93(21): e1944-e1954, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31653706

RESUMO

OBJECTIVE: To determine the association between alcohol abuse (AA) and alcohol withdrawal (AW) with acute ischemic stroke (AIS) outcomes. METHODS: All adult AIS admissions in the United States from 2004 to 2014 were identified from the National Inpatient Sample (weighted n = 4,438,968). Multivariable-adjusted models were used to evaluate the association of AW with in-hospital medical complications, mortality, cost, and length of stay in patients with AIS. RESULTS: Of the AA admissions, 10.6% of patients, representing 0.4% of all AIS, developed AW. The prevalence of AA and AW in AIS increased by 45.2% and 40.0%, respectively, over time (p for trend <0.001). Patients with AA were predominantly men (80.2%), white (65.9%), and in the 40- to 59-year (44.6%) and 60- to 79-year (45.6%) age groups. After multivariable adjustment, AIS admissions with AW had >50% increased odds of urinary tract infection, pneumonia, sepsis, gastrointestinal bleeding, deep venous thrombosis, and acute renal failure compared to those without AW. Patients with AW were also 32% more likely to die during their AIS hospitalization compared to those without AW (odds ratio 1.32, 95% confidence interval 1.11-1.58). AW was associated with ≈15-day increase in length of stay and ≈$5,000 increase in hospitalization cost (p < 0.001). CONCLUSION: AW is associated with increased cost, longer hospitalizations, and higher odds of medical complications and in-hospital mortality after AIS. Proactive surveillance and management of AW may be important in improving outcomes in these patients.


Assuntos
Alcoolismo/epidemiologia , Isquemia Encefálica/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Síndrome de Abstinência a Substâncias/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcoolismo/economia , Alcoolismo/fisiopatologia , Isquemia Encefálica/economia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/terapia , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Mortalidade Hospitalar , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , Respiração Artificial/estatística & dados numéricos , Acidente Vascular Cerebral/economia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Síndrome de Abstinência a Substâncias/economia , Síndrome de Abstinência a Substâncias/fisiopatologia , Síndrome de Abstinência a Substâncias/terapia , Terapia Trombolítica , Estados Unidos/epidemiologia , Adulto Jovem
3.
Artigo em Inglês | MEDLINE | ID: mdl-31381847

RESUMO

Objective: To evaluate the pharmacokinetic and safety profile of a novel continuous release and absorption melatonin (CRA-melatonin) compared with an immediate-release melatonin (IR-melatonin) product. Methods: The REM Absorption Kinetics Trial (REMAKT), an open-label, single-center, randomized, single-dose, 2-way crossover trial, compared the pharmacokinetic and safety profile of CRA-melatonin (5 mg) with IR-melatonin (5 mg) in healthy adult volunteers. The study was conducted from March 18, 2016, to April 20, 2016. Results: Ten subjects completed REMAKT. Plasma melatonin levels exceeded the targeted maintenance threshold level of 1,000 pg/mL for a median of 6.7 hours for CRA-melatonin compared with 3.7 hours for IR-melatonin. The median Cmax was 4,690 pg/mL for CRA-melatonin and 23,352 pg/mL for IR-melatonin. In REMAKT, there were no treatment-emergent adverse events reported in the CRA-melatonin arm. Five treatment-emergent adverse events occurred with IR-melatonin. Conclusions: The novel, well-tolerated CRA-melatonin was shown to achieve quick release and then continuous release and absorption of melatonin for up to 7 hours, making it a significant advancement in the pharmacokinetic release profile of exogenous melatonin delivery and, therefore, an important potential consideration as a baseline therapy for sleep.


Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacocinética , Melatonina/administração & dosagem , Melatonina/farmacocinética , Adolescente , Adulto , Depressores do Sistema Nervoso Central/efeitos adversos , Estudos Cross-Over , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Melatonina/efeitos adversos , Adulto Jovem
4.
eNeuro ; 6(2)2019.
Artigo em Inglês | MEDLINE | ID: mdl-30993181

RESUMO

The transition from adolescence to adulthood is associated with brain remodeling in the final stages of developmental growth. It is also a period when a large proportion of this age group engages in binge alcohol drinking (occasional consumption of four to five drinks leading to intoxication) and heavy alcohol drinking (binge drinking on ≥5 d in a month). Here we report on magnetic resonance imaging of developmental changes in the brain occurring during late adolescence and early adulthood (3.5-7.5 years of age) in a rhesus macaque model of alcohol self-administration. Monkeys were imaged prior to alcohol exposure, and following ∼6 and ∼12 months of daily (22 h/d) access to ethanol and water. The results revealed that the brain volume increases by 1 ml/1.87 years throughout the late adolescence and early adulthood in controls. Heavy alcohol drinking reduced the rate of brain growth by 0.25 ml/year per 1 g/kg daily ethanol. Cortical volume increased throughout this period with no significant effect of alcohol drinking on the cortical growth rate. In subcortical regions, age-dependent increases in the volumes of globus pallidus, thalamus, brainstem, and cerebellum were observed. Heavy drinking attenuated the growth rate of the thalamus. Thus, developmental brain volume changes in the span of late adolescence to young adulthood in macaques is altered by excessive alcohol, an insult that may be linked to the continuation of heavy drinking throughout later adult life.


Assuntos
Alcoolismo , Encéfalo , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Consumo de Álcool por Menores , Fatores Etários , Alcoolismo/complicações , Alcoolismo/diagnóstico por imagem , Alcoolismo/patologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Macaca mulatta , Imagem por Ressonância Magnética , Masculino , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Tálamo/crescimento & desenvolvimento , Tálamo/patologia
5.
J Vis Exp ; (144)2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30799848

RESUMO

Decision making relies on dynamic interactions of distributed, primarily frontal brain regions. Extensive evidence from functional magnetic resonance imaging (fMRI) studies indicates that the anterior cingulate (ACC) and the lateral prefrontal cortices (latPFC) are essential nodes subserving cognitive control. However, because of its limited temporal resolution, fMRI cannot accurately reflect the timing and nature of their presumed interplay. The present study combines distributed source modeling of the temporally precise magnetoencephalography (MEG) signal with structural MRI in the form of "brain movies" to: (1) estimate the cortical areas involved in cognitive control ("where"), (2) characterize their temporal sequence ("when"), and (3) quantify the oscillatory dynamics of their neural interactions in real time. Stroop interference was associated with greater event-related theta (4 - 7 Hz) power in the ACC during conflict detection followed by sustained sensitivity to cognitive demands in the ACC and latPFC during integration and response preparation. A phase-locking analysis revealed co-oscillatory interactions between these areas indicating their increased neural synchrony in theta band during conflict-inducing incongruous trials. These results confirm that theta oscillations are fundamental to long-range synchronization needed for integrating top-down influences during cognitive control. MEG reflects neural activity directly, which makes it suitable for pharmacological manipulations in contrast to fMRI that is sensitive to vasoactive confounds. In the present study, healthy social drinkers were given a moderate alcohol dose and placebo in a within-subject design. Acute intoxication attenuated theta power to Stroop conflict and dysregulated co-oscillations between the ACC and latPFC, confirming that alcohol is detrimental to neural synchrony subserving cognitive control. It interferes with goal-directed behavior that may result in deficient self-control, contributing to compulsive drinking. In sum, this method can provide insight into real-time interactions during cognitive processing and can characterize the selective sensitivity to pharmacological challenge across relevant neural networks.


Assuntos
Intoxicação Alcoólica/fisiopatologia , Encéfalo/fisiopatologia , Depressores do Sistema Nervoso Central/efeitos adversos , Cognição/fisiologia , Etanol/efeitos adversos , Lobo Frontal/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico/métodos , Cognição/efeitos dos fármacos , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/efeitos dos fármacos , Humanos , Imagem por Ressonância Magnética/métodos , Magnetoencefalografia/métodos , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor
6.
Med J Aust ; 210(2): 75-79, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30712302

RESUMO

OBJECTIVE: To compare changes in pregabalin prescribing and misuse-related ambulance attendances; to characterise the patients attended by paramedics for pregabalin misuse-related harms; to assess the association of pregabalin misuse with use of other sedatives and with suicidal ideation and self-harm; to compare the characteristics of pregabalin misuse-related harms in people who misuse pregabalin according to whether or not they also used other sedatives. DESIGN, SETTING, PARTICIPANTS: Retrospective analysis of data on ambulance attendances in Victoria, January 2012 - December 2017, for which pregabalin misuse-related harms were a contributing factor. MAIN OUTCOME MEASURES: Rates of pregabalin misuse-related ambulance attendances, pregabalin prescription rates (each 6-monthly); patient characteristics, including age, sex, history of drug misuse or psychiatric problems, concurrent use of other sedatives, and current suicidal ideation and self-harm. RESULTS: There were 1201 pregabalin misuse-related attendances during the study period; the rate increased from 0.28 cases per 100 000 population in the first half of 2012 to 3.32 cases per 100 000 in the second half of 2017. The attendance rate was strongly correlated with prescription rates in Australia (r = 0.90; P = 0.001). 593 attendances (49%) were for people with a history that may have contraindicated prescribing pregabalin. Pregabalin was frequently misused with other sedatives (812 attendances, 68%), particularly benzodiazepines (440, 37%); 472 attendances (39%) were associated with suicide attempts. People who misused pregabalin with other sedatives more frequently presented with moderate to severe impairments of consciousness, but the frequency of suicide attempts was similar whether other sedatives were concurrently used or not. CONCLUSIONS: Rates of pregabalin misuse-related ambulance attendances in Victoria have increased markedly over the past 6 years. Caution is required when prescribing pregabalin for people taking other sedatives. Limiting the dispensing of this drug may reduce the risks associated with its misuse.


Assuntos
Ambulâncias/estatística & dados numéricos , Depressores do Sistema Nervoso Central , Overdose de Drogas , Pregabalina , Adolescente , Adulto , Depressores do Sistema Nervoso Central/efeitos adversos , Depressores do Sistema Nervoso Central/envenenamento , Overdose de Drogas/epidemiologia , Overdose de Drogas/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pregabalina/efeitos adversos , Pregabalina/envenenamento , Estudos Retrospectivos , Comportamento Autodestrutivo , Vitória/epidemiologia , Adulto Jovem
7.
Appl Neuropsychol Child ; 8(2): 132-139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29185821

RESUMO

Prenatal methamphetamine exposure has become an increasingly pervasive concern, especially in rural-based populations and populations of lower socioeconomic status. While research has begun to highlight the effects of prenatal methamphetamine exposure, the long-term impact of this exposure remains an under-investigated topic. This study attempts to investigate the neurocognitive and neurodevelopmental effects of prenatal methamphetamine exposure by comparing the index and full-scale IQ scores on the WISC-IV between a sample of clinically referred children prenatally exposed to methamphetamine (N = 80) and a sample of clinically referred nonexposed children diagnosed with ADHD (N = 44). Children prenatally exposed to methamphetamine showed significantly lower scores on all WISC-IV domains when compared to peers with ADHD. When taking into account polysubstance exposure to alcohol, these differences remained statistically significant, with the exception of the Processing Speed Index (PSI); children reported to have been prenatally exposed to methamphetamine and to alcohol (PME) remained below ADHD peers on all other WISC-IV index scores. Within the prenatally exposed sample, regression analyses indicated that age was a significant negative predictor of PSI scores. Overall findings suggest that prenatal methamphetamine exposure is associated with a notable cognitive impact independent of polysubstance exposure to alcohol, and that the impact of this exposure on processing speed skills may become more pronounced with age.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central/efeitos adversos , Disfunção Cognitiva , Inteligência/fisiologia , Metanfetamina/efeitos adversos , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Depressores do Sistema Nervoso Central/efeitos adversos , Criança , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Etanol/efeitos adversos , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Escalas de Wechsler
8.
Artigo em Inglês | MEDLINE | ID: mdl-30145183

RESUMO

A 1-day fear memory in ethanol withdrawn (ETOH) rats is resistant to destabilization-reconsolidation process. However, d-cycloserine (DCS) reverts this disturbance. Considering that the formation of pathological fear memories in humans often occurs long time before the requirement of an intervention, the study of older memories is relevant in ETOH rats. In addition, the resistance to destabilization and DCS effect on this memory phase at molecular level in ETOH rats have not been corroborated yet. Firstly, we examined the effect of a pharmacological intervention after reactivation on reconsolidation of a 7-day fear memory in ETOH rats. Then, and considering that enhanced GluN2B expression and ubiquitin-proteasome system (UPS) activity are involved in destabilization, we evaluated them following reactivation in ETOH rats. Furthermore, DCS effect on such destabilization markers was examined. It was found that the pharmacological intervention after reactivation did not affect the 7-day fear memory in ETOH rats with DCS reversing this resistance. Memory reactivation increased GluN2B expression, polyubiquitination levels and proteasome activity in the basolateral amygdala complex (BLA) of control (CON) rats only; without affecting these molecular events in ETOH rats. Finally, ETOH rats treated with DCS and CON animals displayed elevated and similar UPS activities in the BLA after reactivation. In conclusion, the reactivation of an older fear memory formed during ethanol withdrawal does not trigger the molecular events associated with destabilization, and DCS facilitates this memory phase by enhancing the UPS activity.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Medo/fisiologia , Memória/fisiologia , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Antimetabólitos/farmacologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Depressores do Sistema Nervoso Central/efeitos adversos , /fisiologia , Ciclosserina/farmacologia , Etanol/efeitos adversos , Medo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-30367959

RESUMO

Prenatal alcohol exposure (PAE) is known to cause dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyperresponsivity to stressors. Dysregulation of the HPA axis plays a role in vulnerability to stress-related disorders, such as anxiety and depression. Thus, the effects of PAE on HPA function may result in increased vulnerability to the effects of stress and, in turn, lead to the development of stress-related disorders. Indeed, individuals prenatally exposed to alcohol have an increased risk of developing anxiety and depression. However, it is unclear whether hypersecretion of corticosterone (CORT) in response to stress per se is involved with mediating differential effects of stress in PAE and control animals. To investigate the role of CORT in mediating effects of stress in both adult females and males following PAE, adrenalectomy with CORT replacement (ADXR) was utilized to produce similar CORT levels among prenatal treatment groups before exposure to chronic unpredictable stress (CUS). Anxiety-like behavior was evaluated using the open field and elevated plus maze, and depressive-like behavior was examined in the forced swim test. Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA expression was assessed in the medial prefrontal cortex (mPFC), amygdala, and hippocampal formation. Under the non-CUS condition, PAE alone differentially altered anxiety-like behavior in sham but not ADXR females and males, with females showing decreased anxiety-like behavior but males exhibiting increased anxiety-like behavior compared to their control counterparts. There were no effects of PAE alone on depressive-like in females or males. PAE also decreased GR mRNA expression in the hippocampal formation in females but had no effects on MR or GR mRNA expression in any brain region in males. CUS had differential effects on anxiety- and depressive-like behavior in PAE and control animals, and these effects were sex dependent. Importantly, ADXR unmasked differences between PAE and control animals, demonstrating that CORT may play a differential role in modulating behavior and HPA activity/regulation in PAE and control animals, and may do so in a sex-dependent manner.


Assuntos
Transtornos de Ansiedade/metabolismo , Corticosterona/metabolismo , Transtorno Depressivo/metabolismo , Transtornos do Espectro Alcoólico Fetal/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Animais , Depressores do Sistema Nervoso Central/efeitos adversos , Modelos Animais de Doenças , Etanol/efeitos adversos , Feminino , Transtornos do Espectro Alcoólico Fetal/psicologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/crescimento & desenvolvimento , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/crescimento & desenvolvimento , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Caracteres Sexuais , Estresse Psicológico/metabolismo
10.
Neuroscience ; 398: 144-157, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30481568

RESUMO

Many studies have implicated hippocampal dysregulation in the pathophysiology of alcohol use disorder (AUD). However, over the past twenty years, a growing body of evidence has revealed distinct functional roles of the dorsal (dHC) and ventral (vHC) hippocampal subregions, with the dHC being primarily involved in spatial learning and memory and the vHC regulating anxiety- and depressive-like behaviors. Notably, to our knowledge, no rodent studies have examined the effects of chronic ethanol exposure on synaptic transmission along the dorsal/ventral axis. To that end, we examined the effects of the chronic intermittent ethanol vapor exposure (CIE) model of AUD on dHC and vHC synaptic excitability. Adult male Long-Evans rats were exposed to CIE or AIR for 10 days (12 h/day; targeting blood ethanol levels of 175-225 mg%) and recordings were made 24 h into withdrawal. As expected, this protocol increased anxiety-like behaviors on the elevated plus-maze and successive alleys test. Extracellular recordings revealed marked CIE-associated increases in synaptic excitation in the CA1 region that were exclusively restricted to the ventral domain of the hippocampus. Western blot analysis of synaptoneurosomal fractions revealed that the expression of two proteins that regulate synaptic strength, GluA2 and SK2, were dysregulated in the vHC, but not the dHC, following CIE. Together, these findings suggest that the ventral CA1 region may be particularly sensitive to the maladaptive effects of chronic ethanol exposure and provide new insight into some of the neural substrates that may contribute to the negative affective state that develops during withdrawal.


Assuntos
Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Hipocampo/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-30193989

RESUMO

It is well-known that alcohol impairs behavioral control and motor response inhibition, but it has remained rather unclear whether it also impairs cognitive inhibition. As automatized behavior is less vulnerable towards the detrimental effects of alcohol than cognitive control processes, potential cognitive inhibition deficits might however improve with training. We investigated the effect of an acute, binge-like alcohol intoxication in a balanced within-subjects design, asking n=32 healthy young males to perform a backward inhibition paradigm once sober and once while intoxicated (~1.1 ‰). To identify the underlying neurophysiological mechanisms, we analyzed stimulus- and response selection-related processes in neurophysiological data after Residue Iteration Decomposition (RIDE). Alcohol generally impaired behavioral task performance (accuracy and response times) during task switching. This was associated with impaired attentional processing of the task-relevant cue (reflected by reduced P1 and N1 amplitudes), which likely resulted in a larger need for reactive control at the later stage of response selection and control (reflected by increased fronto-central theta power). Without prior practice (~30 minutes), the intoxicated participants further struggled to overcome the cognitive inhibition of a previously relevant task set (reflected by a larger backward inhibition effect). This was linked to reduced posterior theta power, which reflects alcohol-induced impairments in working memory capacity and task set-relevant memory retrieval. As individuals with ~30 min task practice did not show the same alcohol-related deficit, it may be deduced that (partial) task set automatization via stimulus-response associations may help to reduce the detrimental effects of alcohol on cognitive inhibition during task switching.


Assuntos
Intoxicação Alcoólica/psicologia , Bebedeira/psicologia , Cognição , Adulto , Atenção/efeitos dos fármacos , Depressores do Sistema Nervoso Central/efeitos adversos , Cognição/efeitos dos fármacos , Etanol/efeitos adversos , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Adulto Jovem
12.
Behav Brain Res ; 359: 386-395, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30447241

RESUMO

Fetal alcohol exposure leads to severe disruptions in learning and memory involving the hippocampus and prefrontal cortex in humans. Animal model research on FASD has documented impairment of hippocampal neuroanatomy and function but animal studies of cognition involving the prefrontal cortex are sparse. We have found that a variant of contextual fear conditioning in which both the hippocampus and prefrontal cortex is required, the Context Preexposure Facilitation Effect (CPFE), is particularly sensitive to neurobehavioral disruption caused by neonatal ethanol exposure during the third trimester equivalent of human pregnancy in the rat (i.e., PD4-9). In the CPFE, learning about the context, acquiring a context-shock association, and retrieving contextual fear are temporally separated across three days. The current study asked whether neonatal alcohol exposure impairs context learning, consolidation, or retrieval and examined prefrontal and hippocampal molecular signaling as correlates of this impairment. Long-Evans rats that received oral intubation of ethanol (AE; 5.25 g/kg/day, split into two doses) or underwent sham-intubation (SI) from PND4-9 were tested on the CPFE on PD31-33. Extending our previous reports, ethanol abolished both post-shock and retention test freezing in the CPFE. Assays (qPCR) of immediate early gene expression revealed that ethanol disrupted prefrontal but not hippocampal expression of c-Fos, Arc, Egr-1, and Npas4 during context learning. Finally, ethanol-exposed animals were unimpaired in a standard contextual fear conditioning procedure in which learning about the context and acquiring a context-shock association occurs concurrently. These findings implicate impaired prefrontal function in cognitive deficits arising from 3rd-trimester equivalent alcohol exposure in the rat.


Assuntos
Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/psicologia , Genes Precoces , Memória/efeitos dos fármacos , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Animais , Animais Recém-Nascidos , Depressores do Sistema Nervoso Central/efeitos adversos , /fisiologia , Modelos Animais de Doenças , Etanol/efeitos adversos , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Masculino , Memória/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Distribuição Aleatória , Ratos Long-Evans , Maturidade Sexual
13.
PLoS One ; 13(11): e0208061, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30485380

RESUMO

BACKGROUND: Binge drinking, an increasingly common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its effects on the immune system's ability to defend against infectious agents are poorly understood. Burkholderia pseudomallei, the causative agent of melioidosis can occur in healthy humans, yet binge alcohol use is progressively being recognized as a major risk factor. Although our previous studies demonstrated that binge alcohol exposure results in reduced alveolar macrophage function and increased Burkholderia virulence in vitro, no experimental studies have investigated the outcomes of binge alcohol on Burkholderia spp. infection in vivo. PRINCIPAL FINDINGS: In this study, we used the close genetic relatives of B. pseudomallei, B. thailandensis E264 and B. vietnamiensis, as useful BSL-2 model systems. Eight-week-old female C57BL/6 mice were administered alcohol comparable to human binge drinking episodes (4.4 g/kg) or PBS intraperitoneally 30 min before a non-lethal intranasal infection. In an initial B. thailandensis infection (3 x 105), bacteria accumulated in the lungs and disseminated to the spleen in alcohol administered mice only, compared with PBS treated mice at 24 h PI. The greatest bacterial load occurred with B. vietnamiensis (1 x 106) in lungs, spleen, and brain tissue by 72 h PI. Pulmonary cytokine expression (TNF-α, GM-CSF) decreased, while splenic cytokine (IL-10) increased in binge drunk mice. Increased lung and brain permeability was observed as early as 2 h post alcohol administration in vivo. Trans-epithelial electrical resistance (TEER) was significantly decreased, while intracellular invasion of non-phagocytic cells increased with 0.2% v/v alcohol exposure in vitro. CONCLUSIONS: Our results indicate that a single binge alcohol dose suppressed innate immune functions and increased the ability of less virulent Burkholderia strains to disseminate through increased barrier permeability and intracellular invasion of non-phagocytic cells.


Assuntos
Bebedeira/complicações , Bebedeira/imunologia , Infecções por Burkholderia/complicações , Infecções por Burkholderia/imunologia , Animais , Bebedeira/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/microbiologia , Burkholderia/patogenicidade , Burkholderia/fisiologia , Infecções por Burkholderia/sangue , Permeabilidade Capilar , Depressores do Sistema Nervoso Central/efeitos adversos , Modelos Animais de Doenças , Etanol/efeitos adversos , Feminino , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/imunologia , Baço/microbiologia , Virulência
14.
PLoS One ; 13(10): e0204500, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30296276

RESUMO

Basal forebrain cholinergic neurons mature in adolescence coinciding with development of adult cognitive function. Preclinical studies using the rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55) reveal persistent increases of brain neuroimmune genes that are associated with cognitive dysfunction. Adolescent intermittent ethanol exposure also reduces basal forebrain expression of choline acetyltransferase (ChAT), an enzyme critical for acetylcholine synthesis in cholinergic neurons similar to findings in the post-mortem human alcoholic basal forebrain. We report here that AIE decreases basal forebrain ChAT+IR neurons in both adult female and male Wistar rats following early or late adolescent ethanol exposure. In addition, we find reductions in ChAT+IR somal size as well as the expression of the high-affinity nerve growth factor (NGF) receptor tropomyosin receptor kinase A (TrkA) and the low-affinity NGF receptor p75NTR, both of which are expressed on cholinergic neurons. The decrease in cholinergic neuron marker expression was accompanied by increased phosphorylation of NF-κB p65 (pNF-κB p65) consistent with increased neuroimmune signaling. Voluntary wheel running from P24 to P80 prevented AIE-induced cholinergic neuron shrinkage and loss of cholinergic neuron markers (i.e., ChAT, TrkA, and p75NTR) as well as the increase of pNF-κB p65 in the adult basal forebrain. Administration of the anti-inflammatory drug indomethacin (4.0 mg/kg, i.p prior to each ethanol exposure) during AIE also prevented the loss of basal forebrain cholinergic markers and the concomitant increase of pNF-κB p65. In contrast, treatment with the proinflammatory immune activator lipopolysaccharide (1.0 mg/kg, i.p. on P70) caused a loss of cholinergic neuron markers that was paralleled by increased pNF-κB p65 in the basal forebrain. These novel findings are consistent with AIE causing lasting activation of the neuroimmune system that contributes to the persistent loss of basal forebrain cholinergic neurons in adulthood.


Assuntos
Prosencéfalo Basal/efeitos dos fármacos , Bebedeira/prevenção & controle , Terapia por Exercício , Indometacina/farmacologia , Fármacos Neuroprotetores/farmacologia , Consumo de Álcool por Menores , Animais , Prosencéfalo Basal/crescimento & desenvolvimento , Prosencéfalo Basal/imunologia , Prosencéfalo Basal/patologia , Bebedeira/imunologia , Bebedeira/patologia , Depressores do Sistema Nervoso Central/efeitos adversos , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/imunologia , Neurônios Colinérgicos/patologia , Modelos Animais de Doenças , Etanol/efeitos adversos , Feminino , Masculino , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Distribuição Aleatória , Ratos Wistar , Corrida/fisiologia , Maturidade Sexual , Volição
15.
Neuropharmacology ; 143: 239-249, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30273595

RESUMO

Adult male and female GFAP-TK transgenic rats experienced six weeks of chronic intermittent ethanol vapor inhalation (CIE). During the last week of CIE, a subset of male and female TK rats were fed with Valcyte to ablate neural progenitor cells (NPCs). Seventy-two hours after CIE cessation, all CIE and age-matched ethanol naïve controls experienced auditory trace fear conditioning (TFC). Twenty-four hours later all animals were tested for cue-mediated retrieval in the fear context. Adult male CIE rats showed a significant burst in NPCs paralleled by reduction in fear retrieval compared to naïve controls and Valcyte treated CIE rats. Adult female CIE rats did not show a burst in NPCs and showed similar fear retrieval compared to naïve controls and Valcyte treated CIE rats, indicating that CIE-mediated impairment in fear memory and its regulation by NPCs was sex dependent. Valcyte significantly reduced Ki-67 and NeuroD labeled cells in the dentate gyrus (DG) in both sexes, demonstrating a role for NPCs in reduced fear retrieval in males. Valcyte prevented adaptations in GluN2A receptor expression and synaptoporin density in the DG in males, indicating that NPCs contributed to alterations in plasticity-related proteins and mossy fiber projections that were associated with reduced fear retrieval. These data suggest that DG NPCs born during withdrawal and early abstinence from CIE are aberrant, and could play a role in weakening long-term memory consolidation dependent on the hippocampus.


Assuntos
Alcoolismo/fisiopatologia , Medo/fisiologia , Hipocampo/fisiopatologia , Memória/fisiologia , Células-Tronco Neurais/fisiologia , Alcoolismo/patologia , Alcoolismo/psicologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Depressores do Sistema Nervoso Central/efeitos adversos , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Etanol/efeitos adversos , Medo/efeitos dos fármacos , Feminino , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Antígeno Ki-67/metabolismo , Masculino , Memória/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Ratos Long-Evans , Ratos Transgênicos , Caracteres Sexuais , Sinaptofisina/metabolismo
16.
Psychol Addict Behav ; 32(8): 933-943, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30359045

RESUMO

Blackouts (periods of alcohol-induced anterograde amnesia) are common among young adults and place individuals at significant risk for alcohol-related harm; thus, researchers have advocated for increased efforts to educate young adults on blackouts. This qualitative study examined college student knowledge of blackouts as well as their ideas for intervening on blackout drinking behavior in order to inform prevention and intervention efforts. College students who had experienced a blackout in the past 6 months participated in eight focus groups, stratified by gender (N = 50, five to eight/group, 56% female). Discussions followed a semistructured agenda. Audio recordings were transcribed verbatim and coded using applied thematic analysis. Themes related to knowledge were reviewed in comparison to the empirical literature. Empirically derived risk factors for blackouts included biology (e.g., genetics, biological sex), drinking behavior (i.e., rate of consumption), other drug use, and "indirect" influences (e.g., pregaming, drinking location). Participants' knowledge of the risk factors for blackout was inconsistent and, in some cases, inaccurate. While participants generally understood the behavioral risk factors for blackouts, they demonstrated less understanding of the role of genetics, biological sex, drinking speed (vs. quantity), and other drug use. They also identified dehydration and sleep as perceived risk factors for blackout. They suggested avenues for intervention at the policy (e.g., amnesty policies), peer (e.g., expressing concern), and individual (e.g., education) levels. College students with a history of blackout have limited understanding of the biological risk factors for blackout. These knowledge gaps represent targets for intervention. Findings indicate promise for blackout-specific interventions. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Amnésia Anterógrada/etiologia , Conhecimentos, Atitudes e Prática em Saúde , Estudantes , Adolescente , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Feminino , Humanos , Masculino , Grupo Associado , Pesquisa Qualitativa , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias , Universidades , Adulto Jovem
17.
Neurobiol Learn Mem ; 156: 1-16, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30316893

RESUMO

BACKGROUND: Studies in clinical populations and preclinical models have shown that prenatal alcohol exposure (PAE) is associated with impairments in the acquisition, consolidation and recall of information, with deficits in hippocampal formation-dependent learning and memory being a common finding. The glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and extracellular signal-regulated kinase 2 (ERK2) are key regulators of hippocampal formation development, structure and functioning and, thus, are potential mediators of PAE's effects on this brain region. In the present studies, we employed a well-characterized mouse model of PAE to identify biochemical mechanisms that may underlie activity-dependent learning and memory deficits associated with PAE. METHODS: Mouse dams consumed either 10% (w/v) ethanol in 0.066% (w/v) saccharin (SAC) or 0.066% (w/v) SAC alone using a limited (4-h) access, drinking-in-the-dark paradigm. Male and female offspring (∼180-days of age) were trained using a delay conditioning procedure and contextual fear responses (freezing behavior) were measured 24 h later. Hippocampal formation tissue and blood were collected from three behavioral groups of animals: 20 min following conditioning (conditioning only group), 20 min following the re-exposure to the context (conditioning plus re-exposure group), and behaviorally naïve (naïve group) mice. Plasma corticosterone levels were measured by enzyme immunoassay. Immunoblotting techniques were used to measure protein levels of the GR, MR, ERK1 and ERK2 in nuclear and membrane fractions prepared from the hippocampal formation. RESULTS: Adult SAC control male and female mice displayed similar levels of contextual fear. However, significant sex differences were observed in freezing exhibited during the conditioning session. Compared to same-sex SAC controls, male and female PAE mice demonstrated context fear deficits While plasma corticosterone concentrations were elevated in PAE males and females relative to their respective SAC naïve controls, plasma corticosterone concentrations in the conditioning only and conditioning plus re-exposure groups were similar in SAC and PAE animals. Relative to the respective naïve group, nuclear GR protein levels were increased in SAC, but not PAE, male hippocampal formation in the conditioning only group. In contrast, no difference was observed between nuclear GR levels in the naïve and conditioning plus re-exposure groups. In females, nuclear GR levels were significantly reduced by PAE but there was no effect of behavioral group or interaction between prenatal treatment and behavioral group. In males, nuclear MR levels were significantly elevated in the SAC conditioning plus re-exposure group compared to SAC naïve mice. In PAE females, nuclear MR levels were elevated in both the conditioning only and conditioning plus re-exposure groups relative to the naïve group. Levels of activated ERK2 (phospho-ERK2 expressed relative to total ERK2) protein were elevated in SAC, but not PAE, males following context re-exposure, and a significant interaction between prenatal exposure group and behavioral group was found. No main effects or interactions of behavioral group and prenatal treatment on nuclear ERK2 were found in female mice. These findings suggest a sex difference in which molecular pathways are activated during fear conditioning in mice. CONCLUSIONS: In PAE males, the deficits in contextual fear were associated with the loss of responsiveness of hippocampal formation nuclear GR, MR and ERK2 to signals generated by fear conditioning and context re-exposure. In contrast, the contextual fear deficit in PAE female mice does not appear to be associated with activity-dependent changes in GR and MR levels or ERK2 activation during training or memory recall, although an overall reduction in nuclear GR levels may play a role. These studies add to a growing body of literature demonstrating that, at least partially, different mechanisms underlie learning, memory formation and memory recall in males and females and that these pathways are differentially affected by PAE.


Assuntos
Comportamento Animal/fisiologia , Depressores do Sistema Nervoso Central/efeitos adversos , Condicionamento Clássico/fisiologia , Etanol/efeitos adversos , Medo/fisiologia , Hipocampo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Caracteres Sexuais , Transdução de Sinais/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Gravidez , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo
18.
Hum Psychopharmacol ; 33(3): e2661, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29878502

RESUMO

Driving experience and alcohol are two factors associated with a higher risk of crash involvement in young novice drivers. Driving a car is a complex task involving multiple tasks leading to dividing attention. The aim of this study was to compare the single and combined effects of a low and moderate dose of alcohol on single- and dual-task performance between young novice and more experienced young drivers during actual driving. Nine healthy novice drivers were compared with 9 more experienced drivers in a three-way, placebo-controlled, cross-over study design. Driving performance was measured in actual traffic, with standard deviation of lateral position as the primary outcome variable. Secondary task performance was measured with an auditory word learning test during driving. Results showed that standard deviation of lateral position increased dose-dependently at a blood alcohol concentration (BAC) of 0.2 and 0.5 g/L in both novice and experienced drivers. Secondary task performance was impaired in both groups at a BAC of 0.5 g/L. Furthermore, it was found that driving performance in novice drivers was already impaired at a BAC of 0.2 g/L during dual-task performance. The findings suggest that young inexperienced drivers are especially vulnerable to increased mental load while under the influence of alcohol.


Assuntos
Condução de Veículo , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Função Executiva/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Adolescente , Adulto , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Feminino , Humanos , Masculino , Adulto Jovem
19.
ACS Chem Neurosci ; 9(7): 1616-1624, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29708326

RESUMO

Ethanol is a principle ingredient of alcoholic beverages with potential neurotoxicity and genotoxicity, and the ethanol-associated oxidative DNA damage in the central nervous system is well documented. Natural source compounds may offer new options to protect the brain against ethanol-induced genotoxicity. Veratrum maackii Regel is a toxic rangeland plant linked to teratogenicity which is also used in traditional Chinese medicine as "Lilu" and is reported to contain a family of compounds called stilbenes that can have positive biological activity. In this study, nine stilbenes were isolated from the aerial parts of V. maackii Regel, and their structures were identified as cis-mulberroside A (1), resveratrol-4,3'- O-ß-d-diglucopyranoside (2), mulberroside A (3), gentifolin K (4), resveratrol-3,5- O-ß-d-diglucopyranoside (5), oxyresveratrol- 4'- O-ß-d-glucopyranoside (6), oxyresveratrol-3- O-ß-d-glucopyranoside (7), oxyresveratrol (8), and resveratrol (9) using ESI-MS and NMR techniques. The total concentration of extracted compounds 2-9 was 2.04 mg/g, suggesting that V. maackii Regel is a novel viable source of these compounds. In an in vivo comet assay, compounds 1-9 were observed to decrease DNA damage in mouse cerebellum and cerebral cortex caused by acute ethanol administration. Histological observation also revealed decreased brain injury in mice administered with compounds 1-9 after acute ethanol administration. The protective effects of compound 6 were associated with increasing T-SOD and GSH-PX activities and a decrease in NO and MDA concentrations. These findings suggest that these compounds are potent inhibitors of ethanol-induced brain injury possibly via the inhibition of oxidative stress and may be valuable leads for future therapeutic development.


Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Etanol/efeitos adversos , Substâncias Protetoras/farmacologia , Estilbenos/farmacologia , Veratrum , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Masculino , Camundongos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fototerapia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Distribuição Aleatória , Estilbenos/química , Estilbenos/isolamento & purificação
20.
Ugeskr Laeger ; 180(19)2018 May 07.
Artigo em Dinamarquês | MEDLINE | ID: mdl-29761771

RESUMO

Treatment for insomnia with melatonin (MT) in children and adolescents aged 0-17 years has doubled since 2011. The efficacy and safety profile for MT in children has not been determined. Recent clinical trials indicate, that MT only has a clinical effect on sleep latency, not on total sleep time. Furthermore, it has emerged, that proper sleep hygiene can cure the sleep problem in 50% of the children. Typically, the safety evaluation only entails an unclassified report of adverse events. Two long-term studies investigate and dispel the potential influence of MT on puberty.


Assuntos
Depressores do Sistema Nervoso Central/uso terapêutico , Melatonina/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adolescente , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/efeitos adversos , Depressores do Sistema Nervoso Central/farmacocinética , Criança , Pré-Escolar , Humanos , Melatonina/administração & dosagem , Melatonina/efeitos adversos , Melatonina/farmacocinética , Puberdade/efeitos dos fármacos , Sono/efeitos dos fármacos , Sono/fisiologia , Higiene do Sono , Latência do Sono/efeitos dos fármacos , Transtornos do Sono-Vigília/tratamento farmacológico
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