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1.
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A 1-day fear memory in ethanol withdrawn (ETOH) rats is resistant to destabilization-reconsolidation process.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
2.
Acta Neuropsychiatr ; 31(2): 84-92, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30472966

RESUMO

OBJECTIVE: Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk-taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general. METHODS: We have longitudinally examined the behaviour of drunk drivers (n = 203) and controls (n = 211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents. RESULTS: The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI. CONCLUSIONS: Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities.


Assuntos
Acidentes de Trânsito/estatística & dados numéricos , Transtornos Relacionados ao Uso de Álcool , Plaquetas/enzimologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Dirigir sob a Influência/estatística & dados numéricos , Comportamento Impulsivo/fisiologia , Monoaminoxidase/metabolismo , Receptores Acoplados a Proteínas-G/genética , Adulto , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Transtornos Relacionados ao Uso de Álcool/genética , Transtornos Relacionados ao Uso de Álcool/metabolismo , Biomarcadores , Estônia/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
3.
Clin Liver Dis ; 23(1): 141-155, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30454828

RESUMO

Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Alcoolismo/fisiopatologia , Transtornos do Sistema Nervoso Induzidos por Álcool/etiologia , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/psicologia , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Síndrome Alcóolica de Korsakoff/etiologia , Síndrome Alcóolica de Korsakoff/metabolismo , Síndrome Alcóolica de Korsakoff/fisiopatologia , Síndrome Alcóolica de Korsakoff/psicologia , Neuropatia Alcoólica/etiologia , Neuropatia Alcoólica/metabolismo , Neuropatia Alcoólica/fisiopatologia , Alcoolismo/complicações , Alcoolismo/metabolismo , Alcoolismo/psicologia , Ataxia Cerebelar/etiologia , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/fisiopatologia , Humanos , Neurotransmissores/metabolismo
4.
Alcohol ; 72: 33-47, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30217435

RESUMO

Decades of research have described the importance of corticotropin-releasing factor (CRF) signaling in alcohol addiction, as well as in commonly co-expressed neuropsychiatric diseases, including anxiety and mood disorders. However, CRF signaling can also acutely regulate binge alcohol consumption, anxiety, and affect in non-dependent animals, possibly via modulation of central monoaminergic signaling. We hypothesize that basal CRF tone is particularly high in animals and humans with an inherent propensity for high anxiety and alcohol consumption, and thus these individuals are at increased risk for the development of alcohol use disorder and comorbid neuropsychiatric diseases. The current review focuses on extrahypothalamic CRF circuits, particularly those stemming from the bed nucleus of the stria terminalis (BNST), found to play a role in basal phenotypes, and examines whether the intrinsic hyperactivity of these circuits is sufficient to escalate the expression of these behaviors and steepen the trajectory of development of disease states. We focus our efforts on describing CRF modulation of biogenic amine neuron populations that have widespread projections to the forebrain to modulate behaviors, including alcohol and drug intake, stress reactivity, and anxiety. Further, we review the known sex differences and estradiol modulation of these neuron populations and CRF signaling at their synapses to address the question of whether females are more susceptible to the development of comorbid addiction and stress-related neuropsychiatric diseases because of hyperactive extrahypothalamic CRF circuits compared to males.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos de Ansiedade/metabolismo , Ansiedade/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Neurônios/metabolismo , Núcleos Septais/metabolismo , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Ansiedade/epidemiologia , Transtornos de Ansiedade/epidemiologia , Bebedeira/epidemiologia , Bebedeira/metabolismo , Monoaminas Biogênicas/metabolismo , Dopamina/metabolismo , Estradiol/metabolismo , Feminino , Humanos , Masculino , Vias Neurais , Norepinefrina/metabolismo , Serotonina/metabolismo , Fatores Sexuais
5.
Neuropharmacology ; 138: 267-274, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29908241

RESUMO

Environmental conditions, such as stress and environmental enrichment (EE), influence predisposition to alcohol use/abuse; however, the underlying mechanisms remain unknown. To assess the effect of environmental conditions on the initial rewarding effects of alcohol, we examined conditioned place-preference (CPP) to alcohol following exposure to EE in mice. Since social context is a major factor contributing to initial alcohol-drinking, we also assessed the impact of EE on the levels of the "social neuropeptide" oxytocin (OT) and its receptor, OTR. Finally, we assessed the effect of pharmacological manipulations of the oxytocinergic system on EE-induced alcohol CPP. While EE increased sociability and reduced anxiety-like behaviors, it caused a ∼3.5-fold increase in alcohol reward compared to controls. EE triggered profound neuroadaptations of the oxytocinergic system; it increased hypothalamic OT levels and decreased OTR binding in the prefrontal cortex and olfactory nuclei of the brain. Repeated administration of the OT analogue carbetocin (6.4 mg/kg/day) mimicked the behavioral effects of EE on ethanol CPP and induced similar brain region-specific alterations of OTR binding as those observed following EE. Conversely, repeated administration of the OTR antagonist L,369-899 (5 mg/kg/day) during EE exposure, but not during the acquisition of alcohol CPP, reversed the pronounced EE-induced ethanol rewarding effect. These results demonstrate for the first time, a stimulatory effect of environmental enrichment exposure on alcohol reward via an oxytocinergic-dependent mechanism, which may predispose to alcohol abuse. This study offers a unique prospective on the neurobiological understanding of the initial stages of alcohol use/misuse driven by complex environmental-social interplay.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Encéfalo/efeitos dos fármacos , Meio Ambiente , Ocitocina/metabolismo , Receptores de Ocitocina/metabolismo , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Encéfalo/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Etanol/farmacologia , Abrigo para Animais , Camundongos , Ocitocina/análogos & derivados , Ocitocina/farmacologia , Receptores de Ocitocina/antagonistas & inibidores , Recompensa , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia
6.
Neuropharmacology ; 138: 10-19, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29775679

RESUMO

Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode KV7 channels influence alcohol intake and dependence. KV7 channels are a class of slowly activating voltage-dependent K+ channels that regulate neuronal excitability. Studies indicate that the KV7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and KV7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 expression and alcohol intake and seeking behaviors. Kcnq4 expression levels were also correlated with dopaminergic-related phenotypes in BXD strains, and Kcnq4 was present in support intervals for alcohol sensitivity and alcohol withdrawal severity QTLs in rodents. Pharmacological validation studies revealed that VTA KV7 channels regulate excessive alcohol intake in rats with a high-drinking phenotype. Administration of a novel and selective KV7.2/4 channel positive modulator also reduced alcohol drinking in rats. Together, these findings indicate that midbrain Kcnq4 expression regulates alcohol-related behaviors in genetically diverse mice and provide evidence that KV7.4 channels are a critical mediator of excessive alcohol drinking.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Canais de Potássio KCNQ/metabolismo , Área Tegmentar Ventral/metabolismo , Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Animais , Dopamina/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Feminino , Predisposição Genética para Doença , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos Wistar , Área Tegmentar Ventral/efeitos dos fármacos
7.
Neuropharmacology ; 137: 194-201, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29758386

RESUMO

We have previously demonstrated that the neurokinin-1 receptor (NK1R) is upregulated in the central nucleus of the amygdala of alcohol preferring (P) rats and that this receptor mediates escalated alcohol consumption in this strain. However, it is unclear if non-genetic models of escalated consumption are also mediated by NK1R signaling, and if so, what brain regions govern this effect. In the experiments presented here, we use two methods of inducing escalated alcohol intake in outbred Wistar rats: yohimbine pretreatment and intermittent alcohol access (Monday, Wednesday, and Friday availability; 20% alcohol). We found that escalated alcohol consumption induced by both yohimbine injection and intermittent access is attenuated by systemic administration of the NK1R antagonist L822429. Also, when compared to continuous alcohol access or access to water alone, NK1R expression was increased in the nucleus accumbens (NAC) and dorsal striatum, but not the amygdala. Escalated consumption induced by intermittent access was attenuated when the NK1R antagonist L822429 was infused directly into the dorsal striatum, but not when infused into the NAC. Taken together, these results suggest that NK1R upregulation contributes to escalated alcohol consumption that is induced by genetic selection, yohimbine injection, and intermittent access. However there is a dissociation between the regions involved in these behaviors with amygdalar upregulation contributing to genetic predisposition to escalated consumption and striatal upregulation driving escalation that is induced by environmental exposures.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Receptores da Neurocinina-1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Animais não Endogâmicos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Piperidinas/farmacologia , Ratos Wistar , Ioimbina/farmacologia
8.
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
9.
Neuropsychopharmacology ; 43(9): 1867-1875, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29728649

RESUMO

Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Fármacos do Sistema Nervoso Central/farmacologia , Receptores sigma/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/metabolismo , Animais , Caenorhabditis elegans , Fármacos do Sistema Nervoso Central/química , Depressores do Sistema Nervoso Central/administração & dosagem , Relação Dose-Resposta a Droga , Descoberta de Drogas , Etanol/administração & dosagem , Ratos , Receptores sigma/genética , Síndrome de Abstinência a Substâncias/metabolismo
10.
Psychopharmacology (Berl) ; 235(3): 737-747, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29181815

RESUMO

BACKGROUND: Adolescent alcohol exposure may increase depression vulnerability in adulthood by increasing the anhedonic response to stress. METHODS: Male Wistar rats (postnatal days 28-53) were exposed to binge-like adolescent intermittent ethanol (AIE) or water. In adulthood, rats were exposed to social defeat, consisting of daily confrontations with an aggressive conspecific, followed by testing of brain reward function in a discrete-trial current-intensity intracranial self-stimulation procedure for 10 consecutive days. Neurochemistry and corticotropin-releasing factor (CRF) and CRF receptor 1 (CRFR1) mRNA levels were assessed in corticolimbic brain areas on day 11 of social defeat stress. RESULTS: Social defeat elevated reward thresholds in both AIE- and water-exposed rats indicating stress-induced anhedonia. However, AIE-exposed rats were more likely to show threshold elevations after repeated stress compared to water-exposed rats. AIE exposure decreased CRF mRNA levels in the nucleus accumbens and increased CRFR1 mRNA levels in the prefrontal cortex, while stress increased CRF mRNA levels in the central amygdala. In the caudate putamen, AIE exposure decreased dopamine turnover, while stress increased glutamate and serotonin metabolism and turnover. CONCLUSIONS: These results demonstrate increased risk of repeated stress-induced anhedonia after AIE exposure, an effect that may be due to alterations in brain CRF and dopamine systems. These results suggest that the increased rates of depression reported in people with a history of adolescent alcohol exposure may be related to alterations in brain reward and stress systems that may contribute to increased stress-induced anhedonia.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Hormônio Liberador da Corticotropina/metabolismo , Etanol/farmacologia , Ácido Glutâmico/metabolismo , Estresse Psicológico/metabolismo , Transtornos Relacionados ao Uso de Álcool/psicologia , Anedonia/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Depressão , Dopamina/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Recompensa , Autoestimulação , Serotonina/metabolismo
11.
Mol Psychiatry ; 23(2): 422-433, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-27843151

RESUMO

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Transtornos Relacionados ao Uso de Álcool/genética , Metilação de DNA/efeitos dos fármacos , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Biomarcadores/sangue , Ilhas de CpG/genética , Epigênese Genética , Etanol/sangue , Etanol/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
12.
Neuropsychopharmacology ; 43(6): 1224-1234, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29052618

RESUMO

Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.


Assuntos
Agressão/efeitos dos fármacos , Transtornos Relacionados ao Uso de Álcool/metabolismo , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Agressão/fisiologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Feminino , Masculino , Camundongos , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Autoadministração , Territorialidade
13.
Int Rev Neurobiol ; 136: 177-197, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29056151

RESUMO

Neuropeptide Y (NPY) is a neuromodulator that is widely expressed throughout the central nervous system (CNS) and which is cosecreted with classic neurotransmitters including GABA and glutamate. There is a long history of research implicating a role for NPY in modulating neurobiological responses to alcohol (ethanol) as well as other drugs of abuse. Both ethanol exposure and withdrawal from chronic ethanol have been shown to produce changes in NPY and NPY receptor protein levels and mRNA expression in the CNS. Importantly, manipulations of NPY Y1 and Y2 receptor signaling have been shown to alter ethanol consumption and self-administration in a brain region-specific manner, with Y1 receptor activation and Y2 receptor blockade in regions of the extended amygdala promoting robust reductions of ethanol intake. Similar observations have been made in studies examining neurobiological responses to nicotine, psychostimulants, and opioids. When taken together with observations of potential genetic linkage between the NPY system and the human alcohol abuse disorders, NPY represents a promising target for treating problematic alcohol and drug use, and in protecting individuals from relapse during abstinence.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Neuropeptídeo Y/metabolismo , Transtornos Relacionados ao Uso de Opioides/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Tabagismo/metabolismo , Consumo de Bebidas Alcoólicas/genética , Animais , Humanos
14.
Int Rev Neurobiol ; 136: 89-119, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29056157

RESUMO

In the past years, a significant volume of research has implicated the appetitive hormone ghrelin in the mechanisms underlying drug use and addiction. From a neuroscientific standpoint, ghrelin modulates both reward and stress pathways, two key drivers of substance use behaviors. Previous investigations support a connection between the ghrelin system and alcohol, stimulants, and tobacco use in both animals and humans, while the research on opioids and cannabis is scarce. In general, upregulation of the ghrelin system seems to enhance craving for drugs as well as substances use. On the other hand, acute and chronic exposure to drugs of abuse influences the ghrelin system at different levels. This chapter summarizes the literature on the relationship between the ghrelin system and substance-related behaviors. We also review recent work investigating the ghrelin system as a potential pharmacological target for treating substance use disorders and discuss the need for additional research.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Grelina/metabolismo , Abuso de Maconha/metabolismo , Transtornos Relacionados ao Uso de Opioides/metabolismo , Tabagismo/metabolismo , Animais , Humanos
15.
Alcohol Res ; 38(2): 207-217, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28988574

RESUMO

Skeletal muscle dysfunction (i.e., myopathy) is common in patients with alcohol use disorder. However, few clinical studies have elucidated the significance, mechanisms, and therapeutic options of alcohol-related myopathy. Preclinical studies indicate that alcohol adversely affects both anabolic and catabolic pathways of muscle-mass maintenance and that an increased proinflammatory and oxidative milieu in the skeletal muscle is the primary contributing factor leading to alcohol-related skeletal muscle dysfunction. Decreased regenerative capacity of muscle progenitor cells is emerging as an additional mechanism that contributes to alcohol-induced loss in muscle mass and impairment in muscle growth. This review details the epidemiology of alcoholic myopathy, potential contributing pathophysiologic mechanisms, and emerging literature on novel therapeutic options.


Assuntos
Transtornos Relacionados ao Uso de Álcool , Músculo Esquelético , Doenças Musculares , Transtornos Relacionados ao Uso de Álcool/complicações , Transtornos Relacionados ao Uso de Álcool/imunologia , Transtornos Relacionados ao Uso de Álcool/metabolismo , Animais , Humanos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia
16.
Alcohol Res ; 38(2): 289-302, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28988580

RESUMO

Alcohol and nutrition have the potential to interact at multiple levels. For example, heavy alcohol consumption can interfere with normal nutrition, resulting in overall malnutrition or in deficiencies of important micronutrients, such as zinc, by reducing their absorption or increasing their loss. Interactions between alcohol consumption and nutrition also can affect epigenetic regulation of gene expression by influencing multiple regulatory mechanisms, including methylation and acetylation of histone proteins and DNA. These effects may contribute to alcohol-related organ or tissue injury. The impact of alcohol-nutrition interactions has been assessed for several organs and tissues, including the intestine, where heavy alcohol use can increase intestinal permeability, and the liver, where the degree of malnutrition can be associated with the severity of liver injury and liver disease. Alcohol-nutrition interactions also play a role in alcohol-related lung injury, brain injury, and immune dysfunction. Therefore, treatment involving nutrient supplementation (e.g., with zinc or S-adenosylmethionine) may help prevent or attenuate some types of alcohol-induced organ damage.


Assuntos
Consumo de Bebidas Alcoólicas , Transtornos Relacionados ao Uso de Álcool , Deficiências Nutricionais , Fenômenos Fisiológicos da Nutrição/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/imunologia , Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/complicações , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/prevenção & controle , Animais , Deficiências Nutricionais/induzido quimicamente , Deficiências Nutricionais/complicações , Deficiências Nutricionais/metabolismo , Humanos
17.
Neuropharmacology ; 125: 197-206, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28734867

RESUMO

The central amygdala (CeA) GABAergic system is hypothesized to drive the development of alcohol dependence, due to its pivotal roles in the reinforcing actions of alcohol and the expression of negative emotion, anxiety and stress. Recent work has also identified an important role for the CeA corticotropin-releasing factor (CRF) system in the interaction between anxiety/stress and alcohol dependence. We have previously shown that acute alcohol and CRF each increase action potential-independent GABA release in the CeA via their actions at presynaptic CRF type 1 receptors (CRF1s); however, the shared mechanism employed by these two compounds requires further investigation. Here we report that acute alcohol interacts with the CRF/CRF1 system, such that CRF and alcohol act via presynaptic CRF1s and P/Q-type voltage-gated calcium channels to promote vesicular GABA release and that both compounds occlude the effects of each other at these synapses. Chronic alcohol exposure does not alter P/Q-type voltage-gated calcium channel membrane abundance or this CRF1/P/Q-type voltage-gated calcium channel mechanism of acute alcohol-induced GABA release, indicating that alcohol engages this molecular mechanism at CeA GABAergic synapses throughout the transition to dependence. Thus, P/Q-type voltage-gated calcium channels, like CRF1s, are key regulators of the effects of alcohol on GABAergic signaling in the CeA.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Canais de Cálcio Tipo P/metabolismo , Canais de Cálcio Tipo Q/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Modelos Animais de Doenças , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Masculino , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Técnicas de Cultura de Tecidos , Ácido gama-Aminobutírico/metabolismo
18.
Prog Neuropsychopharmacol Biol Psychiatry ; 79(Pt B): 105-111, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28602852

RESUMO

Repeated ethanol (EtOH) consumption induces neurological disorders in humans and is considered an important public health problem. The physiological effects of EtOH are dose- and time-dependent, causing relevant changes in the social behavior. In addition, alcohol-induced oxidative stress has been proposed as a key mechanism involved in EtOH neurotoxicity. Here we investigate for the first time whether repeated EtOH exposure (REE) alters the social behavior of zebrafish and influences brain oxidation processes. Animals were exposed to water (control group) or 1% (v/v) EtOH (EtOH group) for 8 consecutive days (20min per day). EtOH was added directly to the tank water. At day 9, the social behavior and biochemical parameters were assessed. REE increased shoal cohesion by reducing inter-fish and farthest neighbor distances. SOD and CAT activities, as well as NPSH levels decreased in brain tissue. Moreover, REE increased lipid peroxidation suggesting oxidative damage. In summary, changes in oxidation processes may play a role in the CNS effects of EtOH, influencing the social behavior of zebrafish. Furthermore, in a translational neuroscience perspective, our data reinforces the utility of zebrafish to clarify the biochemical and behavioral effects of intermittent EtOH administration.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Comportamento Social , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Peixe-Zebra
19.
Neuropharmacology ; 122: 161-174, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28254370

RESUMO

Long-term alcohol use causes widespread changes in gene expression in the human brain. Aberrant gene expression changes likely contribute to the progression from occasional alcohol use to alcohol use disorder (including alcohol dependence). Transcriptome studies have identified individual gene candidates that are linked to alcohol-dependence phenotypes. The use of bioinformatics techniques to examine expression datasets has provided novel systems-level approaches to transcriptome profiling in human postmortem brain. These analytical advances, along with recent developments in next-generation sequencing technology, have been instrumental in detecting both known and novel coding and non-coding RNAs, alternative splicing events, and cell-type specific changes that may contribute to alcohol-related pathologies. This review offers an integrated perspective on alcohol-responsive transcriptional changes in the human brain underlying the regulatory gene networks that contribute to alcohol dependence. This article is part of the Special Issue entitled "Alcoholism".


Assuntos
Transtornos Relacionados ao Uso de Álcool/genética , Encéfalo/metabolismo , Perfilação da Expressão Gênica , Transtornos Relacionados ao Uso de Álcool/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Transcriptoma
20.
Curr Med Chem ; 24(23): 2528-2558, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28302012

RESUMO

BACKGROUND: The term Alcohol Use Disorder (AUD) incorporates different states of disease related to the recurrent use of alcohol and linked to the relevant impairment, disability and failure to perform major responsibilities in different realms. Many neurotransmitter systems are involved in the phases or states of alcoholism from reward mechanisms, associated to binge intoxication, to stress and anxiety linked to relapse and withdrawal. Some neuropeptides play a key function in the control of anxiety and stress, and establish a close relationship with the pathological mechanisms underlying alcohol addiction. Among them, Neuropeptide Y (NPY), Corticotropin-releasing factor (CRF)/Urocortins and Neuropeptide S (NPS) cross-talk, and are responsible for some of the maladaptation processes that the brain exhibits during the progression of the disease. METHOD: In this study, we review the literature mainly focused on the participation of these neuropeptides in the pathophysiology of AUD, as well as on the use of antagonists designed to investigate signaling mechanisms initiated after ligand binding and their connection to biochemical adaptation events coupled to alcohol addiction. The possibility that these systems may serve as therapeutic objectives to mitigate or eliminate the harm that drinking ethanol generates, is also discussed. CONCLUSION: The peptide systems reviewed here, together with other neurotransmitter systems and their mutual relationships, are firm candidates to be targeted to treat AUD.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Neuropeptídeo Y/antagonistas & inibidores , Neuropeptídeos/antagonistas & inibidores , Urocortinas/antagonistas & inibidores , Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Humanos , Neuropeptídeo Y/metabolismo , Neuropeptídeos/metabolismo , Urocortinas/metabolismo
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