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1.
Alcohol Alcohol ; 54(5): 497-502, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31535696

RESUMO

AIMS: The development of novel and more effective medications for alcohol use disorder (AUD) is an important unmet medical need. Drug repositioning or repurposing is an appealing strategy to bring new therapies to the clinic because it greatly reduces the overall costs of drug development and expedites the availability of treatments to those who need them. Probenecid, p-(di-n-propylsulfamyl)-benzoic acid, is a drug used clinically to treat hyperuricemia and gout due to its activity as an inhibitor of the kidneys' organic anion transporter that reclaims uric acid from urine. Probenecid also inhibits pannexin1 channels that are involved in purinergic neurotransmission and inflammation, which have been implicated in alcohol's effects and motivation for alcohol. Therefore, we tested the effects of probenecid on alcohol intake in rodents. METHODS: We tested the effects of probenecid on operant oral alcohol self-administration in alcohol-dependent rats during acute withdrawal as well as in nondependent rats and in the drinking-in-the-dark (DID) paradigm of binge-like drinking in mice. RESULTS: Probenecid reduced alcohol intake in both dependent and nondependent rats and in the DID paradigm in mice without affecting water or saccharin intake, indicating that probenecid's effect was selective for alcohol and not the result of a general reduction in reward. CONCLUSIONS: These results raise the possibility that pannexin1 is a novel therapeutic target for the treatment of AUD. The clinical use of probenecid has been found to be generally safe, suggesting that it can be a candidate for drug repositioning for the treatment of AUD.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Conexinas/antagonistas & inibidores , Sistemas de Liberação de Medicamentos/métodos , Etanol/administração & dosagem , Proteínas do Tecido Nervoso/antagonistas & inibidores , Probenecid/uso terapêutico , Adjuvantes Farmacêuticos/farmacologia , Adjuvantes Farmacêuticos/uso terapêutico , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/metabolismo , Alcoolismo/psicologia , Animais , Conexinas/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Probenecid/farmacologia , Ratos , Ratos Wistar , Autoadministração
2.
BMC Med ; 17(1): 174, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526369

RESUMO

BACKGROUND: Different methodological choices such as inclusion/exclusion criteria and analytical models can yield different results and inferences when meta-analyses are performed. We explored the range of such differences, using several methodological choices for indirect comparison meta-analyses to compare nalmefene and naltrexone in the reduction of alcohol consumption as a case study. METHODS: All double-blind randomized controlled trials (RCTs) comparing nalmefene to naltrexone or one of these compounds to a placebo in the treatment of alcohol dependence or alcohol use disorders were considered. Two reviewers searched for published and unpublished studies in MEDLINE (August 2017), the Cochrane Library, Embase, and ClinicalTrials.gov and contacted pharmaceutical companies, the European Medicines Agency, and the Food and Drug Administration. The indirect comparison meta-analyses were performed according to different inclusion/exclusion criteria (based on medical condition, abstinence of patients before inclusion, gender, somatic and psychiatric comorbidity, psychological support, treatment administered and dose, treatment duration, outcome reported, publication status, and risk of bias) and different analytical models (fixed and random effects). The primary outcome was the vibration of effects (VoE), i.e. the range of different results of the indirect comparison between nalmefene and naltrexone. The presence of a "Janus effect" was investigated, i.e. whether the 1st and 99th percentiles in the distribution of effect sizes were in opposite directions. RESULTS: Nine nalmefene and 51 naltrexone RCTs were included. No study provided a direct comparison between the drugs. We performed 9216 meta-analyses for the indirect comparison with a median of 16 RCTs (interquartile range = 12-21) included in each meta-analysis. The standardized effect size was negative at the 1st percentile (- 0.29, favouring nalmefene) and positive at the 99th percentile (0.29, favouring naltrexone). A total of 7.1% (425/5961) of the meta-analyses with a negative effect size and 18.9% (616/3255) of those with a positive effect size were statistically significant (p < 0.05). CONCLUSIONS: The choice of inclusion/exclusion criteria and analytical models for meta-analysis can result in entirely opposite results. VoE evaluations could be performed when overlapping meta-analyses on the same topic yield contradictory result. TRIAL REGISTRATION: This study was registered on October 19, 2016, in the Open Science Framework (OSF, protocol available at https://osf.io/7bq4y/ ).


Assuntos
Metanálise como Assunto , Projetos de Pesquisa , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Humanos , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico
3.
Pharmacol Biochem Behav ; 181: 28-36, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30991059

RESUMO

A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is an FDA approved pharmacotherapy for the treatment of obesity. A recent study found that combining BPP with low-dose NTX reduced alcohol drinking in alcohol-preferring male rats. To explore potential pharmacological effects of the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J mice were tested on one-week drinking-in-the dark (DID) and three-week intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer knockout (nPE-/-) mice with hypothalamic-specific deficiency of POMC, and its bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used as a genetic control for the effects of the BPP + NTX. A single administration of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPP + NTX had no effect on alcohol DID in nPE-/- males. Pretreatment with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested were not effective in females. Furthermore, our results suggest a hypothalamic POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol drinking in male mice.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Bupropiona/farmacologia , Bupropiona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Bupropiona/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Etanol/administração & dosagem , Feminino , Técnicas de Inativação de Genes , Hipotálamo/metabolismo , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naltrexona/administração & dosagem , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Fotoperíodo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Sacarina/farmacologia , Fatores Sexuais , Sacarose/farmacologia
4.
Alcohol Alcohol ; 54(3): 272-278, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30977770

RESUMO

AIM: To examine clinical predictors of treatment response to baclofen in patients with alcohol use disorder (AUD). METHODS: Data from a randomised controlled trial (RCT) (N = 104), in which AUD patients received placebo or baclofen (30 mg/day or 75 mg/day) for 12 weeks, were analysed to determine predictive effects of the following four clinical characteristics: alcoholic liver disease (ALD), baseline alcohol consumption, craving and anxiety. Treatment outcomes included: (i) time to lapse and (ii) time to relapse. RESULTS: For both outcome measures, baclofen, irrespective of dose, was more effective when alcohol consumption was higher at baseline. Relative to placebo, baclofen increased time to first lapse in patients with higher baseline alcohol consumption (HR = 0.459, 95% CI = 0.219-0.962, P < 0.05). Similarly, baclofen increased time to first relapse in patients with higher alcohol consumption at baseline (HR = 0.360, 95% CI = 0.168-0.772, P < 0.05). There were no predictive effects of other baseline characteristics on time to lapse nor time to relapse. Directly comparing high dose of baclofen (75 mg/day) with low dose of baclofen (30 mg/day) revealed no differences with regards to predictors of baclofen response. CONCLUSION: Baclofen, relative to placebo, was more effective when alcohol consumption was higher at baseline.


Assuntos
Alcoolismo/tratamento farmacológico , Baclofeno/uso terapêutico , Adolescente , Adulto , Idoso , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/complicações , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Fissura/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Agonistas dos Receptores de GABA-B/uso terapêutico , Humanos , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/prevenção & controle , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
6.
Psychopharmacology (Berl) ; 236(9): 2613-2622, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30923836

RESUMO

RATIONALE: The neuropeptide oxytocin (OXT) has emerged as a potential therapeutic intervention in the treatment of both alcohol use disorder (AUD) and stress-related psychiatric illnesses. OBJECTIVES: The present study evaluates the effects of systemically administered (intraperitoneal (i.p.)) OXT treatment on alcohol relapse-like behavior in male and female mice. METHODS: Adult male and female C57BL/6J mice were trained to lever respond in operant conditioning chambers for alcohol in daily self-administration sessions. Once lever responding and alcohol intake stabilized, mice were tested under extinction conditions for 14 days before reinstatement testing. All mice underwent stress-induced reinstatement testing using either predator odor (2,3,5-trimethyl-3-thiazoline (TMT)) or the α-2 adrenergic receptor agonist yohimbine. In study 1, mice were exposed to TMT for 15 min and then immediately placed into operant conditioning chambers to examine alcohol-seeking behavior under extinction conditions. At 30 min prior to test session, separate groups of mice were injected with vehicle or OXT (0.1, 0.5, 1 mg/kg). In study 2, mice were injected with yohimbine (0.3, 0.625 mg/kg) 1 h prior to reinstatement testing. At 30 min post-yohimbine injection, mice are injected (i.p.) with vehicle or OXT (1 mg/kg). RESULTS: OXT attenuated alcohol-seeking behavior in a dose-related manner in male and female mice in response to acute challenge with a predator odor. Additionally, OXT administration produced a similar decrease in alcohol relapse-like behavior triggered by the pharmacological stressor yohimbine in both sexes. CONCLUSIONS: Systemic oxytocin administration attenuates stress-induced reinstatement of alcohol seeking in male and female mice.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/psicologia , Comportamento Aditivo/tratamento farmacológico , Comportamento Aditivo/psicologia , Etanol/administração & dosagem , Ocitocina/uso terapêutico , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitocina/farmacologia , Autoadministração
7.
Rev. bras. psiquiatr ; 41(1): 44-50, Jan.-Mar. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-985358

RESUMO

Objective: This study aimed to determine the prevalence of benzodiazepine (BZD) use in Brazil and to investigate the direct and indirect effects of alcohol consumption, sedentary lifestyle (SL), depressive symptoms (DS), and sleep dissatisfaction (SD) on BZD use. Methods: The Second Brazilian Alcohol and Drugs Survey (II BNADS) used stratified cluster probabilistic sampling to select 4,607 individuals aged 14 years and older from the Brazilian household population. Results: The lifetime and 12-month prevalence of BZD use was 9.8 and 6.1%, respectively. Older participants (age 40 and older) and women had higher rates. Alcohol use disorder, DS, and SD were significantly more prevalent in BZD users. The parallel multiple mediator model showed a positive direct effect of alcohol consumption on BZD use, with significant positive indirect effects of SL, SD, and DS as simultaneous mediators leading to higher BZD intake. Other statistically significant indirect pathways were DS alone, SD alone, and all of the above except SL. Conclusion: The prevalence of BZD use in Brazil is high compared to that of other countries. Knowledge of the main risk factors and pathways to consumption can guide prevention initiatives and underlie the development of better tailored and effective treatment strategies.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Adulto Jovem , Transtornos do Sono-Vigília/tratamento farmacológico , Benzodiazepinas/administração & dosagem , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Comportamento Sedentário , Fatores Socioeconômicos , Brasil/epidemiologia , Prevalência , Fatores de Risco , Pessoa de Meia-Idade
8.
Psychopharmacology (Berl) ; 236(6): 1887-1900, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30758525

RESUMO

RATIONALE AND OBJECTIVES: Simultaneous alcohol and nicotine consumption occurs in the majority of individuals with alcohol use disorder (AUD) and nicotine dependence. Varenicline (Var) is used to assist in the cessation of nicotine use, while naltrexone (Nal) is the standard treatment for AUD. Despite evidence that ethanol (EtOH) and nicotine (NIC) co-use produces unique neuroadaptations, preclinical research has focused on the effects of pharmacotherapeutics on a single reinforcer. The current experiments examined the effects of Var and Nal on EtOH, NIC, or EtOH+NIC intake. METHODS: Animals were randomly assigned to one of four drinking conditions of 24-h access to a three-bottle choice paradigm, one of which always contained water. Drinking conditions were water only, 0.07 and 0.14 mg/mL NIC (NIC only), 15% and 30% EtOH (EtOH only), or 15% and 30% EtOH with 0.14 mg/mL NIC (EtOH+NIC). The effects of Var (0, 1, or 2 mg/kg) or Nal (0, 1, or 10 mg/kg) injections on maintenance and relapse consumption were determined during four consecutive days. RESULTS: Var reduced maintenance and relapse NIC intake but had no effect on EtOH or EtOH+NIC drinking. Conversely, Nal reduced EtOH maintenance and relapse drinking, but had no effect on NIC or EtOH+NIC drinking. DISCUSSION: The results indicate the standard pharmacological treatments for nicotine dependence and AUD were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC co-use/abuse. These findings suggest that co-abuse may promote unique neuroadaptations that require models of polysubstance abuse to develop pharmacotherapeutics to treat AUD and nicotine dependence.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Etanol/administração & dosagem , Naltrexona/administração & dosagem , Nicotina/administração & dosagem , Tabagismo/tratamento farmacológico , Vareniclina/administração & dosagem , Dissuasores de Álcool/administração & dosagem , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Animais , Feminino , Injeções Subcutâneas , Distribuição Aleatória , Ratos , Autoadministração , Agentes de Cessação do Hábito de Fumar/administração & dosagem , Tabagismo/genética , Tabagismo/psicologia
9.
Neuropharmacology ; 149: 124-132, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772374

RESUMO

The ability of glucagon-like peptide-1 (GLP-1) to reduce food intake involves activation of GLP-1 receptors (GLP-1R) in the nucleus of the solitary tract (NTS). It has also been demonstrated that systemic administration of GLP-1R agonists attenuates alcohol-mediated behaviors via, to date, unknown mechanisms. Therefore, we evaluated the effects of NTS-GLP-1R activation by exendin-4 (Ex4) on alcohol-induced locomotor stimulation, accumbal dopamine release and memory of alcohol reward in the conditioned place preference (CPP) model in mice. Moreover, the ability of Ex4 infusion into the NTS on alcohol intake was explored in rats. Ex4 into the NTS inhibits the acute effects of alcohol as measured by alcohol-induced locomotor stimulation, accumbal dopamine release and the memory consolidation of alcohol reward in the CPP paradigm. In addition, NTS-Ex4 dose-dependently decreases alcohol intake in rats consuming alcohol for 12 weeks. Pharmacological suppression of GLP-1R in the NTS prevents the ability of systemic Ex4 to block the alcohol-induced locomotor stimulation in mice. These data add a functional role of GLP-1R within the NTS, involving alcohol-related behaviors. In addition, they may provide insight into the GLP-1R containing brain areas that modulate the ability of GLP-1R agonists to reduce alcohol reinforcement. Collectively, this further supports GLP-1R as potential treatment targets for alcohol use disorder.


Assuntos
Etanol/antagonistas & inibidores , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Núcleo Solitário/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante , Dopamina/metabolismo , Etanol/administração & dosagem , Etanol/metabolismo , Etanol/farmacologia , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Masculino , Camundongos , Modelos Animais , Atividade Motora/efeitos dos fármacos , Peptídeos/farmacologia , Ratos , Ratos Wistar , Recompensa
10.
Expert Opin Pharmacother ; 20(5): 547-569, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30602322

RESUMO

INTRODUCTION: Depression and alcohol dependence are frequently co-morbid and among the most prevalent mental disorders. They are a serious global health problem with social, interpersonal, and legal interpolations. Among pharmacological alternatives, anti-craving compounds as well as antidepressants, antipsychotics, anticonvulsants, benzodiazepines, and beta-blockers have shown efficacy for depression as well as alcohol consumption. The pharmacological treatment of both complex interwoven mental diseases is still challenging given the inconsistent results of open and double-blind randomized placebo-controlled studies with approved and open label medications. AREAS COVERED: The authors provide a systematic review of the literature with PubMed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to obtain an overview of the pharmacotherapeutic options for co-morbid depression and alcohol dependence. EXPERT OPINION: The effect of treating only depressive or alcohol-related symptoms appears limited. Therapies directly targeting the addiction are warranted among such dually diagnosed patients. Despite limited data, the reviewed pharmacotherapeutic treatments demonstrated efficacy in most but not in all relevant parameters of alcohol dependence and depression.


Assuntos
Alcoolismo/tratamento farmacológico , Depressão/tratamento farmacológico , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Diagnóstico Duplo (Psiquiatria) , Método Duplo-Cego , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
J Vis Exp ; (143)2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30663649

RESUMO

Alcohol Use Disorder (AUD) is a major problem with more than an estimated 76 million people worldwide meeting the diagnostic criteria. Current treatments are limited to three FDA-approved medications that are largely ineffective even when combined with psychosocial intervention, as is evident by the high relapse rate. As such, the search for more novel treatments represents an important public health goal. To this end, the following protocol utilizes two simple rodent drinking models to assess the preclinical efficacy of lead anti-alcohol compounds: two-bottle choice (TBC) and drinking in the dark (DID). The former allows mice to voluntary drink in moderation while the latter induces mice to voluntary consume a large amount of alcohol in a short period that mimics binge drinking. The simple and high throughput nature of both of these paradigms allow for rapid screening of pharmacological agents or for identifying strains of mice that exhibit certain voluntary drinking behavior.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos
13.
Psychopharmacology (Berl) ; 236(6): 1797-1806, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30637435

RESUMO

RATIONALE: GABAA receptors containing the α5 subunit (i.e., α5GABAA receptors) appear to be critically involved in the reinforcing and subjective effects of alcohol. Their role in alcohol relapse remains unknown. OBJECTIVES: Pharmacological approaches were used to probe the role of α5GABAA receptors in alcohol seeking induced by re-exposure to a sweetened alcohol-paired cue, as well as in alcohol + sucrose vs. sucrose self-administration. METHODS: For reinstatement studies, rats were trained to self-administer alcohol under a fixed-ratio schedule in which responding was maintained by alcohol + sucrose deliveries and an alcohol-paired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABAA inverse agonist (L-655,708) or an agonist (QH-ii-066) prior to sessions in which presentation of the sweetened alcohol-paired stimulus was restored, but no solution was delivered. For self-administration studies, rats were trained to self-administer alcohol + sucrose or sucrose under a fixed-ratio schedule. Once stable, animals received pretreatments of QH-ii-066, L-655,708, the inverse agonist RY-023, or naltrexone. RESULTS: L-655,708 attenuated reinstatement of sweetened alcohol seeking by alcohol + sucrose-paired cues; whereas sweetened alcohol-seeking behavior was augmented by QH-ii-066, albeit at different doses in different rats. Both L-655,708 and RY-023 selectively reduced alcohol + sucrose vs. sucrose self-administration. In contrast, naltrexone reduced both alcohol + sucrose and sucrose self-administration; whereas QH-ii-066 enhanced sucrose self-administration only. CONCLUSIONS: α5GABAA receptors play a key role in the modulation of sweetened alcohol cue-induced reinstatement, as well as in alcohol + sucrose but not sucrose self-administration. Inverse agonist activity at α5GABAA receptors may offer a novel strategy for both the reduction of problematic drinking and the prevention of relapse.


Assuntos
Sinais (Psicologia) , Etanol/administração & dosagem , Receptores de GABA-A/fisiologia , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/psicologia , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Agonismo Inverso de Drogas , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração
14.
Neuropharmacology ; 146: 184-197, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496754

RESUMO

Previous findings demonstrate a homeostatic role for oleoylethanolamide (OEA) signaling in the ethanol-related neuroinflammation and behavior. However, extensive research is still required in order to unveil the effects of OEA on a number of neurobiological functions such as adult neurogenesis, cell survival and resident neuroimmunity that become notably altered by alcohol. Daily consumption of ethanol (10%) for 2 weeks (6.3 ± 1.1 g/kg/day during last 5 days) caused hypolocomotor activity in rats. This effect appears to rely on central signaling mechanisms given that alcohol increased the OEA levels, the gene expression of OEA-synthesizing enzyme Nape-pld and the number of PPARα-immunoreactive neurons in the striatum. Ethanol-related neurobiological alterations such as a reduction in the number of microglial cells expressing iNOS (a cytokine-inducible immune defense) and in adult neural stem/progenitor cell (NSPC) proliferation (phospho-H3 and BrdU) and maturation (BrdU/ß3-tubulin), as well as an increase in damage cell activity (FosB) and apoptosis (cleaved caspase 3) were also observed in the rat striatum. Pharmacological administration of OEA (10 mg/kg) for 5 days during ethanol exposure exacerbated ethanol-induced hypolocomotion and cell apoptosis in the striatum. Interestingly, OEA abrogated the impaired effects of ethanol on PPARα-positive cell population and NSPC proliferation and maturation. OEA also decreased astrocyte-related vimentin immunoreactivity and increased microglial cell population (Iba-1, iNOS) in the striatum. These results suggest that OEA-PPARα signaling modulates glial activation, cell apoptosis and NSPC proliferation and maturation in response to striatal-specific neurobiological alterations induced by prolonged ethanol intake in rats.


Assuntos
Proliferação de Células/efeitos dos fármacos , Endocanabinoides/farmacologia , Etanol/farmacologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Ácidos Oleicos/farmacologia , Alanina Transaminase/sangue , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Amidoidrolases/sangue , Animais , Apoptose/efeitos dos fármacos , Ácidos Araquidônicos/farmacologia , Aspartato Aminotransferases/sangue , Proteínas de Ligação ao Cálcio/metabolismo , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Etanolaminas/análise , Etanolaminas/sangue , Proteína Glial Fibrilar Ácida/metabolismo , Eliminação Hepatobiliar , Locomoção/efeitos dos fármacos , Masculino , Proteínas dos Microfilamentos/metabolismo , Neurônios/efeitos dos fármacos , PPAR alfa/metabolismo , Fosfolipase D/sangue , Alcamidas Poli-Insaturadas/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , gama-Glutamiltransferase/sangue
15.
Braz J Psychiatry ; 41(1): 44-50, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30328968

RESUMO

OBJECTIVE: This study aimed to determine the prevalence of benzodiazepine (BZD) use in Brazil and to investigate the direct and indirect effects of alcohol consumption, sedentary lifestyle (SL), depressive symptoms (DS), and sleep dissatisfaction (SD) on BZD use. METHODS: The Second Brazilian Alcohol and Drugs Survey (II BNADS) used stratified cluster probabilistic sampling to select 4,607 individuals aged 14 years and older from the Brazilian household population. RESULTS: The lifetime and 12-month prevalence of BZD use was 9.8 and 6.1%, respectively. Older participants (age 40 and older) and women had higher rates. Alcohol use disorder, DS, and SD were significantly more prevalent in BZD users. The parallel multiple mediator model showed a positive direct effect of alcohol consumption on BZD use, with significant positive indirect effects of SL, SD, and DS as simultaneous mediators leading to higher BZD intake. Other statistically significant indirect pathways were DS alone, SD alone, and all of the above except SL. CONCLUSION: The prevalence of BZD use in Brazil is high compared to that of other countries. Knowledge of the main risk factors and pathways to consumption can guide prevention initiatives and underlie the development of better tailored and effective treatment strategies.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Benzodiazepinas/administração & dosagem , Transtorno Depressivo/tratamento farmacológico , Comportamento Sedentário , Transtornos do Sono-Vigília/tratamento farmacológico , Adolescente , Adulto , Brasil/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Fatores Socioeconômicos , Adulto Jovem
16.
Behav Pharmacol ; 30(4): 363-369, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30272586

RESUMO

Alcohol is the most commonly abused drug in the USA and many people suffer from alcohol use disorder. Many factors are associated with alcohol use disorder, but the causal role of comorbid nicotine use has not been extensively considered. Nicotine has reward-enhancing properties and may increase the value of alcohol. Monoamine oxidase inhibition increases nicotine self-administration and may increase the reward-enhancing effects of nicotine. We assessed the effect of nicotine and nicotine in combination with a commonly used monoamine oxidase inhibitor (tranylcypromine) on the value of alcohol using a progressive ratio schedule of reinforcement in rats. Nicotine administration increased the breakpoint for alcohol, but nicotine in combination with tranylcypromine decreased the breakpoint for alcohol. The current study adds to previous research showing that nicotine increases the value of alcohol. This finding has important implications for the etiology of addiction because of the comorbidity of smoking with many drugs of abuse. The finding that nicotine in combination with tranylcypromine reduces the value of alcohol warrants further investigation.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Nicotina/farmacologia , Tranilcipromina/farmacologia , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Comportamento Aditivo/tratamento farmacológico , Comportamento Aditivo/metabolismo , Condicionamento Operante/efeitos dos fármacos , Etanol/metabolismo , Masculino , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Nicotina/metabolismo , Ratos , Ratos Long-Evans , Recompensa , Autoadministração , Tranilcipromina/metabolismo
17.
Behav Sleep Med ; 17(3): 327-341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28749704

RESUMO

OBJECTIVE/BACKGROUND: College students are at an increased risk for poor sleep and associated sleep problems. Emerging evidence suggests that a substantial subset of college students self-medicate with alcohol, marijuana, or over-the-counter medications to help sleep. The current study identified demographic, psychosocial, and sleep- and alcohol-related correlates of self-medication for sleep, and assessed its concurrent and prospective associations with insomnia symptoms, alcohol drinking, and negative drinking consequences. PARTICIPANTS: Undergraduate students (N = 171; mean age = 19 years [SD = 1.35], 32% male, 74% White) enrolled in a four-year university in the northeastern United States. METHODS: Data were drawn from a short-term two-wave longitudinal study. Participants completed two online surveys, separated by an average interval of 68 days (SD = 10.22). RESULTS: At Time 1, 25% of students reported using at least one substance (alcohol, marijuana, or over-the-counter medications) for sleep aid in the past two weeks. Male and older students were more likely to report using substances for sleep. Sleep aid use at Time 1 was concurrently associated with greater levels of alcohol frequency, negative drinking consequences, and insomnia symptoms. Further, sleep aid use at Time 1 was associated with an increase in negative drinking consequences from Time 1 to Time 2, but not with changes in alcohol frequency or insomnia symptoms. CONCLUSIONS: These findings indicate that substances are widely used among college students for sleep aid. Sleep aid use is associated with greater concurrent drinking and insomnia symptoms, and increases in negative drinking consequences over a short time period.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Automedicação/métodos , Transtornos do Sono-Vigília/tratamento farmacológico , Estudantes/psicologia , Adulto , Feminino , Humanos , Masculino , Estudos Prospectivos , Estudantes/estatística & dados numéricos , Inquéritos e Questionários , Universidades , Adulto Jovem
18.
Exp Clin Psychopharmacol ; 27(3): 227-235, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30570274

RESUMO

Mifepristone, a type II glucocorticoid receptor antagonist, is under investigation as a potential pharmacotherapy for alcohol use disorder. This study examined effects of chronic administration of mifepristone on alcohol-seeking and self-administration in large nonhuman primates. Adult baboons (n = 5) self-administered alcohol 7 days/week under a chained schedule of reinforcement (CSR). The CSR comprised 3 components in which distinct cues were paired with different schedule requirements, with alcohol available for self-administration only in the final component, to model different phases of alcohol anticipation, seeking, and consumption. Under baseline conditions, baboons self-administered an average of 1g/kg/day of alcohol in the self-administration period. Mifepristone (10, 20, and 30 mg/kg) or vehicle was administered orally 30 min before each CSR session for 7 consecutive days. In a separate group of baboons (n = 5) acute doses of mifepristone (10, 20, and 30 mg/kg) were administered, and blood samples were collected over 72 hr to examine mifepristone pharmacokinetics. Some samples also were collected from the baboons that self-administered alcohol under the CSR after the chronic mifepristone condition. Mifepristone did not alter alcohol-seeking or self-administration under the CSR when compared with the vehicle condition. Mifepristone pharmacokinetics were nonlinear, and appear to be capacity limited. In sum, mifepristone did not reduce alcohol-maintained behaviors when administered to baboons drinking 1g/kg daily. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Etanol/administração & dosagem , Mifepristona/farmacologia , Autoadministração , Alcoolismo/tratamento farmacológico , Animais , Sinais (Psicologia) , Masculino , Papio , Esquema de Reforço
19.
J Stud Alcohol Drugs ; 79(6): 918-928, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30573023

RESUMO

OBJECTIVE: Heavy drinking smokers experience significant difficulties with smoking cessation. Craving is closely tied to relapses during cessation attempts, and alcohol consumption increases cigarette craving among heavy drinking smokers. To date, however, few moderators of the relationship between craving and relapse have been identified. Individuals' capacity for distress tolerance predicts smoking cessation outcomes and may be connected to craving. Relatedly, pharmacotherapies like varenicline and naltrexone reduce cigarette and alcohol cravings, respectively. No studies have examined the interrelationships among distress tolerance, craving, and pharmacotherapy effects. This study therefore examines distress tolerance as a moderator of the relationship between overnight abstinence-induced cigarette craving and subsequent alcohol- and cigarette-induced changes in craving among heavy drinking smokers. This study also examines the impact of varenicline and naltrexone on these relationships. METHOD: A total of 120 non-treatment-seeking heavy drinking smokers were randomized and titrated to one of the following conditions: (a) placebo, (b) varenicline, (c) naltrexone, or (d) varenicline + naltrexone. Participants then completed a laboratory paradigm after overnight abstinence that included consumption of alcohol (target .06 g/dl breath alcohol concentration) and one cigarette. Craving was assessed as abstinence-induced (Time 1), alcohol-induced (Time 2), and cigarette-induced (Time 3). RESULTS: Within varenicline + naltrexone, low distress tolerance individuals exhibited higher increases from abstinence- to alcohol-induced cigarette craving relative to high distress tolerance individuals. Across medications, low distress tolerance individuals reported flatter decreases from abstinence- to cigarette-induced cigarette craving relative to high distress tolerance individuals. CONCLUSIONS: Distress tolerance may differentially predict alcohol-induced cigarette craving when titrated to pharmacotherapy, as well as moderate decreases in craving after cigarette consumption. Future exploration of the identified interactive effects could elucidate specific conditions in which cravings are more proximally related to abstinence-induced smoking.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Fumar Cigarros/psicologia , Fissura , Fumantes/psicologia , Abandono do Hábito de Fumar/psicologia , Estresse Psicológico/psicologia , Adulto , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/tratamento farmacológico , Alcoolismo/epidemiologia , Alcoolismo/psicologia , Fumar Cigarros/tratamento farmacológico , Fumar Cigarros/epidemiologia , Fissura/efeitos dos fármacos , Fissura/fisiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Distribuição Aleatória , Abandono do Hábito de Fumar/métodos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/epidemiologia , Vareniclina/farmacologia , Vareniclina/uso terapêutico , Adulto Jovem
20.
eNeuro ; 5(5)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30406194

RESUMO

Alterations in the corticostriatal system have been implicated in numerous substance use disorders, including alcohol use disorder (AUD). Adaptations in this neural system are associated with enhanced drug-seeking behaviors following exposure to cues predicting drug availability. Therefore, understanding how potential treatments alter neural activity in this system could lead to more refined and effective approaches for AUD. Local field potentials (LFPs) were acquired simultaneously in the prefrontal cortex (PFC) and nucleus accumbens (NA) of both alcohol preferring (P) and Wistar rats engaged in a Pavlovian conditioning paradigm wherein a light cue signaled the availability of ethanol (EtOH). On test days, the catechol-o-methyl-transferase (COMT) inhibitor tolcapone was administered prior to conditioning. Stimulus-evoked voltage changes were observed following the presentation of the EtOH cue in both strains and were most pronounced in the PFC of P rats. Phase analyses of LFPs in the θ band (5-11 Hz) revealed that PFC-NA synchrony was reduced in P rats relative to Wistars but was robustly increased during drinking. Presentation of the cue resulted in a larger phase reset in the PFC of P rats but not Wistars, an effect that was attenuated by tolcapone. Additionally, tolcapone reduced cued EtOH intake in P rat but not Wistars. These results suggest a link between corticostriatal synchrony and genetic risk for excessive drinking. Moreover, inhibition of COMT within these systems may result in reduced attribution of salience to reward paired stimuli via modulation of stimulus-evoked changes to cortical oscillations in genetically susceptible populations.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/farmacologia , Tolcapona/farmacologia , Animais , Condicionamento Operante/fisiologia , Etanol/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Wistar , Recompensa
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