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1.
Forensic Sci Int ; 304: 109962, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31610334

RESUMO

Melatonin (MEL) is a neurohormone in humans produced in a number of locations. Starting with the amino acid tryptophan, MEL is produced through a number of enzymatic steps that includes serotonin as an intermediate compound. The primary production of MEL is in the pineal gland located in the brain. It is directly associated with the the suprachiasmatic nucleus (SCN) located in the hypothalamus. In young and adult humans, the blood levels of MEL are typically in the picogram levels and produced in a cyclic schedule highly regulated by light detected in the retina by intrinsically photosensitive retinal ganglion cells (ipRGCs), resulting in production primarily during periods of darkness. During periods of light, MEL levels are typically very low or undetectable. Basal levels of MEL in infants have been observed to be either undetectable or also in the picogram levels, although some medical treatment has involved administration of exogenous MEL resulting in peak levels in the nanogram range. MEL is considered to be well tolerated and there have been limited reports of toxicity. In this case, an infant was found unresponsive and cause of death was ruled as Undetermined. Melatonin was detected in the peripheral blood at a concentration of 1,400ng/mL.


Assuntos
Depressores do Sistema Nervoso Central/envenenamento , Morte Súbita/etiologia , Melatonina/envenenamento , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/sangue , Cromatografia Líquida , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lactente , Melatonina/administração & dosagem , Melatonina/sangue , Espectrometria de Massas em Tandem , Gêmeos
2.
Alcohol Alcohol ; 54(6): 574-583, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557278

RESUMO

AIMS: Alcohol use disorder is highly heterogeneous. One approach to understanding this heterogeneity is the identification of drinker subtypes. A candidate classification consists of reward and relief subtypes. The current study examines a novel self-report measure of reward, relief, and habit drinking for its clinical correlates and subjective response (SR) to alcohol administration. METHODS: Non-treatment-seeking heavy drinkers (n = 140) completed the brief reward, relief, habit drinking scale (RRHDS). A subset of this sample (n = 67) completed an intravenous alcohol administration. Individuals were classified into drinker subtypes. A crowdsourced sample of heavy drinkers (n = 187) completed the RRHDS and a validated reward relief drinking scale to compare drinking classification results. RESULTS: The majority of the sample was classified as reward drinkers (n = 100), with fewer classified as relief (n = 19) and habit (n = 21) drinkers. Relief and habit drinkers reported greater tonic alcohol craving compared to reward drinkers. Reward drinkers endorsed drinking for enhancement, while relief drinkers endorsed drinking for coping. Regarding the alcohol administration, the groups differed in negative mood, such that relief/habit drinkers reported a decrease in negative mood during alcohol administration, compared to reward drinkers. The follow-up crowdsourcing study found a 62% agreement in reward drinker classification between measures and replicated the tonic craving findings. CONCLUSIONS: Our findings suggest that reward drinkers are dissociable from relief/habit drinkers using the brief measure. However, relief and habit drinkers were not successfully differentiated, which suggests that these constructs may overlap phenotypically. Notably, measures of dysphoric mood were better at detecting group differences than measures capturing alcohol's rewarding effects.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/psicologia , Testes Neuropsicológicos , Recompensa , Administração Intravenosa , Adulto , Intoxicação Alcoólica , Alcoolismo/classificação , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacologia , Fissura , Manual Diagnóstico e Estatístico de Transtornos Mentais , Etanol/administração & dosagem , Etanol/farmacologia , Feminino , Seguimentos , Hábitos , Humanos , Individualidade , Masculino , Reprodutibilidade dos Testes , Adulto Jovem
3.
Int J Neuropsychopharmacol ; 22(11): 724-734, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31556948

RESUMO

BACKGROUND: Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488. METHODS: We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression. RESULTS: Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area. CONCLUSIONS: These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.


Assuntos
(trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Alcoolismo/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Genes fos/efeitos dos fármacos , Prazosina/farmacologia , Receptores Opioides kappa/agonistas , Estresse Psicológico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Long-Evans
4.
Ital J Pediatr ; 45(1): 122, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547831

RESUMO

INTRODUCTION: Melatonin has been studied and used for several years as a sleep-wake cycle modulator in patients with sleep disorders. Experimental evidence has demonstrated the multiple neuroprotective benefits of this indoleamine secreted by the pineal gland. Melatonin is also used in neurological investigations, for its ability to induce sleep in children. In fact, it favors falling asleep during electroencephalogram, Magnetic Resonance Imaging (MRI), and during brainstem auditory evoked potentials. Previous studies are focused on infants and children. No investigation have been performed in neonates, before or during instrumental assessments. MATERIAL AND METHODS: One hundred ten newborns (term and preterm) undergoing brain MRI were enrolled in the study. Thirty minutes before the planned time for the examination, we administered a single dose solution of melatonin- tryptophan-vitamin B6. Twenty minutes after the initial administration of 2 mg, a second dose of 1 mg was administered, if the baby was still awake. If after further 15 min the baby was still not sleeping, an additional dose of 1 mg was administered. RESULTS: In 106 patients we obtained adequate sedation without adverse events, allowing us to perform an adequate quality MRI, with a median time of 25 min to reach sleeping. Only in three patients MRI could not be performed. In patients having a large weight, higher doses of melatonin were necessary to reach sleeping. Considering the pro kg dose of melatonin, the average dose that induced sleepiness in neonates was 0,64 ± 0.16 mg/Kg. CONCLUSION: A solution based on Melatonin- tryptophan-vitamin B6 can be a helpful sedative to administer to neonates undergoing brain MRI, avoiding the use of anesthetics and achieving adequate assessments.


Assuntos
Encéfalo/diagnóstico por imagem , Depressores do Sistema Nervoso Central/administração & dosagem , Imagem por Ressonância Magnética , Melatonina/administração & dosagem , Triptofano/administração & dosagem , Vitamina B 6/administração & dosagem , Antidepressivos de Segunda Geração/administração & dosagem , Sedação Consciente , Feminino , Humanos , Hipnóticos e Sedativos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Complexo Vitamínico B/administração & dosagem
5.
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
6.
Pharmacol Biochem Behav ; 184: 172742, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31348944

RESUMO

Ketamine has become increasingly popular in adolescent drug abusers worldwide. Meanwhile, alcohol is usually used by ketamine users. However, little work has been conducted to examine the chronic combined effects of ketamine and ethanol on adolescent brain. Here we probed into the effects of chronic administration of ketamine at recreational doses alone or combined with ethanol on behaviors and neuron damage in an adolescent rat model. 28-day old rats were treated with either 20 or 30 mg/kg ketamine plus or not plus 10% ethanol daily for 21 days. Depressive like behaviors, anxiety like behavior and memory impairment were tested using open field test, forced swimming test, elevated plus maze and Morris water maze. Apoptosis in prefrontal cortex (PFC) and hippocampus (HIP) were determined by the TdT-mediated dUTP Nick-End Labeling (TUNEL) and protein and mRNA levels of caspase-3, Bax and Bcl-2. Results show that co-application of ketamine and ethanol significantly increased immobility time in the forced swimming test, up-regulated TUNEL positive cells and both protein and mRNA expressions of caspase-3 and Bax, compared with the control group and ketamine and ethanol use alone groups in the PFC, but not in the HIP. Our study suggests that chronic co-administration of ketamine and ethanol results in depressive-like behavior and the caspase-dependent apoptosis in the PFC of adolescent rats' brains.


Assuntos
Anestésicos Dissociativos/farmacologia , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Anestésicos Dissociativos/administração & dosagem , Animais , Ansiedade/induzido quimicamente , Caspase 3/genética , Caspase 3/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Depressão/induzido quimicamente , Etanol/administração & dosagem , Hipocampo/metabolismo , Ketamina/administração & dosagem , Masculino , Memória/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
7.
Vet Anaesth Analg ; 46(5): 560-567, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31351807

RESUMO

OBJECTIVE: To investigate the preoperative calming effect of melatonin and its influence on propofol dose for anesthesia induction in dogs. STUDY DESIGN: Prospective, randomized, blinded, placebo-controlled clinical study. ANIMALS: A total of 50 healthy, adult, client-owned dogs scheduled for elective surgery. METHODS: Dogs were equally divided into treatment group M, which received 5 mg kg-1 melatonin, and placebo-control group P (sucrose), both administered orally 2 hours prior to induction of anesthesia. Dogs were subjectively characterized and further designated as skeptical (group S; n = 18) or trustful (group T; n = 32). Behavior, calming effect and vital parameters (pulse rate, respiratory rate, blood pressure, rectal temperature) were evaluated before and after treatment. Propofol dose [mg kg-1 intravenously (IV)] to allow endotracheal intubation and anesthesia induction quality was documented. Data were analyzed using a general linear model and Mann-Whitney U tests. RESULTS: Dogs in group MS (n = 10) were calmer than those in group PS (n = 8) at 90 minutes after drug administration (p = 0.047). Group MT (n = 15) required less propofol (5.98 ± 0.96 mg kg-1) than group PT (n = 17; 7.04 ± 1.82 mg kg-1 IV; p = 0.048) and group MS (9.48 ± 3.22 mg kg-1 IV; p = 0.007). Group PS required 7.69 ± 2.71 mg kg-1 IV. Skeptical dogs showed more reactions during induction (p = 0.013). Vital parameters were within physiological ranges before and after treatment. CONCLUSION AND CLINICAL RELEVANCE: Results showed that melatonin may be used to reduce propofol dose for anesthesia induction in trustful dogs. Skeptical dogs benefitted from the calming properties. Potentially, melatonin could be used to minimize the level of excitement before general anesthesia and to reduce the required propofol dose for induction.


Assuntos
Anestesia Geral/veterinária , Anestésicos Intravenosos/farmacocinética , Depressores do Sistema Nervoso Central/farmacologia , Cães/fisiologia , Melatonina/farmacologia , Propofol/farmacocinética , Anestésicos Intravenosos/administração & dosagem , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Cães/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Masculino , Melatonina/administração & dosagem , Período Pré-Operatório , Propofol/administração & dosagem , Estudos Prospectivos , Valores de Referência , Taxa Respiratória/efeitos dos fármacos
8.
Pharmacol Biochem Behav ; 183: 87-97, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31163180

RESUMO

Lsamp, in combinations with other members of the IgLON family of cell adhesion molecules, promotes and inhibits neurite outgrowth and synapse formation during development. Mice lacking Lsamp gene display decreased social behaviour, hyperactivity; decreased anxiety level, alongside with altered balance in GABAA receptor α1 and α2 subunits; and decreased sensitivity to amphetamine, alongside with elevated serotonin function. In human studies, Lsamp has been associated with several psychiatric diseases, including schizophrenia, and suicide. Here, we provide a more thorough characterization of the pharmacological phenotype of Lsamp-deficient mice, including testing for sensitivity to morphine, cocaine, MK-801 and ketamine. More thorougly, sensitivity to GABA modulators (diazepam, alprazolam, ethanol, pentobarbital, TP003, and SL651498) was assessed. In brief, Lsamp-deficient mice were more sensitive to the locomotor activating effects of cocaine and morphine, and hypersensitive to the sedative and muscle relaxant effects of GABA modulators, most likely reflecting enhanced function of α1 and α5 subunits of the GABAA receptor. No gross differences in sensitivity to NMDA receptor modulators were observed. Thus, as the lack of Lsamp gene leads to widespread imbalances in major neurotransmitter systems in the brain accompanied by remarkable changes in behavioural phenotype as well, Lsamp-deficient mice are a promising model for mimicking psychiatric disorders.


Assuntos
Comportamento Animal/efeitos dos fármacos , Moléculas de Adesão Celular Neuronais/genética , Estimulantes do Sistema Nervoso Central/farmacologia , Moduladores GABAérgicos/farmacologia , Alprazolam/administração & dosagem , Alprazolam/farmacologia , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cocaína/administração & dosagem , Cocaína/farmacologia , Diazepam/administração & dosagem , Diazepam/farmacologia , Modelos Animais de Doenças , Maleato de Dizocilpina/administração & dosagem , Maleato de Dizocilpina/farmacologia , Etanol/administração & dosagem , Etanol/farmacologia , Feminino , Moduladores GABAérgicos/administração & dosagem , Proteínas Ligadas por GPI/genética , Técnicas de Inativação de Genes , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Knockout , Morfina/administração & dosagem , Morfina/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Fenótipo , Receptores de GABA-A/metabolismo
9.
Neuroscience ; 413: 77-85, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31242442

RESUMO

Genetic factors significantly contribute to the risk for developing alcoholism. To study these factors and other associated phenotypes, rodent lines have been developed using selective breeding for high alcohol preference. One of these models, the alcohol preferring (P) rat, has been used in hundreds of preclinical studies over the last few decades. However, very few studies have examined relapse-like behavior in this rat strain. In this study, we used operant self-administration and yohimbine-induced reinstatement models to examine relapse-like behavior in P rats. Our previous work has demonstrated that P rats show increased expression of the neurokinin-1 receptor (NK1R) in the central nucleus of the amygdala (CeA), and this functionally contributes to escalated alcohol consumption in this strain. We hypothesized that P rats would show increased sensitivity to yohimbine-induced reinstatement that is also mediated by NK1R in the CeA. Using Fos staining, site-specific infusion of NK1R antagonist, and viral vector overexpression, we examined the influence of NK1R on the sensitivity to yohimbine-induced reinstatement of alcohol seeking. We found that P rats displayed increased sensitivity to yohimbine-induced reinstatement as well as increased neuronal activation in the CeA after yohimbine injection compared to the control Wistar strain. Intra-CeA infusion of NK1R antagonist attenuates yohimbine-induced reinstatement in P rats. Conversely, upregulation of NK1R within the CeA of Wistar rats increases alcohol consumption and sensitivity to yohimbine-induced reinstatement. These findings suggest that NK1R upregulation in the CeA contributes to multiple alcohol-related phenotypes in the P rat, including alcohol consumption and sensitivity to relapse.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Transtornos Relacionados ao Uso de Álcool/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Ioimbina/farmacologia , Animais , Núcleo Central da Amígdala/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Condicionamento Operante , Modelos Animais de Doenças , Masculino , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Receptores da Neurocinina-1/metabolismo , Recidiva , Autoadministração
10.
J Coll Physicians Surg Pak ; 29(7): 600-603, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31253206

RESUMO

OBJECTIVE: To determine the effects of prenatal administration of ethanol on cell count in pars distalis of pituitary gland in the rat pups. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Anatomy, College of Physicians and Surgeons Pakistan, Regional Centre, Islamabad, Pakistan, from April 2014 to April 2015. METHODOLOGY: Sixteen female rats (Sprague Dawley) were selected by random sampling method. Rats were mated and divided into control group A and experimental group B. From gestational day 10 to 18, mother rats received intraperitoneal injection of ethanol (Group B) and normal saline (Group A). Mother rats were allowed to complete their gestation and deliver spontaneously. When pups were born, only male pups were selected for the study. They were reared till day five. At 5ᵗʰ; day, pituitary glands were taken out and histological study was done in PAS-OG stain. Cell count was made in unit area (10,000 µ2) of pars distalis of pituitary gland. Student t-test was applied for analysing the data of cell counts in unit area. RESULTS: Mean acidophil count was reduced in experimental group (70.19 ± 11.4) as compared to control group (92.65 ± 8.52, p<0.001). Mean basophil count was reduced in experimental group (27.05 ± 3.9) in comparison to control group (34.03 ± 7.9, p<0.001). Mean chromophobe count was increased (131.95 ± 10.7) in experimental group against the control group (104.62 ± 7.62, p < 0.001). CONCLUSION: Pups exposed to ethanol during gestation, showed significant reduction in acidophil and basophil count while increase in chromophobe cell count in pars distalis of pituitary gland.


Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Hipófise/efeitos dos fármacos , Hipófise/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Animais Recém-Nascidos , Contagem de Células , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley
11.
Pharmacol Biochem Behav ; 183: 32-37, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31199934

RESUMO

Behavioral sensitization is thought to be relevant to the psychopathology of drug addiction. A previous study from our research group demonstrated cross-sensitization between cocaine and ethanol. Although these findings suggest a common mechanism of action between these two drugs, little is known about the molecular or cellular aspects of this commonality. The AMPK pathway functions as an intracellular energy sensor and plays a critical role in maintaining cellular energy homeostasis. Thus, the present study examined AMPK signaling following reciprocal cross-sensitization between cocaine and ethanol in the rat prefrontal cortex and dorsal striatum. Male Sprague-Dawley rats were repeatedly treated with either cocaine (15 mg/kg, 5 times) or ethanol (0.5 g/kg, 15 times) and then challenged reciprocally with the other drug. When sensitized to either cocaine or ethanol, the phosphorylation in response to additional challenges with the same drug was enhanced, indicating the development of sensitization. However, responses to the cocaine challenge were enhanced in the ethanol-sensitized state, whereas the responses to the ethanol challenge were not apparently enhanced in the cocaine-sensitized state. This was likely due to the ceiling effect of cocaine sensitization, which suggested that cocaine had more robust effects than ethanol. Although the same changes were found for two upstream kinases of AMPK (LKB1 and CaMK4), TAK1 responded differently and was not affected by acute challenges from either cocaine or ethanol. In the prefrontal cortex, there was an increase in activity, whereas there was a decrease in activity in the dorsal striatum. This difference might be due to dopamine D1 receptor dominance in the prefrontal cortex and D2 receptor dominance in the dorsal striatum. Taken together, these results suggest that both cocaine and ethanol may share overlapping molecular pathways in the process of behavioral sensitization. However, the action of cocaine was stronger than that of ethanol.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Comportamento Animal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Etanol/farmacologia , Animais , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Cocaína/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/administração & dosagem , Etanol/administração & dosagem , MAP Quinase Quinase Quinases/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo
12.
Pharmacol Biochem Behav ; 183: 22-31, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31220547

RESUMO

The endocannabinoid (eCB) system is a particularly important neuronal mechanism implicated in alcohol use disorders. Animal models are key to broadening our knowledge of the neurobiological mechanisms underlying alcohol dependence. This study has two main aims: i) to assess how eCB levels in different brain areas are modified by alcohol-induced conditioning place preference (CPP), and ii) to study how cannabinoid type 2 receptor (CB2R) is involved in alcohol-rewarding properties, using pharmacological manipulation in C57BL/6 mice. Our results suggest that the eCB system is dysregulated throughout the mesocorticolimbic system by repeated alcohol exposure during the CPP paradigm, and that levels of anandamide (AEA) and several other N-acylethanolamines are markedly decreased in the medial prefrontal cortex and ventral midbrain of alcohol-CPP mice. We also observed that the administering an antagonist/inverse agonist of the CB2R (AM630) during the acquisition phase of CPP reduced the rewarding effects of alcohol. However, activating CB2R signalling using the agonist JWH133 seems to reduce both alcohol- and food-rewarding behaviours. Therefore, our findings indicate that the rewarding effects of alcohol are related to its disruptive effect on AEA and other N-acylethanolamine signalling pathways. Thus, pharmacological manipulation of CB2R is an interesting candidate treatment for alcohol use disorders.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Endocanabinoides/metabolismo , Etanol/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Comportamento Animal/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Indóis/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Alcamidas Poli-Insaturadas/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Recompensa
13.
J Autism Dev Disord ; 49(8): 3218-3230, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31079275

RESUMO

A randomized, 13-weeks, placebo-controlled double-blind study in 125 subjects aged 2-17.5 years with Autism Spectrum Disorder or Smith-Magenis syndrome and insomnia demonstrated efficacy and safety of easily-swallowed prolonged-release melatonin mini-tablets (PedPRM; 2-5 mg) in improving sleep duration and onset. Treatment effects on child behavior and caregiver's quality of life were evaluated. PedPRM treatment resulted in significant improvement in externalizing but not internalizing behavior (Strengths and Difficulties questionnaire; SDQ) compared to placebo (p = 0.021) with clinically-relevant improvements in 53.7% of PedPRM-treated versus 27.6% of placebo-treated subjects (p = 0.008). Caregivers' quality of life also improved with PedPRM versus placebo (p = 0.010) and correlated with the change in total SDQ (p = 0.0005). PedPRM alleviates insomnia-related difficulties, particularly externalizing behavior in the children, subsequently improving caregivers' quality of life.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Cuidadores , Depressores do Sistema Nervoso Central/uso terapêutico , Comportamento Infantil/efeitos dos fármacos , Melatonina/uso terapêutico , Qualidade de Vida , Sono/efeitos dos fármacos , Adolescente , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacologia , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Melatonina/administração & dosagem , Melatonina/farmacologia
14.
Life Sci ; 229: 180-186, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31077720

RESUMO

AIMS: The present study aimed to verify changes in cerebellar and plasmatic expression of miRNAs after the chronic consumption of ethanol and caffeine in the UChB rat, an experimental model for alcoholism. MATERIAL AND METHODS: Male rats at 5 months of age, were divided into the following groups (n = 10/group): 1. Ethanol (UChB rats receiving 10% ethanol solution and water ad libitum); 2. Ethanol + caffeine (UChB rats receiving 10% ethanol solution + 3g/l caffeine and water ad libitum); 3. Control (rats receiving water ad libitum). The cerebellum and plasma of the animals were collected and processed by RT-PCR for the miRNAs-155-5p, -146a-5p, -126-3p, -132-3p, -339-5p. KEY FINDINGS: Ethanol and caffeine were capable of regulating the expression of miRNAs associated with the inflammatory process in the tissue and plasma of the UChB rats. Increased expression of the analyzed miRNAs-155-5p, -146a-5p, -126-3p, -132-3p was observed for the cerebellar tissue in the Ethanol group and reduced expression of them in the Ethanol + caffeine group. In plasma, caffeine significantly elevated the miR-126-3p and miR-132-3p levels and decreased miR-155-5p levels. Ethanol consumption increased miR-146a-5p expression and decreased miR-339-5p levels. In brief, altered plasmatic levels of the miRNAs did not reflect the miRNAs levels found in cerebellar tissue. SIGNIFICANCE: Considering the results herein, we concluded that ethanol predisposes to an inflammatory process while caffeine has a neuroprotective effect on the cerebellar tissue.


Assuntos
Cafeína/farmacologia , Cerebelo/patologia , Etanol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Plasma/metabolismo , Animais , Cafeína/administração & dosagem , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/farmacologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Etanol/administração & dosagem , Perfilação da Expressão Gênica , Masculino , Ratos
15.
Artigo em Inglês | MEDLINE | ID: mdl-30797952

RESUMO

The selection of a controlled substance (CS) for use as the positive control article in a nonclinical drug abuse liability (DAL) assessment study should be contemplated carefully and with full understanding of the stated intent of the study design. Any CS that can maintain day-to-day stable baseline responding of voluntary intravenous intakes in animals may be selected under the current guidelines. Schedule I - IV CNS stimulants, depressants, and sedative/hypnotics can serve as maintenance drugs in these protocols, but not all of these compounds will provide comparatively efficient, robust, and stable daily intakes. Each Sponsor is directed to select a positive control article and training dose that will provide the most balanced, predictive, and scientifically-sound comparison consistent with the mechanism of action or therapeutic target of the test article. The SA study design is not a "one-size-fits-all" assay. This is a discussion of the critical design factors to be considered in selecting the most appropriate positive control article to use for a SA study.


Assuntos
Autoadministração/métodos , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Transtornos Relacionados ao Uso de Substâncias/etiologia
16.
Crit Care ; 23(1): 3, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616675

RESUMO

BACKGROUND: ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. METHODS: This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. RESULTS: There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01). CONCLUSIONS: Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01360346 . Registered on 25 March 2011.


Assuntos
Sedação Profunda/normas , Nutrição Enteral/normas , Hipnóticos e Sedativos/administração & dosagem , Idoso , Anestesia/métodos , Antipruriginosos/administração & dosagem , Antipruriginosos/uso terapêutico , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/uso terapêutico , Estado Terminal/terapia , Sedação Profunda/métodos , Nutrição Enteral/métodos , Feminino , Humanos , Hidroxizina/administração & dosagem , Hidroxizina/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Melatonina/administração & dosagem , Melatonina/uso terapêutico , Pessoa de Meia-Idade , Distribuição de Poisson , Escala Psicológica Aguda Simplificada , Método Simples-Cego
17.
J Int Adv Otol ; 15(1): 43-50, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30541731

RESUMO

OBJECTIVES: To investigate the effects of topical and systemic administrations of melatonin and dexamethasone on facial nerve regeneration. MATERIALS AND METHODS: In total, 50 male albino Wistar rats underwent facial nerve axotomy and neurorrhaphy. The animals were divided into 5 groups: control, topical melatonin, systemic melatonin, topical dexamethasone, and systemic dexamethasone. Nerve conduction studies were performed preoperatively and at 3, 6, 9, and 12 weeks after drug administrations. Amplitude and latency of the compound muscle action potentials were recorded. Coapted facial nerves were investigated under light and electron microscopy. Nerve diameter, axon diameter, and myelin thickness were recorded quantitatively. RESULTS: Amplitudes decreased and latencies increased in both the melatonin and dexamethasone groups. At the final examination, the electrophysiological evidence of facial nerve degeneration was not significantly different between the groups. Histopathological examinations revealed the largest nerve diameter in the melatonin groups, followed by the dexamethasone and control groups (p<0.05). Axon diameter of the control group was smaller than those of the melatonin (topical and systemic) and topical dexamethasone groups (p<0.05). The melatonin groups had almost normal myelin ultrastructure. CONCLUSION: Electrophysiological evaluation did not reveal any potential benefit of dexamethasone and melatonin in contrast to histopathological examination, which revealed beneficial effects of melatonin in particular. These agents may increase the regeneration of facial nerves, but electrophysiological evidence of regeneration may appear later.


Assuntos
Dexametasona/farmacologia , Nervo Facial/efeitos dos fármacos , Nervo Facial/transplante , Melatonina/farmacologia , Administração Tópica , Animais , Axotomia/métodos , Depressores do Sistema Nervoso Central/administração & dosagem , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Nervo Facial/fisiopatologia , Nervo Facial/ultraestrutura , Glucocorticoides/administração & dosagem , Masculino , Melatonina/administração & dosagem , Bainha de Mielina/ultraestrutura , Regeneração Nervosa/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Procedimentos Neurocirúrgicos/métodos , Ratos , Ratos Wistar , Procedimentos Cirúrgicos Reconstrutivos/métodos , Recuperação de Função Fisiológica
18.
Addict Biol ; 24(1): 17-27, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29044813

RESUMO

Neuroinflammation has been reported to follow chronic ethanol intake and may perpetuate alcohol consumption. Present studies determined the effect of human mesenchymal stem cells (hMSCs), known for their anti-inflammatory action, on chronic ethanol intake and relapse-like ethanol intake in a post-deprivation condition. Rats were allowed 12-17 weeks of chronic voluntary ethanol (10% and 20% v/v) intake, after which a single dose of activated hMSCs (5 × 105 ) was injected into a brain lateral ventricle. Control animals were administered vehicle. After assessing the effect of hMSCs on chronic ethanol intake for 1 week, animals were deprived of ethanol for 2 weeks and thereafter an ethanol re-access of 60 min was allowed to determine relapse-like intake. A single administration of activated hMSCs inhibited chronic alcohol consumption by 70% (P < 0.001), an effect seen within the first 24 hours of hMSCs administration, and reduced relapse-like drinking by 80% (P < 0.001). In the relapse-like condition, control animals attain blood ethanol ('binge-like') levels >80 mg/dl. The single hMSC administration reduced relapse-like blood ethanol levels to 20 mg/dl. Chronic ethanol intake increased by 250% (P < 0.001) the levels of reactive oxygen species in hippocampus, which were markedly reduced by hMSC administration. Astrocyte glial acidic fibrillary protein immunoreactivity, a hallmark of neuroinflammation, was increased by 60-80% (P < 0.001) by chronic ethanol intake, an effect that was fully abolished by the administration of hMSCs. This study supports the neuroinflammation-chronic ethanol intake hypothesis and suggest that mesenchymal stem cell administration may be considered in the treatment of alcohol use disorders.


Assuntos
Consumo de Bebidas Alcoólicas/imunologia , Astrócitos/imunologia , Bebedeira/imunologia , Encéfalo/imunologia , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Proteína Glial Fibrilar Ácida/imunologia , Inflamação/imunologia , Transplante de Células-Tronco Mesenquimais , Alcoolismo/imunologia , Animais , Doença Crônica , Humanos , Ventrículos Laterais , Ratos , Recidiva , Autoadministração
19.
Addict Biol ; 24(1): 28-39, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29094432

RESUMO

Mu opioid receptors (MORs) are widely distributed throughout brain reward circuits and their role in drug and social reward is well established. Substantial evidence has implicated MOR and the endogenous opioid system in alcohol reward, but circuit mechanisms of MOR-mediated alcohol reward and intake behavior remain elusive, and have not been investigated by genetic approaches. We recently created conditional knockout (KO) mice targeting the Oprm1 gene in GABAergic forebrain neurons. These mice (Dlx-MOR KO) show a major MOR deletion in the striatum, whereas receptors in midbrain (including the Ventral Tegmental Area or VTA) and hindbrain are intact. Here, we compared alcohol-drinking behavior and rewarding effects in total (MOR KO) and conditional KO mice. Concordant with our previous work, MOR KO mice drank less alcohol in continuous and intermittent two-bottle choice protocols. Remarkably, Dlx-MOR KO mice showed reduced drinking similar to MOR KO mice, demonstrating that MOR in the forebrain is responsible for the observed phenotype. Further, alcohol-induced conditioned place preference was detected in control but not MOR KO mice, indicating that MOR is essential for alcohol reward and again, Dlx-MOR KO recapitulated the MOR KO phenotype. Taste preference and blood alcohol levels were otherwise unchanged in mutant lines. Together, our data demonstrate that MOR expressed in forebrain GABAergic neurons is essential for alcohol reward-driven behaviors, including drinking and place conditioning. Challenging the prevailing VTA-centric hypothesis, this study reveals another mechanism of MOR-mediated alcohol reward and consumption, which does not necessarily require local VTA MORs but rather engages striatal MOR-dependent mechanisms.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Neurônios GABAérgicos/metabolismo , Neostriado/metabolismo , Receptores Opioides mu/genética , Recompensa , Área Tegmentar Ventral/metabolismo , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Comportamento Animal , Mesencéfalo/metabolismo , Camundongos , Camundongos Knockout , Prosencéfalo/metabolismo , Rombencéfalo/metabolismo , Autoadministração
20.
Psychopharmacology (Berl) ; 236(2): 603-611, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30382353

RESUMO

BACKGROUND: Preclinical studies in rodents have demonstrated inhibitory effects of glucagon-like peptide-1 (GLP-1) receptor stimulation on alcohol consumption. The effects of GLP-1 receptor stimulation on alcohol intake in primates have not been investigated. METHODS: We performed placebo-controlled studies on the effects of the GLP-1 receptor agonists exenatide and liraglutide on alcohol consumption in alcohol-preferring male African vervet monkeys. Monkeys selected for voluntary alcohol drinking were observed for at least 10 days of baseline drinking and allocated to drug or vehicle (n = 11-12 per group) balanced with respect to alcohol intake. Monkeys had access to alcohol 4 h/day. In a first study, monkeys were treated with exenatide 0.04 mg/kg or vehicle once weekly for 5 weeks to obtain steady-state plasma levels. In a second study, monkeys were treated daily with liraglutide (increasing dosing, 10 to 50 µg/kg/day) or vehicle over 2 weeks. In both studies, access to alcohol was suspended during drug up-titration. Then, alcohol was again made available 4 h/day and treatment was continued for 2 weeks, during which alcohol intake was recorded. Observation of alcohol intake was continued for a week of drug washout. RESULTS: Liraglutide and to a lesser extent exenatide significantly reduced alcohol consumption without causing any signs of emesis and with no effect on water intake as compared to vehicle. CONCLUSIONS: The present study demonstrates for the first time that GLP-1 receptor agonists can reduce voluntary alcohol drinking in non-human primates. The data substantiate the potential usefulness of GLP-1 receptor agonists in the treatment of alcohol use disorder.


Assuntos
Consumo de Bebidas Alcoólicas , Comportamento Animal/efeitos dos fármacos , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Liraglutida/farmacologia , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Chlorocebus aethiops , Ingestão de Líquidos/efeitos dos fármacos , Etanol/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon , Humanos , Masculino , Autoadministração , Água
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