RESUMO
Some BDNF (brain-derived neurotrophic factor)-targeted microRNAs such as miR-30a-5p associate with alcohol dependence phenomenon however their relationship with AWS is not described. We aimed to measure serum BDNF concentration and relative content of miR-30a-5p over the course of alcohol abstinence and compare obtained results with clinics of AWS. Additionally, we studied relative serum content of miR-30a-5p, a microRNA which does not target BDNF but relates to alcohol use disorder. Serum BDNF concentration increased over the course of alcohol abstinence, contrary relative content of miR-122 but not miR-30a-5p decreased. Moreover, during AWS miR-122 but miR-30a-5p negatively correlated with serum BDNF concentrations. Relative content of miR-122 negatively correlated with depression and state anxiety levels on 8th day of abstinence. According to multiple regressions on 21st day of abstinence alcohol craving and cognitive disturbances may be predictors of serum BDNF concentration, and vice versa. Thus, serum BDNF concentration and relative content of miR-122 associate with some aspects of AWS clinics and may dynamically reflect AWS severity.
Assuntos
Alcoolismo , MicroRNAs , Síndrome de Abstinência a Substâncias , Alcoolismo/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Humanos , MicroRNAs/genética , Síndrome de Abstinência a Substâncias/genéticaRESUMO
BACKGROUND: The development of cholinergic deficit is considered an early sign of a number of pathological conditions, including Alzheimer's disease. Cholinergic dysfunction underlies cognitive decline associated with both normal aging and Alzheimer's disease. OBJECTIVE: Here, we studied a possible mechanism of functional impairment of cholinergic neurons using an olfactory bulbectomy model. METHODS: Male mice were subjected to olfactory bulbectomy or sham surgery. Three weeks after that they were trained in Morris water maze and then euthanized one month after surgery. The cholinergic indices as well as the indices of oxidative stress were studied using immunohistochemistry, western blot and ELISA. Gene expression was studied using RT-qPCR. RESULTS: The experimental treatment was followed by impaired learning of a standard spatial task in a water maze. This was associated with a decrease in the number of cells containing choline acetyltransferase (ChAT), in relation to total number of neurons in the medial septum and lower ChAT enzymatic activity in the hippocampus. However, the levels of mRNAs of ChAT, vesicular ACh transporter and acetylcholine esterase remained unchanged in bulbectomized mice compared to sham-operated animals. These alterations were preceded by the accumulation of protein-bound carbonyls, indicating oxidative damage of proteins, whereas oxidative damage of nucleic acids was not detected. CONCLUSION: We assume that in olfactory bulbectomy model, oxidative damage of proteins may cause cholinergic dysfunction rather than irreversible neuronal damage. These data indicate that cholinergic neurons of the basal forebrain are very sensitive to oxidative stress, which may be responsible for the appearance of early cognitive decline in Alzheimer's disease.
Assuntos
Colina O-Acetiltransferase , Colinérgicos , Estresse Oxidativo , Animais , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , FenótipoRESUMO
Infectious diseases in early postnatal ontogenesis can induce neuroinflammation, disrupt normal central nervous system development, and contribute to pathogenesis of cerebral pathologies in adults. To study long-term consequences of such early stress, we induced neonatal proinflammatory stress (NPS) by injecting bacterial lipopolysaccharide into rat pups on postnatal days 3 and 5 and then assessed the levels of corticosterone, proinflammatory cytokines and their mRNAs, and neurotrophins and their mRNAs in the hippocampus and neocortex of the one-month-old animals. Long-term potentiation (LTP) was studied in hippocampal slices as an index of synaptic plasticity. NPS-induced impairments of LTP were accompanied by the accumulation of corticosterone and IL-6 in the hippocampus. In the neocortex, a decrease in exon IV BDNF mRNA was detected. We suggest that excessive corticosterone delivery to hippocampal receptors and proinflammatory changes persisting during brain maturation are among the principal molecular mechanisms responsible for NPS-induced neuroplasticity impairments.
Assuntos
Corticosterona/metabolismo , Hipocampo/metabolismo , Interleucina-6/metabolismo , Potenciação de Longa Duração , Plasticidade Neuronal , Estresse Fisiológico , Animais , Hipocampo/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Ratos , Ratos WistarRESUMO
Opiate reinforcement is considered as a stimulus inducing addiction, however underlying neurobiological mechanisms remain obscure. According to the literature, BDNF (brain-derived neurotrophic factor) in the lateral ventral tegmental area (VTA) could modulate morphine reinforcement, but the role of BDNF in the midline VTA has not been studied yet. The aim of the study was to investigate the effect of a single intra-mid- line VTA injection on the acquisition and expression of morphine conditioned place preference (CPP). CPP procedure was composed of eight conditioning sessions (one session per day): morphine (i.p., 10 mg/kg) and saline injections were paired to the compartments and counterbalanced.Recombinant human BDNF (0.75 ug) or phosphate-buffered saline (PBS) as a vehicle were injected once into the midline VTA one day before or after conditioning. According to the CPP test rats spent more time in the morphine-paired compartments a scompared to the saline-paired compartments (p < 0.05). After a single BDNF injection into the midline VTA be- fore conditioning, but not after conditioning, differences in time spent in morphine and saline-paired compartments did not reach significance (p > 0.05). Thus, taking into account limitations of the results, we sug- gest that BDNF in the midline VTA may block morphine reinforcement.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Reforço Psicológico , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Eletrodos Implantados , Humanos , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Ratos , Ratos Wistar , Solução Salina/farmacologia , Técnicas Estereotáxicas , Área Tegmentar Ventral/fisiologiaRESUMO
This study was aimed at evaluating the role of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in mechanisms of morphine dependency formation. Morphine was introduced by intraperitoneal (i.p.) injections in rats twice per day over six days in doses increasing from 10 to 100 mg/kg, For evaluating the role of NO/cGMP cascade, NO synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME) was introduced (10 mg/kg, i.p.) 1 h prior to every injection of morphine. The L-NAME introduction led to enhancement of spontaneous withdrawal syndrome manifestations, which was accompanied by more pronounced decrease in the cGMP levels in midbrain and striatum. It is suggested that the region specific decrease in NO/cGMP cascade signaling activity in the brain can be among mechanisms determining the development of opium dependency.
Assuntos
Corpo Estriado/metabolismo , GMP Cíclico/metabolismo , Mesencéfalo/metabolismo , Dependência de Morfina/metabolismo , Óxido Nítrico/metabolismo , Animais , Masculino , Morfina/efeitos adversos , Morfina/farmacologia , NG-Nitroarginina Metil Éster/efeitos adversos , NG-Nitroarginina Metil Éster/farmacologia , Entorpecentes/efeitos adversos , Entorpecentes/farmacologia , Ratos , Ratos Wistar , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
We studied the expression of mRNA for genes, whose protein products regulate the glutamate/NO/cGMP signal cascade in the frontal cortex, striatum, midbrain, and hippocampus of rats with various degrees of spontaneous morphine withdrawal syndrome. The concentration of Grin2a mRNA (subunit of the NMDA glutamate receptor) in the frontal cortex increased mainly in animals with severe abstinence. By contrast, the expression of mRNA for the Grin2b subunit in the striatum decreased in animals with mild abstinence. Variations in the content of mRNA for other products of the cascade (isoforms of NO-dependent guanylate cyclase and cGMP-dependent protein kinase) after morphine withdrawal were not related to the degree of abstinence. Our results suggest that the region-specific expression of mRNA for certain subunits of the NMDA glutamate receptor after morphine withdrawal can determine the degree of abstinence.
Assuntos
Corpo Estriado/metabolismo , Lobo Frontal/metabolismo , Dependência de Morfina/genética , RNA Mensageiro/genética , Receptores de N-Metil-D-Aspartato/genética , Síndrome de Abstinência a Substâncias/genética , Animais , Corpo Estriado/fisiopatologia , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Lobo Frontal/fisiopatologia , Expressão Gênica , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Morfina/efeitos adversos , Dependência de Morfina/etiologia , Dependência de Morfina/metabolismo , Dependência de Morfina/fisiopatologia , Óxido Nítrico/metabolismo , Especificidade de Órgãos , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologiaRESUMO
Opiate dependence results from impairments of neuronal plasticity, i.e., so-called aberrant neuroplasticity, formation of which involves long-term structural-functional rearrangements persisting even during drug abstinence. Nitric oxide (NO) is involved both in mediating the effects of opiates and in the mechanisms of some types of neuroplasticity, so NO may potentially take part in the development of psychopathological processes on opiate withdrawal. The present study addressed measures of the nitrergic system (nitric oxide synthase (NOS) activity and nitrite and nitrate (NO (x) (-) ) concentrations) in areas of the rat brain; anxiety was also assessed, in terms of behavioral measures in the elevated plus maze, during morphine withdrawal. NOS activity was found to increase by day 3, while the NO (x) (-) concentration was increased by day 6 of withdrawal, these changes being seen only in the hippocampus. At six days after morphine withdrawal, rats showed more entries into the open arms of the elevated plus maze and remained in these arms longer. Correlations were found between measures of the NO system in the hippocampus and the behavior of the animals in the maze. These results suggest that changes in the activity of the nitrergic system in the hippocampus represent one of the molecular mechanisms impairing the behavior of animals in abstinence.
Assuntos
Ansiedade/metabolismo , Hipocampo/metabolismo , Morfina/farmacologia , Entorpecentes/farmacologia , Óxido Nítrico Sintase/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Ansiedade/complicações , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Nitratos/metabolismo , Ácido Nítrico/metabolismo , Ratos , Ratos Wistar , Síndrome de Abstinência a Substâncias/complicações , Síndrome de Abstinência a Substâncias/psicologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Fatores de TempoRESUMO
Opiate addiction is accompanied by long-term structural and functional changes in brain regions persisting during abstinence, this status being an experimental model of the aberrant neuroplasticity. Nitric oxide is known to be involved in mechanisms of psychopathological events during opiate abstinence. In this study, indices of a nitregic system (nitric synthase activity--NOS, nitrites and nitrates concentration--NOx-) were measured in the rat brain region during morphine abstinence. Prior to this, the rats were tested for anxiety in an elevated plus maze. NOS activity increased in hippocampus 3 days after morphine withdrawal, while NOx--6 days after withdrawal. No changes of the nitrergic system could be revealed in other brain regions under study. Six days (but not 3 days) after morphine withdrawal, rats visited the open arms of the plus maze more frequently and spent more time in these arms as compared with respective controls. The data suggest that nitrergic system changes in the hippocampus may be involved in molecular mechanisms of behavioural alteration during morphine abstinence in rats.
Assuntos
Ansiedade/induzido quimicamente , Hipocampo/metabolismo , Morfina/efeitos adversos , Entorpecentes/efeitos adversos , Óxido Nítrico/metabolismo , Síndrome de Abstinência a Substâncias , Animais , Ansiedade/metabolismo , Hipocampo/química , Masculino , Nitratos/análise , Nitratos/metabolismo , Óxido Nítrico Sintase/análise , Óxido Nítrico Sintase/metabolismo , Nitritos/análise , Nitritos/metabolismo , Ratos , Ratos WistarRESUMO
Nitric oxide synthase (NOS) activity and nitrate/nitrites (NO(x)-) concentrations were measured in brain regions of rats during the spontaneous morphine withdrawal. Male Wistar rats were injected intraperotoneally with morphine hydrochloride at increasing doses (10-100 mg/kg) during 6 days twice a day. Thirty six hours after the last injection the severity of the spontaneous morphine withdrawal syndrome was determined by specific autonomic and locomotor indices. Both NOS activity and NO(x)- levels increased in the midbrain and the hippocampus, decreased in the striatum and the hypothalamus, and did not change in the cerebral cortex and the brain stem. NO(x)- concentrations in the cerebellum did not change, while NOS activity decreased. Both NOS activities and NO(x)- concentrations in the cerebral cortex, striatum, midbrain, and cerebellum correlated with withdrawal syndrome severity on the whole, and with the specific signs of abstinence.
Assuntos
Encéfalo/metabolismo , Morfina/efeitos adversos , Nitratos/metabolismo , Óxido Nítrico Sintase/metabolismo , Nitritos/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Encéfalo/enzimologia , Masculino , Atividade Motora , Especificidade de Órgãos , Ratos , Ratos Wistar , Síndrome de Abstinência a Substâncias/enzimologia , Síndrome de Abstinência a Substâncias/fisiopatologiaRESUMO
Indices of oxidative stress, nitric oxide (NO) metabolism as well as the activity of caspase-3, an important enzyme of apoptotic cell death, were measured during the morphine withdrawal syndrome in liver and thymus of rats. Male Wistar rats were administered with morphine hydrochloride (i.p., at increasing doses from 10 to 100 mg/kg, twice a day, for 6 days). Thirty-six hours after the last administration the withdrawal syndrome was monitored using the specific autonomic and locomotor indices. During this period, weights of body and thymus significantly decreased. Oxidative stress in liver was accompanied by an increase in aspartate aminotransferase and gamma-glutamyl transferase in blood serum. No signs of oxidative stress could be demonstrated in thymus. The activity of the Ca(2+)-dependent isoform of nitric oxide synthase (NOS) in liver increased, while, the activity of the Ca(2+)-independent NOS diminished, the total activity of NOS in liver and thymus remained unchanged. The concentration of nitrates/nitrites in blood was decreased, in thymus increased, and in liver unchanged. Caspase-3 activity changed neither in liver, nor in thymus. The results are discussed from the perspective of possible antioxidant and antiapoptotic role of NO during morphine withdrawal syndrome.