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1.
Trends Neurosci ; 44(12): 1004-1015, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34702580

RESUMO

Alcohol use produces wide-ranging and diverse effects on the central nervous system. It influences intracellular signaling mechanisms, leading to changes in gene expression, chromatin remodeling, and translation. As a result of these molecular alterations, alcohol affects the activity of neuronal circuits. Together, these mechanisms produce long-lasting cellular adaptations in the brain that in turn can drive the development and maintenance of alcohol use disorder (AUD). We provide an update on alcohol research, focusing on multiple levels of alcohol-induced adaptations, from intracellular changes to changes in neural circuits. A better understanding of how alcohol affects these diverse and interlinked mechanisms may lead to the identification of novel therapeutic targets and to the development of much-needed novel and efficacious treatment options.


Assuntos
Alcoolismo , Etanol , Alcoolismo/tratamento farmacológico , Alcoolismo/genética , Alcoolismo/metabolismo , Encéfalo/metabolismo , Montagem e Desmontagem da Cromatina , Etanol/metabolismo , Etanol/farmacologia , Etanol/uso terapêutico , Humanos , Neurônios/metabolismo
2.
Addict Biol ; 26(2): e12890, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32135570

RESUMO

Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs (miRs) targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the two-bottle choice paradigm (IA20%2BC) and measured circulating levels of BDNF protein and miRs targeting BDNF in the serum of Long-Evans rats before and after 8 weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified, whereas 70% of the rats gradually escalate their alcohol intake (late onset), and 30% of alcohol users exhibit a very rapid onset of drinking (rapid onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both rapid onset and late onset rats. In contrast, increased expression of the miRs targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the rapid onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Together, these data suggest that rats exhibit both late and rapid onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the rapid onset rats.


Assuntos
Alcoolismo/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , MicroRNAs/biossíntese , Córtex Pré-Frontal/patologia , Animais , Masculino , Gravidade do Paciente , Ratos , Ratos Long-Evans
3.
Proc Natl Acad Sci U S A ; 117(1): 677-688, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871190

RESUMO

A robust body of evidence supports the concept that phosphodiesterase 10A (PDE10A) activity in the basal ganglia orchestrates the control of coordinated movement in human subjects. Although human mutations in the PDE10A gene manifest in hyperkinetic movement disorders that phenocopy many features of early Huntington's disease, characterization of the maladapted molecular mechanisms and aberrant signaling processes that underpin these conditions remains scarce. Recessive mutations in the GAF-A domain have been shown to impair PDE10A function due to the loss of striatal PDE10A protein levels, but here we show that this paucity is caused by irregular intracellular trafficking and increased PDE10A degradation in the cytosolic compartment. In contrast to GAF-A mutants, dominant mutations in the GAF-B domain of PDE10A induce PDE10A misfolding, a common pathological phenotype in many neurodegenerative diseases. These data demonstrate that the function of striatal PDE10A is compromised in disorders where disease-associated mutations trigger a reduction in the fidelity of PDE compartmentalization.


Assuntos
Membrana Celular/metabolismo , Doença de Huntington/genética , Neurônios/enzimologia , Diester Fosfórico Hidrolases/genética , Domínios Proteicos/genética , Animais , Autofagia/genética , Corpo Estriado/citologia , Corpo Estriado/patologia , AMP Cíclico/metabolismo , Embrião de Mamíferos , Células HEK293 , Humanos , Doença de Huntington/patologia , Hidrólise , Isoenzimas/genética , Isoenzimas/metabolismo , Mutação , Neurônios/citologia , Técnicas de Patch-Clamp , Diester Fosfórico Hidrolases/metabolismo , Cultura Primária de Células , Proteólise , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
4.
Cell Signal ; 60: 31-38, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30951862

RESUMO

The dual-specific cAMP/cGMP phosphodiesterase PDE10A is exclusively localised to regions of the brain and specific cell types that control crucial brain circuits and behaviours. The downside to this expression pattern is that PDE10A is also positioned to be a key player in pathology when its function is perturbed. The last decade of research has seen a clear role emerge for PDE10A inhibition in modifying behaviours in animal models of psychosis and Huntington's disease. Unfortunately, this has not translated to the human diseases as expected. More recently, a series of families with hyperkinetic movement disorders have been identified with mutations altering the PDE10A protein sequence. As these mutations have been analysed and characterised in other model systems, we are beginning to learn more about PDE10A function and perhaps catch a glimpse into how PDE10A activity could be modified for therapeutic benefit.


Assuntos
Corpo Estriado/metabolismo , Doença de Huntington/metabolismo , Hipercinese/metabolismo , Diester Fosfórico Hidrolases/fisiologia , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Ratos
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