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sexta-feira, 18 de outubro de 2019
Sleep Regulates Incubation of Cocaine Craving
After withdrawal from cocaine, chronic cocaine users often experience persistent reduction in total sleep time, which is accompanied by
increased sleep fragmentation resembling chronic insomnia. This and other sleep abnormalities have long been speculated to foster
relapse and further drug addiction, but direct evidence is lacking. Here, we report that after prolonged withdrawal from cocaine selfadministration, rats exhibited persistent reductionin nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep, as well as
increased sleep fragmentation. In an attempt to improve sleep after cocaine withdrawal, we applied chronic sleep restriction to the rats
duringtheir active (dark) phase ofthe day, which selectively decreasedthe fragmentation of REM sleep duringtheir inactive (light) phase
without changing NREM or the total amount of daily sleep. Animals with improved REM sleep exhibited decreased incubation of cocaine
craving, a phenomenon depictingthe progressiveintensification of cocaine seeking after withdrawal. In contrast, experimentallyincreasing sleep fragmentation after cocaine self-administration expedited the development of incubation of cocaine craving. Incubation of
cocaine craving is partially mediated by progressive accumulation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus
accumbens (NAc). After withdrawal from cocaine, animals with improved REM sleep exhibited reduced accumulation of CP-AMPARs in
the NAc, whereas increasing sleep fragmentation accelerated NAc CP-AMPAR accumulation. These results reveal a potential molecular
substratethat can be engaged by sleepto regulate cocaine craving and relapse, anddemonstrate sleep-basedtherapeutic opportunitiesfor
cocaine addiction.
sexta-feira, 8 de fevereiro de 2019
terça-feira, 15 de janeiro de 2019
What do the genetic association data say about the high risk of suicide in people with depression?
BACKGROUND: Available sources indicate that the risk of suicide in people with major depression is higher than other psychiatric disorders. Although it seems that these two conditions may have a shared cause in some cases, no studies have been conducted to identify a common basis for them.
METHODS: In this study, following an extensive review of literature, we found almost all the genes that are involved in major depression and suicidal behavior, and we isolated genes shared between the two conditions. Then, we found all physical or functional interactions within three mentioned gene sets and reconstructed three genetic interactive networks. All networks were analyzed topologically and enriched functionally. Finally, using a drug repurposing approach, we found the main available drugs that interacted with the most central genes shared between suicidal behavior and depression.
RESULTS: The results demonstrated that BDNF, SLC6A4, CREB1, and TNF are the most fundamental shared genes; and generally, disordered dopaminergic, serotonergic, and immunologic pathways in neuronal projections are the main shared deficient pathways. In addition, we found two genes, SLC6A4 and SLC6A2, to be the main therapeutic targets, and Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) and Tricyclic Antidepressants (TCA) to be the most effective drugs for individuals with depression at risk for suicide.
CONCLUSIONS: Our results, in addition to shedding light on the integrated molecular basis of depression-suicide, offer new therapeutic targets for individuals with depression at high risk for suicide and could pave the way for future preclinical and clinical studies. However, integrative systems biology-based studies highly depend on existing data and related databases, as well as the arrival of new experimental data sources in the future, possibly affecting the current results.
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Association of DNA methylation in BDNF with escitalopram treatment response in depressed Chinese Han patients
Purpose: The neurotrophin brain-derived neurotrophic factor (BDNF) has been found to be associated with both the pathophysiology of depression and antidepressants response. Gene expression differences were partly mediated by SNP, which might be identified as a predictor of antidepressant response. In the present study, we attempt to identify whether DNA methylation, another factor known to affect gene transcription, might also predict antidepressant response.
mETHODS: A total of 85 depressed Chinese Han patients were followed-up 8 weeks after initiating escitalopram treatment. Treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The bisulfate sequencing was used to assess DNA methylation. Four single nucleotide polymorphisms (SNPs) in the BDNF gene were genotyped using PCR-RFLP or PCR sequencing.
RESULTS: We identified a DNA methylation predictor (P = 0.006-0.036) and a DNA methylation by LES interaction predictor (OR = 1.442 [1.057-1.968], P = 0.021) of general antidepressant treatment response. Lower mean BDNF DNA methylation was associated with impaired antidepressant response. Furthermore, the present data indicated that age, life stress, and SNPs genotype might be likely related to DNA methylation status. Average DNA methylation of BDNF at baseline was significantly lower than that at endpoint after 8 weeks of escitalopram treatment, which was based only on a subset of cases (n = 44).
CONCLUSIONS: Our results suggest that BDNF DNA hypomethylation and its interaction with lower LES score might result in impaired antidepressant treatment response. The pharmacoepigenetic study could eventually help in finding epigenetic biomarkers of antidepressant response.
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