scholarly journals Modulation of the mTOR pathway in male Lewis rats after morphine self-administration and subsequent extinction training

2018 ◽  
Author(s):  
Marcos Ucha ◽  
Santiago M Coria ◽  
Adrián E Núñez ◽  
Raquel Santos-Toscano ◽  
David Roura-Martínez ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Opposite Effect ◽  
Elevated Risk ◽  
Neural Mechanisms ◽  
Reward Learning ◽  
Mtor Signaling Pathway ◽  
Self Administration ◽  
Brain Areas ◽  
Behavioral Traits ◽  
Chronic Disorder

AbstractAddiction is a chronic disorder with an elevated risk of relapse, even after long periods of abstinence. Some of the neural mechanisms mediating addictions require protein synthesis, which could be relevant for the development of more effective treatments. The mTOR signaling pathway regulates protein synthesis processes that have recently been linked to the development of drug addiction. Thus, we have assessed the effects of morphine self-administration and its subsequent extinction on the expression of several genes that act in this pathway, and on the levels of some phosphoproteins in three brain areas related to reward learning and extinction: the amygdala, the nucleus accumbens, and the prefrontal cortex. We found an increase in Raptor and Eif4ebp2 gene expression in the amygdala of rats that self-administered morphine, and this persisted beyond the extinction period. The expression of Insr in the amygdala of control animals decreased over time while the opposite effect was seen in the rats that self-administered morphine. We also found a strong correlation between some of the biochemical variables measured and behavioral traits, suggesting a significant role for the genes and phosphoproteins identified, mostly in the amygdala, in the behavioral effects of morphine.

Nucleotide sequences required for the regulation of a rat alpha 2u-globulin gene by glucocorticoids

1986 ◽  
Vol 6 (7) ◽  
pp. 2334-2346
Author(s):  
W R Addison ◽  
D T Kurtz
Keyword(s):  
Protein Synthesis ◽  
Unknown Function ◽  
Opposite Effect ◽  
Nucleotide Sequences ◽  
Secondary Response ◽  
L Cells ◽  
Mutant Genes ◽  
Globulin Gene

alpha 2u-Globulin is a rat protein of as yet unknown function whose synthesis can be induced by glucocorticoids and several other hormones. Induction by glucocorticoids is a secondary response to the hormone: protein synthesis is required before the hormone can exert its stimulatory effect on alpha 2u-globulin transcription. We have used the linker-scanning mutagenesis procedure, followed by transfer of the mutant genes into mouse L-cells for analysis of their phenotype, to determine sequences within a cloned alpha 2u-globulin promoter that are required for its regulation by glucocorticoids. Mutations between positions -115 and -160 abolish or greatly reduce the inducibility of alpha 2u-globulin by the hormone. Mutations just upstream from this region, between positions -177 and -220, have an opposite effect; they increase induction two- to fourfold.

scholarly journals Early environmental enrichment and impoverishment differentially affect addiction-related behavioral traits, cocaine-taking, and dopamine D2/3 receptor signaling in a rat model of vulnerability to drug abuse

2021 ◽  
Author(s):  
Lidia Bellés ◽  
Andrea Dimiziani ◽  
François R. Herrmann ◽  
Nathalie Ginovart
Keyword(s):  
Environmental Enrichment ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Novelty Preference ◽  
Self Administration ◽  
Rearing Environment ◽  
Behavioral Traits ◽  
Da Release ◽  
Early Rearing

Abstract Rationale Risk factors for drug addiction include genetics, environment, and behavioral traits such as impulsivity and novelty preference (NP), which have been related to deficits in striatal dopamine (DA) D2/3-receptors (D2/3R) and heightened amphetamine (AMPH)-induced DA release. However, the influence of the early rearing environment on these behavioral and neurochemical variables is not clear. Objectives We investigated the influence of early rearing environment on striatal D2/3R availabilities and AMPH-induced DA release in relation to impulsivity, NP, and propensity to drug self-administration (SA) in “addiction-prone” Roman high- (RHA) and “addiction-resistant” Roman low-avoidance (RLA) rats. Methods Animals were reared post-weaning in either environmental enrichment (EE) or impoverishment (EI) and were assessed at adulthood for impulsivity, NP, and propensity to cocaine SA. EE and EI rats were also scanned using single-photon emission computed tomography to concurrently measure in vivo striatal D2/3R availability and AMPH-induced DA release. Results EE vs. EI was associated with heightened impulsivity and a lack of NP in both rat lines. Higher dorsal striatal D2/3R densities were found in RHA EE and higher AMPH-induced DA release in RLA EE. Both impulsivity and NP were negatively correlated to dorsal striatal D2/3R availabilities and positively correlated with AMPH-induced DA release in EI but not in EE. EE vs. EI was related to a faster rate of cocaine intake and elevated active timeout responses in RHAs. Conclusion Our results suggest non-monotonic, environment-dependent, relationships between impulsivity, NP, and D2/3R-mediated signaling, and suggest that EI vs. EE may decrease the reinforcing effects of psychostimulants in predisposed individuals.

Abstract 1: Role of MicroRNAs in Postranscriptional Regulation of Apolipoprotein B-100 mRNA

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sahar A Basir ◽  
Tiffany Asante ◽  
Khosrow Adeli
Keyword(s):  
Protein Synthesis ◽  
Mrna Expression ◽  
Apolipoprotein B ◽  
Opposite Effect ◽  
Translational Repression ◽  
Luciferase Reporter ◽  
Hepatoma Cell Line ◽  
P Bodies ◽  
Apob Mrna ◽  
Reporter Assays

Hepatic apolipoprotein B-100 (apoB) synthesis and secretion appears to be regulated largely at the posttranscriptional and posttranslational levels. MicroRNAs (miRNAs) are among posttranscriptional regulators of gene expression that bind to complementary sequences on target messenger RNA (mRNA) transcripts, usually resulting in translational repression or degradation. It is unknown whether specific miRNAs are involved in posttranscriptional regulation of apoB mRNA. We performed bioinformatic analysis, showing that two specific miRNAs with satisfactory E-values level (with levels indicating greater similarity between the input and its match) namely, miR-544 (E-value = 0.91) and miR-1202 (E-value=0.86) have potential to interact with 3’ and 5’ UTR of apoB, respectively. We hypothesized that the interaction of these specific miRNAs (miR-544 and miR-1202) with the 3’ and 5’UTR of apoB mRNA leads to apoB mRNA translational repression and/or activation. Using a human hepatoma cell line model, HepG2, the effects of overexpressed miRNAs and inhibition of endogenous miRNAs on the expression of apoB mRNA and apoB protein synthesis were investigated. We further examined the effect of these miRNAs on apoB mRNA traffic into cytoplasmic P-bodies. Transfection of HepG2 cells with miR-544 led to a significant reduction in apoB mRNA expression and protein synthesis and induced an increase in the co-localization of apoB mRNA into P-bodies. The opposite effect was observed when anti-miR-544 was employed to inhibit the endogenous miR-544. Results from luciferase reporter assays indicated that the effects of miR-544 may be mediated via interaction with the 3’UTR of apoB mRNA. In contrast to miR-544, miR-1202 overexpression induced an increase in apoB mRNA expression and protein synthesis. Similarly, the opposite effect was observed when using anti-miR-1202. Data from luciferase reporter assays showed an increased expression of the reporter gene in constructs carrying 5’UTR of apoB mRNA suggesting that miR-1202 may function via the 5’UTR. In summary, these data demonstrate that specific miRNAs are involved in the regulation of expression and translational control of apoB mRNA in hepatocytes. However, these miRNAs do not appear to mediate insulin regulation.

scholarly journals Neural Mechanisms of Reward Prediction Error in Autism Spectrum Disorder

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Maya G. Mosner ◽  
R. Edward McLaurin ◽  
Jessica L. Kinard ◽  
Shabnam Hakimi ◽  
Jacob Parelman ◽  
...  
Keyword(s):  
Prediction Error ◽  
Autism Spectrum ◽  
Neural Mechanisms ◽  
Reward Learning ◽  
Prediction Errors ◽  
Frontal Pole ◽  
Neural Basis ◽  
Reward Prediction ◽  
Behavioral Impairments ◽  
Adults With Asd

Few studies have explored neural mechanisms of reward learning in ASD despite evidence of behavioral impairments of predictive abilities in ASD. To investigate the neural correlates of reward prediction errors in ASD, 16 adults with ASD and 14 typically developing controls performed a prediction error task during fMRI scanning. Results revealed greater activation in the ASD group in the left paracingulate gyrus during signed prediction errors and the left insula and right frontal pole during thresholded unsigned prediction errors. Findings support atypical neural processing of reward prediction errors in ASD in frontostriatal regions critical for prediction coding and reward learning. Results provide a neural basis for impairments in reward learning that may contribute to traits common in ASD (e.g., intolerance of unpredictability).

ANG II activates effectors of mTOR via PI3-K signaling in human coronary smooth muscle cells

2004 ◽  
Vol 287 (3) ◽  
pp. H1232-H1238 ◽  
Author(s):  
Sassan Hafizi ◽  
Xuemin Wang ◽  
Adrian H. Chester ◽  
Magdi H. Yacoub ◽  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Signaling Pathway ◽  
Initiation Factor ◽  
Ang Ii ◽  
Eukaryotic Initiation Factor ◽  
Mtor Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Eukaryotic Initiation Factor 4E

We have previously shown that the vasoconstrictive peptide angiotensin II (ANG II) is a hypertrophic agent for human coronary artery smooth muscle cells (cSMCs), which suggests that it plays a role in vascular wall thickening. The present study investigated the intracellular signal transduction pathways involved in the growth response of cSMCs to ANG II. The stimulation of protein synthesis by ANG II in cSMCs was blocked by the immunosuppressant rapamycin, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway that includes the 70-kDa S6 kinase (p70S6k) and plays a key role in cell growth. The inhibitory effect of rapamycin was reversed by a molar excess of FK506; this indicates that both agents act through the common 12-kDa immunophilin FK506-binding protein. ANG II caused a rapid and sustained activation of p70S6k activity that paralleled its phosphorylation, and both processes were blocked by rapamycin. In addition, both of the phosphatidylinositol 3-kinase inhibitors wortmannin and LY-294002 abolished the ANG II-induced increase in protein synthesis, and wortmannin also blocked p70S6k phosphorylation. Furthermore, ANG II triggered dissociation of the translation initiation factor, eukaryotic initiation factor-4E, from its regulatory binding protein 4E-BP1, which was also inhibited by rapamycin and wortmannin. In conclusion, we have shown that ANG II activates components of the rapamycin-sensitive mTOR signaling pathway in human cSMCs and involves activation of phosphatidylinositol 3-kinase, p70S6k, and eukaryotic initiation factor-4E, which leads to activation of protein synthesis. These signaling mechanisms may mediate the growth-promoting effect of ANG II in human cSMCs.

l-Arginine stimulates the mTOR signaling pathway and protein synthesis in porcine trophectoderm cells

2012 ◽  
Vol 23 (9) ◽  
pp. 1178-1183 ◽  
Author(s):  
Xiangfeng Kong ◽  
Bie Tan ◽  
Yulong Yin ◽  
Haijun Gao ◽  
Xilong Li ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Trophectoderm Cells

Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats

2011 ◽  
Vol 301 (5) ◽  
pp. E873-E881 ◽  
Author(s):  
Yu Chen ◽  
Sumita Sood ◽  
Kevin McIntire ◽  
Richard Roth ◽  
Ralph Rabkin
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Signaling Pathway ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Exercise Induced ◽  
Rps6 Phosphorylation

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.

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