Abstract
Background
Dopamine neurotransmission plays a critical role in reward in drug abuse and drug addiction. However, the role of dopamine in the recognition of drug-associated environmental ...stimuli, retrieval of drug-associated memory, and drug-seeking behaviors is not fully understood.
Methods
Roles of dopamine neurotransmission in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in the cocaine-conditioned place preference (CPP) paradigm were evaluated using in vivo microdialysis.
Results
In mice that had acquired cocaine CPP, dopamine levels in the PFC, but not in the NAc, increased in response to cocaine-associated cues when mice were placed in the cocaine chamber of an apparatus with 2 separated chambers. The induction of the dopamine response and the development of cocaine CPP were mediated through activation of glutamate NMDA (N-methyl-D-aspartate)/AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor signaling in the PFC during conditioning. Activation of dopamine D1 or D2 receptor signaling in the PFC was required for cocaine-induced locomotion, but not for the induction of the dopamine response or the development of cocaine CPP. Interestingly, dopamine levels in the NAc increased in response to cocaine-associated cues when mice were placed at the center of an apparatus with 2 connected chambers, which requires motivated exploration associated with cocaine reward.
Conclusions
Dopamine neurotransmission in the PFC is activated by the exposure to the cocaine-associated cues, whereas dopamine neurotransmission in the NAc is activated in a process of motivated exploration of cues associated with cocaine reward. Furthermore, the glutamate signaling cascade in the PFC is suggested to be a potential therapeutic target to prevent the progression of drug addiction.
BDNF Is a Negative Modulator of Morphine Action Koo, Ja Wook; Mazei-Robison, Michelle S.; Chaudhury, Dipesh ...
Science (American Association for the Advancement of Science),
10/2012, Letnik:
338, Številka:
6103
Journal Article
Recenzirano
Odprti dostop
Brain-derived neurotrophic factor (BDNF) is a key positive regulator of neural plasticity, promoting, for example, the actions of stimulant drugs of abuse such as cocaine. We discovered a surprising ...opposite role for BDNF in countering responses to chronic morphine exposure. The suppression of BDNF in the ventral tegmental area (VTA) enhanced the ability of morphine to increase dopamine (DA) neuron excitability and promote reward. In contrast, optical stimulation of VTA DA terminals in nucleus accumbens (NAc) completely reversed the suppressive effect of BDNF on morphine reward. Furthermore, we identified numerous genes in the NAc, a major target region of VTA DA neurons, whose regulation by BDNF in the context of chronic morphine exposure mediated this counteractive function. These findings provide insight into the molecular basis of morphine-induced neuroadaptations in the brain's reward circuitry.
The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) has been reported to be lower in Japan than in many other countries. However, extensive surveillance for CRE carriage has not been ...performed in Japan.
To investigate the prevalence of CRE carriage in Japan among convalescent patients considered to be at high risk of being CRE carriers using an improved selective culture medium.
A cross-sectional survey was conducted in 22 acute care hospitals (ACHs) and 21 long-term care hospitals (LTCHs) in northern Osaka from December 2015 to January 2016. Patients who used incontinence aids, an enteral feeding tube or a urinary catheter were enrolled. Faecal specimens were examined using the newly developed M-ECC for imipenemase (IMP)-producing CRE, which is the most prevalent form of CRE in Japan. The positive isolates were analysed by polymerase chain reaction and sequencing. Risk factors associated with carriage were analysed by logistic regression.
Among 1507 patients, 184 (12.2%) carried CRE. The percentage of positive patients was significantly higher in LTCHs (14.9%) than in ACHs (3.6%) (P<0.001). Risk factors for CRE carriage were longer hospital stay odds ratio (OR) 2.59; 95% confidence interval (CI) 1.87–3.60, enteral feeding (OR 3.03, 95% CI 2.08–4.42) and antibiotic exposure (OR 2.00, 95% CI 1.40–2.87). Among the 233 CRE isolates identified, 223 were IMP producers; the remaining isolates did not produce carbapenemase.
This is the first Japanese report to demonstrate the significant spread of CRE in both ACHs and LTCHs using an improved selective medium. A coordinated regional approach may help to prevent further spread.
Tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant mutations of epidermal growth factor receptor (EGFR) are associated with lung adenocarcinoma. EGFR mutants were previously shown to exhibit ...ligand-independent activation. We have previously demonstrated that pulmonary surfactant protein D (SP-D, SFTPD) suppressed wild-type EGFR signaling by blocking ligand binding to EGFR. We herein demonstrate that SFTPD downregulates ligand-independent signaling in cells harboring EGFR mutations such as TKI-sensitive exon 19 deletion (Ex19del) and L858R mutation as well as TKI-resistant T790M mutation, subsequently suppressing cellular growth and motility. Lectin blotting and ligand blotting in lung cancer cell lines suggested that EGFR mutants express oligomannose-type N-glycans and interact with SFTPD directly. Cross-linking assay indicated that SFTPD inhibits ligand-independent dimerization of EGFR mutants. We also demonstrated that SFTPD reduced dimerization-independent phosphorylation of Ex19del and T790M EGFR mutants using point mutations that disrupted the asymmetric dimer interface. It was confirmed that SFTPD augmented the viability-suppressing effects of EGFR-TKIs. Furthermore, retrospective analysis of 121 patients with lung adenocarcinoma to examine associations between serum SFTPD levels and clinical outcome indicated that in TKI-treated patients with lung cancer harboring EGFR mutations, including Ex19del or L858R, high serum SFTPD levels correlated with a lower number of distant metastases and prolonged overall survival and progression-free survival. These findings suggest that SFTPD downregulates both TKI-sensitive and -resistant EGFR mutant signaling, and SFTPD level is correlated with clinical outcome. These findings illustrate the use of serum SFTPD level as a potential marker to estimate the efficacy of EGFR-TKIs.
Highlights • Δ FosB mRNA gives rise to ΔFosB and to the minor alternatively translated Δ2ΔFosB. • Overexpression of ΔFosB alone confirms its pro-reward and pro-resilience phenotype. • In contrast, ...Δ2ΔFosB has no effect on cocaine reward or stress vulnerability. • Full-length FosB, encoded by FosB mRNA, also does not affect reward or resilience.
ΔFosB is a stable transcription factor which accumulates in the nucleus accumbens (NAc), a key part of the brain's reward circuitry, in response to chronic exposure to cocaine or other drugs of ...abuse. While ΔFosB is known to heterodimerize with a Jun family member to form an active transcription factor complex, there has not to date been an open-ended exploration of other possible binding partners for ΔFosB in the brain. Here, by use of yeast two-hybrid assays, we identify PSMC5-also known as SUG1, an ATPase-containing subunit of the 19S proteasomal complex-as a novel interacting protein with ΔFosB. We verify such interactions between endogenous ΔFosB and PSMC5 in the NAc and demonstrate that both proteins also form complexes with other chromatin regulatory proteins associated with gene activation. We go on to show that chronic cocaine increases nuclear, but not cytoplasmic, levels of PSMC5 in the NAc and that overexpression of PSMC5 in this brain region promotes the locomotor responses to cocaine. Together, these findings describe a novel mechanism that contributes to the actions of ΔFosB and, for the first time, implicates PSMC5 in cocaine-induced molecular and behavioral plasticity.
In the largest avascular low-nutrient intervertebral disc, resident cells would utilize autophagy, a stress-response survival mechanism by self-digestion and recycling wastes. Our goal was to ...elucidate the involvement of autophagy in disc homeostasis through RNA interference of autophagy-related gene 5 (Atg5).
In vitro, small interfering RNAs (siRNAs) targeting autophagy-essential Atg5 were transfected into rat disc cells. Cell viability with levels of autophagy including Atg5 expression, apoptosis, and senescence was assessed under serum starvation and/or pro-inflammatory interleukin-1 beta (IL-1β) stimulation. In vivo, time-course autophagic flux was monitored following Alexa Fluor® 555-labeled Atg5-siRNA injection into rat tail discs. Furthermore, 24-h temporary static compression-induced disruption of Atg5 siRNA-injected discs was observed by radiography, histomorphology, and immunofluorescence.
In disc cells, three different Atg5 siRNAs consistently suppressed autophagy with Atg5 protein knockdown (mean 44.4% 95% confidence interval: −51.7, −37.1, 51.5% −80.5, −22.5, 62.3% −96.6, −28.2). Then, Atg5 knockdown reduced cell viability through apoptosis and senescence not in serum-supplemented medium (93.6% −0.8, 21.4) but in serum-deprived medium (66.4% −29.8, −8.6) further with IL-1β (44.5% −36.9, −23.5). In disc tissues, immunofluorescence detected intradiscal signals for the labeled siRNA even at 56-d post-injection. Immunoblotting found 56-d autophagy suppression with prolonged Atg5 knockdown (33.2% −52.8, −5.3). With compression, Atg5 siRNA-injected discs presented radiographic height loss (−43.9, −0.8), histological damage (−5.5, −0.2), and immunofluorescent apoptosis (2.2, 22.2) and senescence (4.1, 19.9) induction compared to control siRNA-injected discs at 56 d.
This loss-of-function study suggests Atg5-dependent autophagy-mediated anti-apoptosis and anti-senescence. Autophagy could be a molecular therapeutic target for degenerative disc disease.
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