Altered Ratio of D1 and D2 Dopamine Receptors in Mouse Striatum Is Associated with Behavioral Sensitization to Cocaine

BACKGROUND: Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R) availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified. METHODS AND FINDINGS: ETHICS STATEMENT: All animal work was approved by the Gallo Center IACUC committee and was performed in our AAALAC approved facility. In this study, we used wild type (WT) and G protein coupled receptor associated sorting protein-1 (GASP-1) knock out (KO) mice to assess molecular changes that accompany cocaine sensitization. Here, we show that downregulation of D2Rs or upregulation of D1Rs is associated with a sensitized locomotor response to an acute injection of cocaine. Furthermore, we demonstrate that disruption of GASP-1, that targets D2Rs for degradation after endocytosis, prevents cocaine-induced downregulation of D2Rs. As a consequence, mice with a GASP-1 disruption show a reduction in the sensitized locomotor response to cocaine. CONCLUSIONS: Together, our data suggests that changes in the ratio of the D1:D2R could contribute to cocaine-induced behavioral plasticity and demonstrates a role of GASP-1 in regulating both the levels of the D2R and cocaine sensitization

Malaria parasites regulate the duration of the intra-erythrocytic cycle via serpentine receptor 10 and coordinate development with host daily rhythms

Malaria parasites complete their intra-erythrocytic developmental cycle (IDC) in multiples of 24 h suggesting a circadian basis, but the mechanism controlling this periodicity is unknown. Combining in vivo and in vitro approaches utilizing rodent and human malaria parasites, we reveal that: (i) 57% of Plasmodium chabaudi genes exhibit daily rhythms in transcription; (ii) 58% of these genes lose transcriptional rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 6% of Plasmodium falciparum genes show 24 h rhythms in expression under free-running conditions; (iv) Serpentine receptor 10 (SR10) has a 24 h transcriptional rhythm and disrupting it in rodent malaria parasites shortens the IDC by 2-3 h; (v) Multiple processes including DNA replication, and the ubiquitin and proteasome pathways, are affected by loss of coordination with host rhythms and by disruption of SR10. Our results reveal malaria parasites are at least partly responsible for scheduling the IDC and coordinating their development with host daily rhythms

Natural radionuclide of Po210 in the edible seafood affected by coal-fired power plant industry in Kapar coastal area of Malaysia

<p>Abstract</p> <p>Background</p> <p>Po²¹⁰can be accumulated in various environmental materials, including marine organisms, and contributes to the dose of natural radiation in seafood. The concentration of this radionuclide in the marine environment can be influenced by the operation of a coal burning power plant but existing studies regarding this issue are not well documented. Therefore, the aim of this study was to estimate the Po²¹⁰concentration level in marine organisms from the coastal area of Kapar, Malaysia which is very near to a coal burning power plant station and to assess its impact on seafood consumers.</p> <p>Methods</p> <p>Concentration of Po²¹⁰was determined in the edible muscle of seafood and water from the coastal area of Kapar, Malaysia using radiochemical separation and the Alpha Spectrometry technique.</p> <p>Results</p> <p>The activities of Po²¹⁰in the dissolved phase of water samples ranged between 0.51 ± 0.21 and 0.71 ± 0.24 mBql^-1whereas the particulate phase registered a range of 50.34 ± 11.40 to 72.07 ± 21.20 Bqkg^-1. The ranges of Po²¹⁰activities in the organism samples were 4.4 ± 0.12 to 6.4 ± 0.95 Bqkg^-1dry wt in fish (<it>Arius maculatus</it>), 45.7 ± 0.86 to 54.4 ± 1.58 Bqkg^-1dry wt in shrimp (<it>Penaeus merguiensis</it>) and 104.3 ± 3.44 to 293.8 ± 10.04 Bqkg^-1dry wt in cockle (<it>Anadara granosa</it>). The variation of Po²¹⁰in organisms is dependent on the mode of their life style, ambient water concentration and seasonal changes. The concentration factors calculated for fish and molluscs were higher than the recommended values by the IAEA. An assessment of daily intake and received dose due to the consumption of seafood was also carried out and found to be 2083.85 mBqday^-1person^-1and 249.30 μSvyr^-1respectively. These values are comparatively higher than reported values in other countries. Moreover, the transformation of Po²¹⁰in the human body was calculated and revealed that a considerable amount of Po²¹⁰can be absorbed in the internal organs. The calculated values of life time mortality and morbidity cancer risks were 24.8 × 10^-4and 34 × 10^-4respectively which also exceeded the recommended limits set by the ICRP.</p> <p>Conclusions</p> <p>The findings of this present study can be used to evaluate the safety dose uptake level of seafood as well as to monitor environmental health. However, as the calculated dose and cancer risks were found to cross the limit of safety, finding a realistic way to moderate the risk is imperative.</p

Interactive Responses of a Thalamic Neuron to Formalin Induced Lasting Pain in Behaving Mice

Thalamocortical (TC) neurons are known to relay incoming sensory information to the cortex via firing in tonic or burst mode. However, it is still unclear how respective firing modes of a single thalamic relay neuron contribute to pain perception under consciousness. Some studies report that bursting could increase pain in hyperalgesic conditions while others suggest the contrary. However, since previous studies were done under either neuropathic pain conditions or often under anesthesia, the mechanism of thalamic pain modulation under awake conditions is not well understood. We therefore characterized the thalamic firing patterns of behaving mice in response to nociceptive pain induced by inflammation. Our results demonstrated that nociceptive pain responses were positively correlated with tonic firing and negatively correlated with burst firing of individual TC neurons. Furthermore, burst properties such as intra-burst-interval (IntraBI) also turned out to be reliably correlated with the changes of nociceptive pain responses. In addition, brain stimulation experiments revealed that only bursts with specific bursting patterns could significantly abolish behavioral nociceptive responses. The results indicate that specific patterns of bursting activity in thalamocortical relay neurons play a critical role in controlling long-lasting inflammatory pain in awake and behaving mice

The worldwide NORM production and a fully automated gamma-ray spectrometer for their characterization

Materials containing radionuclides of natural origin, which is modified by human made processes and being subject to regulation because of their radioactivity are known as NORM. We present a brief review of the main categories of non-nuclear industries together with the levels of activity concentration in feed raw materials, products and waste, including mechanisms of radioisotope enrichments. The global management of NORM shows a high level of complexity, mainly due to different degrees of radioactivity enhancement and the huge amount of worldwide waste production. The future tendency of guidelines concerning environmental protection will require both a systematic monitoring based on the ever-increasing sampling and high performance of gamma ray spectroscopy. On the ground of these requirements a new low background fully automated high-resolution gamma-ray spectrometer MCA_Rad has been developed. The design of Pb and Cu shielding allowed to reach a background reduction of two order of magnitude with respect to laboratory radioactivity. A severe lowering of manpower cost is obtained through a fully automation system, which enables up to 24 samples to be measured without any human attendance. Two coupled HPGe detectors increase the detection efficiency, performing accurate measurements on sample volume (180 cc) with a reduction of sample transport cost of material. Details of the instrument calibration method are presented. MCA_Rad system can measure in less than one hour a typical NORM sample enriched in U and Th with some hundreds of Bq/kg, with an overall uncertainty less than 5%. Quality control of this method has been tested. Measurements of certified reference materials RGK-1, RGU-2 and RGTh-1 containing concentrations of K, U and Th comparable to NORM have been performed, resulting an overall relative discrepancy of 5% among central values within the reported uncertainty.Comment: 21 pages, 4 figures, 6 table

Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation

Severe pulmonary arterial hypertension, whether idiopathic or secondary, is characterized by structural alterations of microscopically small pulmonary arterioles. The vascular lesions in this group of pulmonary hypertensive diseases show actively proliferating endothelial cells without evidence of apoptosis. In this article, we review pathogenetic concepts of severe pulmonary arterial hypertension and explain the term "complex vascular lesion ", commonly named "plexiform lesion", with endothelial cell dysfunction, i.e., apoptosis, proliferation, interaction with smooth muscle cells and transdifferentiation