(C) 2010 Elsevier B.V. All rights reserved.”
“Asymmetric ortho-lithiation of N-dialkyl-P, P-diphenylphosphinamides using [n-BuLi.(-)-sparteine] is described as an efficient method for the synthesis of P-chiral ortho-functionalized derivatives in high yields and ee’s from 45 to >99%. The Epigenetics inhibitor method allows access to new enantiomerically pure P-chiral phosphine and diimine ligands.”
“Background: Taking intraoperative frozen sections (FS) is a widely used procedure in oncologic surgery. However so far no evidence of an association of FS analysis and premalignant

changes in the surgical margin exists. Therefore, the aim of this study was to evaluate the impact of FS on different categories of the final margins of squamous cell carcinoma (SCC) of the oral cavity and lips.\n\nMethods: FS, pT-stage, grading, and tumor localization of 178 patients with SCC of the oral cavity and lips were compared by uni-and multivariate analysis in patients with positive, dysplastic and negative surgical margin status.\n\nResults: Performed on 111 patients (62.4%), intraoperative FS did not have any statistically significant influence on final margin status, independent of whether it was positive (p = 0.40), dysplastic (p = 0.70), or negative (p = 0.70). Positive surgical margins in permanent sections

were significantly associated with pT4-tumors (OR 5.61, p = 0.001). The chance for negative margins in permanent sections AZD1208 molecular weight was significantly higher in tumors located in the tongue (OR 4.70, p = 0.01).\n\nConclusions: Our data suggests that intraoperative FS in SCC can be useful in selected cases. However it is not advisable as a routine approach.”
“Background: Medication-overuse headache (MOH) is a chronic headache condition that results find more from the overuse of analgesics drugs, triptans,

or other antimigraine compounds. The epidemiology of drug-induced disorders suggests that medication overuse could lead to nephrotoxicity, particularly in chronic patients. The aim of this work was to confirm and extend the results obtained from a previous study, in which we analyzed the urinary proteome of 3 MOH patients groups: non-steroidal anti-inflammatory drugs (NSAIDs), triptans and mixtures abusers, in comparison with non-abusers individuals (controls).\n\nMethods: In the present work we employed specialized proteomic techniques, namely two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry (MS), and the innovative Surface-Enhanced Laser Desorption/Ionization Time-of-Flight mass spectrometry (SELDI-TOF-MS), to discover characteristic proteomic profiles associated with MOH condition.\n\nResults: By 2-DE and MS analysis we identified 21 over-excreted proteins in MOH patients, particularly in NSAIDs abusers, and the majority of these proteins were involved in a variety of renal impairments, as resulted from a literature search.

trans-Resveratrol and IS were detected using a triple-quadrupole mass spectrometer in the selective reaction monitoring (SRM) mode with the parent-to-product quantifier transitions [M-H](-) m/z 226.8 -> 142.9 and [M-H](-) m/z 252.9 -> 252.9 GKT137831 research buy for trans-resveratrol and IS, respectively. The method was confirmed to be accurate and precise with a linearity range of 0.1-500 ng mL(-1) with r > 0.99. Recoveries

for trans-resveratrol and IS were within 90-101%. The accuracy and precision for the assay were determined by calculating the intra- and inter-batch variation for quality control (QC) samples at four concentration levels with a relative standard deviation (RSD) of < 15%. This method was successfully applied to determine trans-resveratrol in rat plasma and proved suitable for pharmacokinetic study after intragastric administration of trans-resveratrol in sustained release granules and normal granules, respectively.”
“The brominated tryptophan-derived ent-eusynstyelamide B (1) and three new derivatives, eusynstyelamides

D, E, and F (2-4), were isolated from the Arctic bryozoan Tegella cf. spitzbergensis. The structures were elucidated by spectroscopic methods including 1D and 2D NMR and analysis of mass spectrometric data. The enantiomer of 1, eusynstyelamide Duvelisib cost 13; has previously been isolated from the Australian ascidian Eusynstyela latericius. Antimicrobial activities are here reported for 1-4, With minimum inhibitory concentrations (MIC) as low is 6.25 mu g/mL for 1 and 4 against Staphylococcus aureus. Eusynstyelamides 2 and 3 showed weak cytotoxic activity against the human melanoma A 2058 cell line.,”
“Since its inception, ChIP technology has evolved immensely. Technological advances have improved its specificity and sensitivity, its scale has expanded to a genome-wide level, and its relative ease of use has made it a virtually ubiquitous tool. This year marks the 25th anniversary of the development of ChIP. In honor of this milestone, we briefly

revisit its history, offer a review of recent articles employing ChIP on a genome-wide scale, and lay out our views for the future of ChIP. J. Cell. Biochem. 107: 6-10, 2009. (C) 2009 Wiley-Liss, this website Inc.”
“Interleukin-23 (IL-23) is a novel cytokine involved in the regulation of organ-specific immune responses. We hypothesized that expression of IL-23 in the human endometrium is menstrual cycle and pregnancy dependent, and is involved in endometrial immune regulation. IL-23 expression and regulation was investigated in the human endometrium and placenta in vivo using immunohistochemistry and in vitro using Western blot and cell viability analyses. IL-23 immunoreactivity in endometrial glandular cells was highest in the late proliferative and early secretory phases, as compared to other cycle phases and first trimester tissues.

More association studies are needed to further elucidate association of different HTR2C polymorphisms and antipsychotic-induced metabolic disturbance.”
“The role played by different mammal species in the maintenance

of Trypanosoma cruzi is not constant and varies in time and place. This study aimed to characterise the importance of domestic, wild and peridomestic hosts in the transmission of T. cruzi in Taua, state of Ceara, Caatinga area, Brazil, with an emphasis on those environments colonised by Triatoma brasiliensis. Direct parasitological examinations were performed on insects and mammals, serologic tests were performed on household and outdoor mammals and multiplex polymerase chain reaction was used on wild mammals. Cytochrome b

was used as a food source for wild insects. The serum prevalence in dogs was 38% (20/53), while in pigs it was 6% (2/34). The percentages of the most abundantly infected wild animals were as follows: INCB28060 nmr Thrichomys laurentius 74% (83/112) and Kerodon rupestris 10% (11/112). Of the 749 triatomines collected in the household research, 49.3% (369/749) were positive for T. brasiliensis, while 6.8% were infected with T. cruzi (25/369). In captured animals, T. brasiliensis shares a natural environment with T. laurentius, K. rupestris, Didelphis XMU-MP-1 in vitro albiventris, Monodelphis domestica, Galea spixii, Wiedomys pyrrhorhinos, Conepatus semistriatus and Mus musculus. In animals identified via their food source, T. brasiliensis shares a natural environment with G. spixii, K. rupestris, Capra hircus, Gallus gallus, Tropidurus oreadicus and Tupinambis merianae. The high prevalence of T. cruzi in household and peridomiciliar

animals reinforces the narrow relationship between the enzootic cycle and humans in environments with T. brasiliensis and characterises it as ubiquitous.”
“Introduction: Secondary intramedullary nailing (SIN) following external fixation (EF) of tibial shaft fracture is controversial, notably due to the infection risk, which is not precisely known. The present MI-503 mw study therefore analysed a continuous series of tibial shaft SIN, to determine (1) infection and union rates, and( 2) whether 1-stage SIN associated to EF ablation increased the risk of infection. Hypothesis: Factors exist for union and onset of infection following tibial shaft SIN. Materials and methods: A retrospective series of SIN performed between 1998 and 2012 in over 16-year-old patients with non-pathologic tibial shaft fracture was analysed. EF pin site infection was an exclusion criterion. Fractures were graded according to AO and Gustilo classifications. Study parameters were: time to SIN, 1-versus 2-stage procedure, bacteriologic results on reaming product, post-nailing onset of infection, and time to union. Results: Fifty-five patients (55 fractures) were included. There were 16 closed and 39 open fractures: 7 Gustilo type I, 26 type II and 6 type IIIA; 33 AO type A, 14 type B and 8 type C. Mean time to SIN was 9 +/- 9.

More recently, immunophenotypic and molecular analyses have begun to clarify the etiologic nature of these tumors. Recent evidence suggests that histopathologic features that suggest more aggressiveness in Spitz tumors relate to mitoses and inflammation. (J Am Acad Dermatol 2011;65:1073-84.)”
“Freeze-dried boneless skinless cubes of pink (Oncorhynchus gorbuscha), sockeye (Oncorhynchus

nerka), and chum (Oncorhynchus keta) salmon were prepared and physical properties evaluated. To minimize freeze-drying time, the kinetics of dehydration FG-4592 datasheet and processing yields were investigated. The physical characteristics of the final product including bulk density, shrinkage, hardness, color, and rehydration kinetics were determined. Results showed that freeze-dried salmon cubes from each of the 3 Pacific salmon U0126 cost species can be produced with a moisture content of less that 10% and a(w) less 0.4 and freeze-drying time of 9 h. Processing yields ranged from 26% to 28.4%, depending on fish species. Shrinkage was less than 12% and rehydration of freeze-dried cubes was rapid. The value-added products developed have the potential to be utilized as ingredients for ready-to-eat soups, as snack food, salad topping, and baby finger-food.”
“The genotoxic effect of dye effluents was assessed in indigenous

goats inhabiting textile industry areas encompassing dyeing and bleaching units by means of mitotic drive, mitotic index, chromosome aberrations and the mean SCEs frequency. Peripheral blood leucocyte cultures were set up with culture medium and pokeweed mitogen. The cultures were supplemented without bromodeoxyuridine (BrdU) for chromosome aberrations and with BrdU for the

mean SCEs frequency for 2 cell cycles. Air-dried slides were stained with Giemsa for chromosome aberrations and the fluorescent plus Giemsa (FPG) technique was adopted for the display of sister chromatid differentiation and the estimation of the mean SCEs frequency. No gross structural and numerical chromosome abnormalities were noticed in all animals screened based on G-banding and karyotyping. The mitotic drive for the control and exposed populations was 37.58 +/- 1.29 and 26.13 +/- 0.78%, respectively. The mitotic drive in exposed population was significantly (p<0.01) lower when compared to control animals. The mitotic index FG-4592 order for the control and exposed populations was 12.49 +/- 0.42 and 11.49 +/- 0.43%, respectively. Though there was a decrease in mitotic index in the exposed population, it was not statistically significant. The frequency of SCEs did not follow the Poisson distribution in both the control and exposed populations of goats. The pooled mean +/- S.E (range) of SCEs frequency for the control and exposed populations of goats were 4.83 +/- 0.16 (1-11) and 12.98 +/- 0.16 (8-19), respectively. There was significant (p<0.01) increase in the mean SCEs frequency of goats (exposed) reared in industrial areas.

Diffusional GW4869 order kurtosis imaging can provide additional and complementary information to DTI on spinal cord pathology.”
“Foot-and-mouth disease (FMD) is a highly contagious, debilitating, and globally significant viral disease typically affecting cloven-hoofed hosts. The diagnosis of FMD in bears in Vietnam is described. The current study describes a confirmed case of FMD in a bear species, and the clinical signs compatible with FMD in a Malayan sun bear.

Thirteen Asiatic black bears (Ursus thibetanus) and 1 Malayan sun bear (Helarctos malayanus) were apparently affected. In August 2011, an adult bear became lethargic, and developed footpad vesicles. Over 15 days, 14 out of 17 bears developed similar signs; the remaining 3 co-housed bears and another 57 resident bears did not. All affected bears developed vesicles on all footpads, and most were lethargic for 24-48 hr. Nasal and oral lesions were noted in 6 and 3 cases, respectively. Within 1 month, all looked normal. Foot-and-mouth disease virus (FMDV) was detected by reverse transcription polymerase chain reaction, classified as serotype O, and isolated by virus isolation techniques. Phylogenetic analysis find more demonstrated clustering of 3 bear isolates, in a branch distinct from other FMDV type O isolates. The outbreak likely occurred due to indirect contact with livestock,

and was facilitated by the high density of captive bears. It showed that Asiatic black bears are capable of contracting FMDV and developing clinical disease, and that the virus spreads easily between bears in close contact.”
“Controlled wear testing of total hip replacements in hip joint simulators is a well-established and powerful method, giving an extensive prediction of the long-term Rabusertib Cell Cycle inhibitor clinical performance. To understand the wear behavior of a bearing and its limits under in vivo conditions, testing scenarios should be designed as physiologically as possible. Currently, the ISO standard protocol 14242 is the most common preclinical testing procedure for total hip replacements, based on a simplified gait cycle for normal walking conditions. However, in recent years, wear patterns have increasingly

been observed on retrievals that cannot be replicated by the current standard. The purpose of this study is to review the severe testing conditions that enable the generation of clinically relevant wear rates and phenomena. These conditions include changes in loading and activity, third-body wear, surface topography, edge wear and the role of aging of the bearing materials.”
“The epidemiological transition has produced a society with a growing number of the elderly affected by multiple chronic diseases which often requires polypharmacy. Despite being the main users of medications, the elderly are largely underrepresented in clinical trials, especially if they have multimorbidity. It follows that the results of these trials are not applicable in the real world and potentially harmful.

In one case, urine concentrations were also determined to be 700 mu g/kg for mephedrone and 190 mu g/kg for hydroxytolyl-mephedrone. All compounds were detected or quantified with an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) system and an ultra performance liquid chromatography-time of flight/mass spectrometry (UPLC-TOF/MS) system. Copyright (c) 2012 John Wiley & Sons, AZD7762 nmr Ltd.”
“Objective Biotechnology has promoted the discovery and development of new types of therapeutical agents for use in humans: biotech drugs offer innovative, targeted

therapies with enormous potential to address unmet medical needs of patients with cancer, AIDS and other serious diseases. However, the therapeutic application of these novel therapies poses serious problems concerning the connection between cost sustainability and innovative value. The aims of the present study are to assess the level of therapeutic innovation of biotech drugs approved by the European Medicines Agency between 2004 and 2011, to make a comparison with the trend of biotech drugs approved between 1995-2003, as previously reported, and to evaluate their economic impact on the Italian healthcare system.\n\nMethods The data source used was the European Public Assessment Dorsomorphin PI3K/Akt/mTOR inhibitor Report (EPAR) of human medicines available on European Medicines

Agency (EMA) website. The scores for therapeutic innovation were assigned according to the algorithm created by Motola et al. Drug expenditure data was obtained from Information Management System-Health Italy database. The list of drugs under analysis was downloaded from European Medicines Agency website and information on approved drugs were retrieved from the

European Public Assessment Reports as well as from PubMed databank.\n\nResults From 2004 to 2011, the European Medicines Agency approved 47 biotech drugs: 43 biopharmaceutical innovators and 4 vaccines. Our analysis involved 33 of the 47 biotech drugs approved: 18 products resulted in important therapeutic innovations, 6 in moderate and 5 in modest therapeutic innovations, 2 in pharmacological innovations and finally, 2 involved ERK assay only technological innovations. We also evaluated the influence of biotech drugs and their different scores for innovation with regard to expenditure as well as consumption. In 2010 and in 2011, the major part of expenditure and consumption concerned biotech drugs classified as important therapeutic innovations, while moderate, modest, pharmacological and technological innovators revealed very reduced contributions in this regard.\n\nConclusions Our study revealed that 50% of biotech drugs approved between 2004-2011 represented an important or moderate therapeutic innovation.

Runx2, an osteoblast master transcription factor, is aberrantly expressed in PCa cells, and promotes

their metastatic phenotype. The transcriptional programs regulated by Runx2 have been extensively studied during osteoblastogenesis, where it activates or represses GNS-1480 nmr target genes in a context-dependent manner. However, little is known about the gene regulatory networks influenced by Runx2 in PCa cells. We therefore investigated genome wide mRNA expression changes in PCa cells in response to Runx2.\n\nResults: We engineered a C4-2B PCa sub-line called C4-2B/Rx2(dox), in which Doxycycline (Dox) treatment stimulates Runx2 expression from very low to levels observed in other PCa cells. Transcriptome profiling using whole genome expression array followed by in silico analysis indicated that Runx2 upregulated a multitude of genes with prominent cancer associated functions. They included secreted factors (CSF2, SDF-1), proteolytic enzymes compound screening assay (MMP9, CST7), cytoskeleton modulators (SDC2, Twinfilin, SH3PXD2A), intracellular signaling molecules (DUSP1, SPHK1, RASD1) and transcription factors (wSox9, SNAI2, SMAD3) functioning in epithelium to mesenchyme transition (EMT), tissue invasion, as well as homing and attachment to bone. Consistent with the gene expression data, induction of Runx2 in C4-2B cells enhanced their invasiveness. It also promoted cellular quiescence by blocking the G1/S phase transition during

cell cycle progression. Furthermore, the cell cycle block was reversed as Runx2 levels

declined after Dox withdrawal.\n\nConclusions: The effects of Runx2 in C4-2B/Rx2dox cells, as well as similar observations made by employing LNCaP, 22RV1 and PC3 cells, highlight multiple mechanisms by which Runx2 promotes the metastatic phenotype of PCa cells, including tissue invasion, homing to bone and induction of high bone turnover. Runx2 is therefore an attractive target for the development of novel diagnostic, prognostic and therapeutic approaches to PCa management. Targeting Runx2 may prove more effective than focusing on its individual PRT062607 clinical trial downstream genes and pathways.”
“Esophagus squamous cell carcinoma (ESCC) is one of the most deadly malignances because of its high frequency of metastasis. Given the associations of MUC1 with ESCC and tumor metastasis, we explored a potential role of MUC1 in ESCC metastasis. Among 40 ESCC and 20 paired normal tissue specimens examined, we found a significant increase of MUC1 expression in ESCC and more importantly, that expression of MUC1 and MMP13 are strongly correlated in patients who had lymph node metastasis. Studies with cell models indicated that overexpression of MUC1 upregulates the expression of MMP13, leading to increased cell migration. In support of a mode of transcriptional regulation, promoter analysis revealed that MUC1 stimulates MMP13 expression through the Runx-2-binding site.

\n\nResults. Eighty-five spine surgeons completed our survey, for a response rate of 84.1%. Most respondents (77.6%) were interested in working with an NPC

AZD6094 to screen patients with low back-related complaints referred for elective surgical assessment. Perception of suboptimal wait time for consultation and poor screening efficiency for surgical candidates were associated with greater surgeon interest in an NPC model of care. We achieved majority consensus regarding the core components for a low back-related complaints history and examination, and findings that would support surgical assessment. A majority of respondents (75.3%) agreed that they would be comfortable not assessing patients with low back-related complaints referred to their practice if indications for surgery were ruled out by an NPC.\n\nConclusion. The majority of Canadian spine surgeons were open to an NPC model of care to assess and triage nonurgent or emergent low back-related complaints. Clinical trials to establish the effectiveness and acceptance of this website an NPC model of care

by all stakeholders are urgently needed.”
“Synthesis and characterization of Cu0.5Tl0.5Ba2(Ca2-yMgy)(Cu0.5Zn2.5)O10-delta (y=0, 1.0, and 1.5) superconductor with 0%, 50%, and 75% Mg-doping at the Ca sites are reported. The samples were synthesized by solid-state reaction and characterized by X-ray diffraction (XRD), dc-resistivity (rho) and fluctuation induced conductivity (FIC) analysis. The zero resistivity critical temperature Protein Tyrosine Kinase inhibitor T-c(R=0) was decreased with the increase of Mg-doping at Ca sites. The microscopic parameters such as the cross-over temperature (T-o), zero temperature coherence length xi(c)(0) and interlayer coupling (J) were deduced

from FIC analysis. According to Aslamazov Larkin equations, a distinct cross-over temperature (T-o1) from three-dimensional (3D) to two-dimensional (2D) fluctuation induced conductivity regions was observed in all samples. Another crossover temperature (T-o2) from 2D to zero-dimensional (0D) fluctuations was also witnessed. FIC analysis revealed the deterioration of superconductivity with increased Mg-content. (C) 2013 Elsevier Ltd and Techna Group S.r.l. All rights reserved.”
“The probiotic properties of two selected lactobacilli strains were assessed. L. salivarius and L. plantarum displayed higher hydrophobicity (48% and 54%, resp.) and coaggregation ability with four pathogens (from 7.9% to 57.5%). L. salivarius and L. plantarum had good inhibitory effects on S. aureus (38.2% and 49.5%, resp.) attachment to Caco-2 cells.

We identify the G protein-coupled receptor (GPCR) T1R1/T1R3 as a direct sensor of the fed state and amino acid availability. Knocking Quizartinib down this receptor, which is found in most tissues, reduces the ability of amino acids to signal to mTORC1. Interfering with this receptor alters localization of mTORC1, downregulates expression of pathway inhibitors, upregulates key amino acid transporters, blocks translation initiation, and induces autophagy. These findings reveal a mechanism for communicating amino acid availability through a GPCR to mTORC1 in mammals.”
“Although

there are several studies describing bacteria associated with marine fish, the bacterial composition associated with seahorses has not been extensively investigated since these studies have been restricted to the identification of bacterial pathogens. In this study, the phylogenetic affiliation of seahorse-associated bacteria was assessed by 16S rRNA

gene sequencing of cloned DNA fragments. Fluorescence in situ hybridization (FISH) was used to confirm the presence of the predominant groups indicated by 16S rRNA analysis. Both methods revealed that Vibrionaceae was the dominant GSK2879552 mouse population in Artemia sp. (live prey) and intestinal content of the seahorses, while Rhodobacteraceae was dominant in water samples from the aquaculture system and cutaneous mucus of the seahorses. To our knowledge, this is the first time that bacterial communities associated with healthy seahorses in captivity have been described. Crown Copyright (C) 2010 Published by Elsevier GmbH. All rights reserved.”
“The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis. Enhanced intracellular survival (Eis) protein, secreted by Mtb, enhances

survival of Mycobacterium smegmatis (Msm) in macrophages. Mtb Eis was shown to suppress host immune defenses by negatively modulating autophagy, inflammation, and cell death through JNK-dependent inhibition of reactive oxygen species (ROS) generation. Mtb Eis was recently demonstrated to contribute to drug resistance by acetylating multiple amines of aminoglycosides. However, the mechanism of enhanced intracellular survival by Mtb Eis remains unanswered. Therefore, we have characterized both Mtb and Msm Eis proteins biochemically and structurally. We have discovered Pexidartinib concentration that Mtb Eis is an efficient N-epsilon-acetyltransferase, rapidly acetylating Lys55 of dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7), a JNK-specific phosphatase. In contrast, Msm Eis is more efficient as an N alpha-acetyltransferase. We also show that Msm Eis acetylates aminoglycosides as readily as Mtb Eis. Furthermore, Mtb Eis, but not Msm Eis, inhibits LPS-induced JNK phosphorylation. This functional difference against DUSP16/MKP-7 can be understood by comparing the structures of two Eis proteins.

Design The antiviral activity of curcumin and its derivatives was evaluated using HCV pseudo-particles (HCVpp) and cell-culture-derived HCV (HCVcc) in hepatoma cell lines and primary human hepatocytes. The mechanism of action was dissected using R18-labelled virions and a membrane fluidity assay.

Results Curcumin treatment had no effect on HCV RNA replication or viral assembly/release. However, co-incubation of HCV with curcumin potently inhibited entry of all major HCV genotypes. Similar antiviral activities were also exerted by other curcumin derivatives but not by tetrahydrocurcumin, 4SC-202 order suggesting the importance of alpha,beta-unsaturated ketone groups for the antiviral activity. Expression levels of known HCV receptors were unaltered, www.selleckchem.com/products/10058-f4.html while pretreating the virus with the compound reduced viral infectivity without viral lysis.

Membrane fluidity experiments indicated that curcumin affected the fluidity of the HCV envelope resulting in impairment of viral binding and fusion. Curcumin has also been found to inhibit cell-to-cell transmission and to be effective in combination with other antiviral agents. Conclusions Turmeric curcumin inhibits HCV entry independently of the genotype and in primary human hepatocytes by affecting membrane fluidity thereby impairing virus binding and fusion.”
“Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. Wedemonstrate that both dopamine D1- and D2- receptor- ZD1839 nmr expressing MSNs (D- MSNs) additionally harbor extrasynaptic GABA(A)Rs incorporating alpha 4, beta, and delta subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Boththe selective delta-GABA(A) RagonistTHIPandDS2, aselective positive allostericmodulator, greatlyincreasedthe toniccurrentof allMSNsfrom wild- type (WT), but not from delta(-/-) or alpha 4(-/-) mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1- MSNs but not D2- MSNs. In contrast, prolonged D2 receptor activationmodestlyreducedthe

tonicconductanceof D2-MSNs. Behaviorally, WTandconstitutive alpha 4(-/)-micedidnotdiffer in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the alpha 4 deletion specific to D1-expressing neurons (alpha 4(D1-/-)) showed increased CPP. Furthermore, THIP administered systemically or directly into theNAcofWT, but not alpha 4(-/)-or alpha 4D1(-/)-mice, blocked cocaine enhancement of CPP. In comparison, alpha 4(D2-/)-mice exhibited normal CPP, but no cocaine enhancement. In conclusion, dopamine modulation of GABAergic tonic inhibition of D1- and D2-MSNs provides an intrinsic mechanism to differentially affect their excitability in response to psychostimulants and thereby influence their ability to potentiate conditioned reward.