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1.  Variation in low food access areas due to data source inaccuracies 
Applied geography (Sevenoaks, England)  2013;45:10.1016/j.apgeog.2013.08.014.
Several spatial measures of community food access identifying so called “food deserts” have been developed based on geospatial information and commercially-available, secondary data listings of food retail outlets. It is not known how data inaccuracies influence the designation of Census tracts as areas of low access. This study replicated the U.S. Department of Agriculture Economic Research Service (USDA ERS) food desert measure and the Centers for Disease Control and Prevention (CDC) non-healthier food retail tract measure in two secondary data sources (InfoUSA and Dun & Bradstreet) and reference data from an eight-county field census covering169 Census tracts in South Carolina. For the USDA ERS food deserts measure accuracy statistics for secondary data sources were 94% concordance, 50–65% sensitivity, and 60–64% positive predictive value (PPV). Based on the CDC non-healthier food retail tracts both secondary data demonstrated 88–91% concordance, 80–86% sensitivity and 78–82% PPV. While inaccuracies in secondary data sources used to identify low food access areas may be acceptable for large-scale surveillance, verification with field work is advisable for local community efforts aimed at identifying and improving food access.
PMCID: PMC3869099  PMID: 24367136
food environment; food desert; policy; field census; infoUSA; Dun & Bradstreet
2.  Characterizing the Food Retail Environment: Impact of Count, Type and Geospatial Error in Two Secondary Data Sources 
Commercial listings of food retail outlets are increasingly used by community members, food policy councils, and in multi-level intervention research to identify areas with limited access to healthier food. This study quantified the amount of count, type and geospatial error in two commercial data sources.
InfoUSA and Dun & Bradstreet (D&B) were compared to a validated field census and validity statistics calculated.
Considering only completeness, D&B data undercounted 24% of existing supermarkets and grocery stores and InfoUSA 29%. Additionally, considering accuracy of outlet type assignment increased the undercount error to 42% and 39%, respectively. Marked overcount existed as well and only 43% of existing supermarkets were correctly identified with respect to presence, outlet type, and location.
Conclusions and Implications
Relying exclusively on secondary data to characterize the food environment will result in substantial error. While extensive data cleaning can offset some error, verification of outlets with a field census is still the method of choice.
PMCID: PMC3713101  PMID: 23582231
retail food environment; secondary data sources; validity; geography
3.  Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia 
Autosomal recessive hypercholesterolemia (ARH) is a rare inherited disorder characterized by extremely high total and low-density lipoprotein cholesterol levels that has been previously linked to mutations in LDLRAP1. We identified a family with ARH not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular etiology of ARH in this family.
Approach and Results
We used exome sequencing to assess all protein coding regions of the genome in three family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Since homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease (CESD), we performed directed follow-up phenotyping by non-invasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of CESD. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27,000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance.
By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent CESD in the affected individuals from this kindred and addressed an outstanding question regarding risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.
PMCID: PMC4002172  PMID: 24072694
hypercholesterolemia; genetics; myocardial infarction
4.  Test-retest reliability of a questionnaire measuring perceptions of neighborhood food environment 
Health & place  2013;21:65-69.
There is a lack of validated and reliable instruments on perception of the food environment, in particular for rural environments. We estimated the test-retest reliability of a questionnaire assessing perceptions of the food environment. A total of 101 primary food shoppers in South Carolina were interviewed by phone to assess their perceptions of the food environment and presence of different food outlet types in their neighborhood. The survey was repeated approximately one month after the initial administration. The intra-class correlation (ICC) and Phi coefficient are reported as measures of reliability. The majority of questions on perceptions of the neighborhood food environment appear highly reliable (ICCs range from 0.55 to 0.71), including the 3-item scale on healthy food availability (ICC 0.71). Compared to participants in rural areas, those in urban areas demonstrated better reliability for questions on opportunities to purchase fast food and perceived presence of a supercenter. More research is needed to evaluate potential rural-urban differences in reliability.
PMCID: PMC3634345  PMID: 23434497
5.  Availability of physical activity resources in the environment for adults with intellectual disabilities 
Disability and Health Journal  2011;5(1):41-48.
Adults with intellectual disabilities (ID) have high rates of physical inactivity, yet little is known about the prevalence of facilitators and barriers in the built environment contributing to these high rates.
To describe the physical activity resources available to adults with ID in both the home and day programs outside of the home.
Demographic information was collected on a sample of adults with ID. A survey checklist of the physical activity environment at the participants’ home and the facility or workplace where the participant spent his/her weekdays was collected by trained research staff. Differences in the prevalence of environmental resources between those living in group homes and those living alone or with family were tested using χ2 tests.
A total of 103 participants had complete demographic and environmental data. Of these, only 37.9% had exercise equipment available, 39.8% had sports equipment, and 15.5% had a bicycle in the home environment. At the facility where the individual attended a day program or where the individual was employed, 55.4 had sports equipment, 50.5% had an outdoor recreation area, 41.8% had an indoor recreation area, and 41.8 had organized physical activities. Those who lived in group homes were more likely to have access to basketball hoops, sports fields, and recreation centers than those who lived alone or with family (p < .01).
Adults with ID have few physical activity environmental resources and opportunities available to them, especially those not living in group homes. Future interventions are needed to increase physical activity opportunities in this underserved population.
PMCID: PMC3319065  PMID: 22226297
Physical activity; Environment; Intellectual disabilities
Hypertension  2011;58(6):1073-1078.
Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in four cohorts of 1611 white European families comprising a total of 8199 individuals, we undertook staged testing of candidate SNPs for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes as well as expression of SCNN1G in human kidneys. We found that an intronic SNP of SCNN1G (rs13331086) was significantly associated with age-, sex- and BMI-adjusted blood pressure in each of the four populations (P < 0.05). In an inverse variance-weighted meta-analysis of this SNP in all four populations each additional minor allele copy was associated with a 1 mmHg increase in systolic blood pressure and 0.52 mmHg increase in diastolic blood pressure (SE = 0.33, P = 0.002 for SBP; SE = 0.21, P = 0.011 for DBP). The same allele was also associated with higher 12-h overnight urinary potassium excretion (P = 0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a non-significant (P = 0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.
PMCID: PMC3220739  PMID: 22006290
blood pressure; genetics; meta-analysis; risk factors; cardiovascular diseases
7.  Representation of motion onset and offset in an augmented Barlow-Levick model of motion detection 
Kinetic occlusion produces discontinuities in the optic flow field, whose perception requires the detection of an unexpected onset or offset of otherwise predictably moving or stationary contrast patches. Many cells in primate visual cortex are directionally selective for moving contrasts, and recent reports suggest that this selectivity arises through the inhibition of contrast signals moving in the cells’ null direction, as in the rabbit retina. This nulling inhibition circuit (Barlow-Levick) is here extended to also detect motion onsets and offsets. The selectivity of extended circuit units, measured as a peak evidence accumulation response to motion onset/offset compared to the peak response to constant motion, is analyzed as a function of stimulus speed. Model onset cells are quiet during constant motion, but model offset cells activate during constant motion at slow speeds. Consequently, model offset cell speed tuning is biased towards higher speeds than onset cell tuning, similarly to the speed tuning of cells in the middle temporal area when exposed to speed ramps. Given a population of neurons with different preferred speeds, this asymmetry addresses a behavioral paradox—why human subjects in a simple reaction time task respond more slowly to motion offsets than onsets for low speeds, even though monkey neuron firing rates react more quickly to the offset of a preferred stimulus than to its onset.
PMCID: PMC3484280  PMID: 22528025
Acceleration; Accretion and deletion; Occlusion; Visual cortex; Visual motion
8.  Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome 
Lancet  2012;379(9819):915-922.
A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.
We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.
Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.
The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.
British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.
PMCID: PMC3314981  PMID: 22325189
9.  FGF21 signalling pathway and metabolic traits – genetic association analysis 
European Journal of Human Genetics  2010;18(12):1344-1348.
Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol – LDL-C, HDL-cholesterol – HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.
PMCID: PMC2988092  PMID: 20717167
fibroblast growth factor 21; fibroblast growth factor receptor 2; cholesterol; single-nucleotide polymorphism; genome-wide association studies
10.  Large-scale association analyses identifies 13 new susceptibility loci for coronary artery disease 
Schunkert, Heribert | König, Inke R. | Kathiresan, Sekar | Reilly, Muredach P. | Assimes, Themistocles L. | Holm, Hilma | Preuss, Michael | Stewart, Alexandre F. R. | Barbalic, Maja | Gieger, Christian | Absher, Devin | Aherrahrou, Zouhair | Allayee, Hooman | Altshuler, David | Anand, Sonia S. | Andersen, Karl | Anderson, Jeffrey L. | Ardissino, Diego | Ball, Stephen G. | Balmforth, Anthony J. | Barnes, Timothy A. | Becker, Diane M. | Becker, Lewis C. | Berger, Klaus | Bis, Joshua C. | Boekholdt, S. Matthijs | Boerwinkle, Eric | Braund, Peter S. | Brown, Morris J. | Burnett, Mary Susan | Buysschaert, Ian | Carlquist, Cardiogenics, John F. | Chen, Li | Cichon, Sven | Codd, Veryan | Davies, Robert W. | Dedoussis, George | Dehghan, Abbas | Demissie, Serkalem | Devaney, Joseph M. | Do, Ron | Doering, Angela | Eifert, Sandra | El Mokhtari, Nour Eddine | Ellis, Stephen G. | Elosua, Roberto | Engert, James C. | Epstein, Stephen E. | Faire, Ulf de | Fischer, Marcus | Folsom, Aaron R. | Freyer, Jennifer | Gigante, Bruna | Girelli, Domenico | Gretarsdottir, Solveig | Gudnason, Vilmundur | Gulcher, Jeffrey R. | Halperin, Eran | Hammond, Naomi | Hazen, Stanley L. | Hofman, Albert | Horne, Benjamin D. | Illig, Thomas | Iribarren, Carlos | Jones, Gregory T. | Jukema, J.Wouter | Kaiser, Michael A. | Kaplan, Lee M. | Kastelein, John J.P. | Khaw, Kay-Tee | Knowles, Joshua W. | Kolovou, Genovefa | Kong, Augustine | Laaksonen, Reijo | Lambrechts, Diether | Leander, Karin | Lettre, Guillaume | Li, Mingyao | Lieb, Wolfgang | Linsel-Nitschke, Patrick | Loley, Christina | Lotery, Andrew J. | Mannucci, Pier M. | Maouche, Seraya | Martinelli, Nicola | McKeown, Pascal P. | Meisinger, Christa | Meitinger, Thomas | Melander, Olle | Merlini, Pier Angelica | Mooser, Vincent | Morgan, Thomas | Mühleisen, Thomas W. | Muhlestein, Joseph B. | Münzel, Thomas | Musunuru, Kiran | Nahrstaedt, Janja | Nelson, Christopher P. | Nöthen, Markus M. | Olivieri, Oliviero | Patel, Riyaz S. | Patterson, Chris C. | Peters, Annette | Peyvandi, Flora | Qu, Liming | Quyyumi, Arshed A. | Rader, Daniel J. | Rallidis, Loukianos S. | Rice, Catherine | Rosendaal, Frits R. | Rubin, Diana | Salomaa, Veikko | Sampietro, M. Lourdes | Sandhu, Manj S. | Schadt, Eric | Schäfer, Arne | Schillert, Arne | Schreiber, Stefan | Schrezenmeir, Jürgen | Schwartz, Stephen M. | Siscovick, David S. | Sivananthan, Mohan | Sivapalaratnam, Suthesh | Smith, Albert | Smith, Tamara B. | Snoep, Jaapjan D. | Soranzo, Nicole | Spertus, John A. | Stark, Klaus | Stirrups, Kathy | Stoll, Monika | Tang, W. H. Wilson | Tennstedt, Stephanie | Thorgeirsson, Gudmundur | Thorleifsson, Gudmar | Tomaszewski, Maciej | Uitterlinden, Andre G. | van Rij, Andre M. | Voight, Benjamin F. | Wareham, Nick J. | Wells, George A. | Wichmann, H.-Erich | Wild, Philipp S. | Willenborg, Christina | Witteman, Jaqueline C. M. | Wright, Benjamin J. | Ye, Shu | Zeller, Tanja | Ziegler, Andreas | Cambien, Francois | Goodall, Alison H. | Cupples, L. Adrienne | Quertermous, Thomas | März, Winfried | Hengstenberg, Christian | Blankenberg, Stefan | Ouwehand, Willem H. | Hall, Alistair S. | Deloukas, Panos | Thompson, John R. | Stefansson, Kari | Roberts, Robert | Thorsteinsdottir, Unnur | O’Donnell, Christopher J. | McPherson, Ruth | Erdmann, Jeanette | Samani, Nilesh J.
Nature genetics  2011;43(4):333-338.
We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
PMCID: PMC3119261  PMID: 21378990
11.  FGF21 signalling pathway and metabolic traits - genetic association analysis 
Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGF receptor 2 (FGFR2) and FGF receptor 3 (FGFR3). We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage we examined associations between 63 common single nucleotide polymorphisms (SNPs) in 5 genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and 4 metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol, triglycerides and body mass index - BMI) in 629 individuals from Silesian Hypertension Study. Replication analyses were performed in 5,478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3,030 directly genotyped individuals of the German Myocardial Infarction Family Study. Of 54 SNPs that met quality control criteria after genotyping in Silesian Hypertension Study, four (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (p=0.0006, p=0.0013, p=0.0055, p=0.011, respectively) and one (rs2608819 in KLB) was associated with BMI (p=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both the CoLaus cohort (p=0.009) and men from the German Myocardial Infarction Family Study (p=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variation in FGFR2 may be associated with LDL-C in subjects of white European ancestry.
PMCID: PMC2988092  PMID: 20717167
fibroblast growth factor 21; fibroblast growth factor receptor 2; cholesterol; single nucleotide polymorphism; genome-wide association studies
12.  Validation of 3 Food Outlet Databases: Completeness and Geospatial Accuracy in Rural and Urban Food Environments 
American Journal of Epidemiology  2010;172(11):1324-1333.
Despite interest in the built food environment, little is known about the validity of commonly used secondary data. The authors conducted a comprehensive field census identifying the locations of all food outlets using a handheld global positioning system in 8 counties in South Carolina (2008–2009). Secondary data were obtained from 2 commercial companies, Dun & Bradstreet, Inc. (D&B) (Short Hills, New Jersey) and InfoUSA, Inc. (Omaha, Nebraska), and the South Carolina Department of Health and Environmental Control (DHEC). Sensitivity, positive predictive value, and geospatial accuracy were compared. The field census identified 2,208 food outlets, significantly more than the DHEC (n = 1,694), InfoUSA (n = 1,657), or D&B (n = 1,573). Sensitivities were moderate for DHEC (68%) and InfoUSA (65%) and fair for D&B (55%). Combining InfoUSA and D&B data would have increased sensitivity to 78%. Positive predictive values were very good for DHEC (89%) and InfoUSA (86%) and good for D&B (78%). Geospatial accuracy varied, depending on the scale: More than 80% of outlets were geocoded to the correct US Census tract, but only 29%–39% were correctly allocated within 100 m. This study suggests that the validity of common data sources used to characterize the food environment is limited. The marked undercount of food outlets and the geospatial inaccuracies observed have the potential to introduce bias into studies evaluating the impact of the built food environment.
PMCID: PMC2991633  PMID: 20961970
environment; food; geography; reproducibility of results; residence characteristics
13.  A common variant in low density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol 
A rare mutation in low density lipoprotein receptor-related protein 6 gene (LRP6) was identified as the primary molecular defect underlying monogenic form of coronary artery disease. We hypothesised that common variants in LRP6 could predispose subjects to elevated LDL-cholesterol (LDL-C).
Methods and Results
12 common (minor allele frequency ≥0.1) single nucleotide polymorphisms in LRP6 were genotyped in 703 individuals from 213 Polish pedigrees (Silesian Cardiovascular Study families). The family-based analysis revealed that the minor allele of rs10845493 clustered with elevated LDL-C in offspring more frequently than expected by chance (p=0.0053). The quantitative analysis restricted to subjects free of lipid-lowering treatment confirmed the association between rs10845493 and age-, sex- and BMI-adjusted circulating levels of LDL-C in families as well as 2 additional populations - 218 unrelated subjects from Silesian Cardiovascular Study replication panel and 1138 individuals from Young Men Cardiovascular Association cohort (p=0.0268, p=0.0476 and p=0.0472, respectively). In the inverse variance weighted meta-analysis of the 3 populations each extra minor allele copy of rs10845493 was associated with 0.14 mmol/L increase in age-, sex- and BMI-adjusted LDL-C (SE=0.05, p=0.0038).
Common polymorphism in the gene underlying monogenic form of coronary artery disease impacts on risk of LDL-C elevation.
PMCID: PMC2814817  PMID: 19667113
gene; genetics; LDL-cholesterol; lipids; association
14.  Pharmacological profiles of presynaptic nociceptin/orphanin FQ receptors modulating 5-hydroxytryptamine and noradrenaline release in the rat neocortex 
British Journal of Pharmacology  2003;138(1):91-98.
The pharmacological profiles of presynaptic nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) modulating 5-hydroxytryptamine (5-HT) and noradrenaline (NE) release in the rat neocortex were characterized in a preparation of superfused synaptosomes challenged with 10 mM KCl.N/OFQ concentration-dependently inhibited K+-evoked [3H]-5-HT and [3H]-NE overflow with similar potency (pEC50 ∼7.9 and ∼7.7, respectively) and efficacy (maximal inhibition ∼40%).N/OFQ (0.1 μM) inhibition of [3H]-5-HT and [3H]-NE overflow was antagonized by selective NOP receptor antagonists of peptide ([Nphe1]N/OFQ(1-13)NH2 and UFP-101; 10 and 1 μM, respectively) and non-peptide (J-113397 and JTC-801; both 0.1 μM) nature. Antagonists were routinely applied 3 min before N/OFQ. However, a 21 min pre-application time was necessary for J-113397 and JTC-801 to prevent N/OFQ inhibition of [3H]-NE overflow.The NOP receptor ligand [Phe1ψ(CH2-NH)Gly2]N/OFQ(1-13)NH2 ([F/G]N/OFQ(1-13)NH2; 3 μM) did not affect K+-evoked [3H]-NE but inhibited K+-evoked [3H]-5-HT overflow in a UFP-101 sensitive manner. [F/G]N/OFQ(1-13)NH2 antagonized N/OFQ actions on both neurotransmitters.The time-dependency of JTC-801 action was studied in CHO cells expressing human NOP receptors. N/OFQ inhibited forskolin-stimulated cAMP accumulation and JTC-801, tested at different concentrations (0.1–10 μM) and pre-incubation times (0, 40 and 90 min), antagonized this effect in a time-dependent manner. The Schild-type analysis excluded a competitive type of antagonism.We conclude that presynaptic NO receptors inhibiting 5-HT and NE release in the rat neocortex have similar pharmacological profiles. Nevertheless, they can be differentiated pharmacologically on the basis of responsiveness to [F/G]N/OFQ(1-13)NH2 and time-dependent sensitivity towards non-peptide antagonists.
PMCID: PMC1573632  PMID: 12522077
[F/G]N/OFQ(1-13)NH2; J-113397; JTC-801; 5-hydroxytryptamine; nociceptin/orphanin FQ; noradrenaline; [Nphe1]N/OFQ(1-13NH2; release; synaptosomes; UFP-101

Results 1-14 (14)