Ethanol and Phencyclidine Interact with Respect to Nucleus Accumbens Dopamine Release: Differential Effects of Administration Order and Pretreatment Protocol

Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP) injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP's effect was potentiated by ethanol (180% increase vs 150%). To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pretreated for 5 days with 2.58 mg/kg PCP according to previously used ‘PFC hypofunction protocols’. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this low PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1) or Glut3 (SLC2A3), monocarboxylate transporter MCT2 (SLC16A7), glutamate transporters GLT-1 (SLC1A2) or GLAST (SLC1A3), the immediate early gene Arc (Arg3.1) or GABAergic neuron markers GAT-1 (SLC6A1) and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration

Intake levels of dietary long-chain PUFAs modify the association between genetic variation in FADS and LDL-C

Polymorphisms of the FA desaturase (FADS) gene cluster have been associated with LDL, HDL, and triglyceride concentrations. Because FADS converts alpha-linolenic acid (ALA) and linoleic acid into PUFAs, we investigated the interaction between different PUFA intakes and the FADS polymorphism rs174547 (T>C) on fasting blood lipid and lipoprotein concentrations. We included 4,635 individuals (60% females, 45-68 years) from the Swedish population-based Malmo Diet and Cancer cohort. Dietary intakes were assessed by a modified diet history method including 7-day registration of cooked meals. The C-allele of rs174547 was associated with lower LDL concentration (P = 0.03). We observed significant interaction between rs174547 and long-chain omega-3 PUFA intakes on LDL (P = 0.01); the C-allele was only associated with lower LDL among individuals in the lowest tertile of long-chain omega-3 PUFA intakes (P < 0.001). In addition, significant interaction was observed between rs174547 and the ratio of ALA and linoleic FA intakes on HDL (P = 0.03). However, no significant associations between the C-allele and HDL were detected within the intake tertiles of the ratio. Our findings suggest that dietary intake levels of different PUFAs modify the associated effect of genetic variation in FADS on LDL and HDL.-Hellstrand, S., E. Sonestedt, U. Ericson, B. Gullberg, E. Wirfalt, B. Hedblad, and M. Orho-Melander. Intake levels of dietary PUFAs modify the association between genetic variation in FADS and LDL-C. J. Lipid Res. 2012. 53: 1183-1189

Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABAA Receptors

The flow of cortical information through the basal ganglia is a complex spatiotemporal pattern of increased and decreased firing. The striatum is the biggest input nucleus to the basal ganglia and the aim of this study was to assess the role of inhibitory GABAA and glycine receptors in regulating synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc). Local field potential recordings from coronal brain slices of juvenile and adult Wistar rats showed that GABAA receptors and strychnine-sensitive glycine receptors are tonically activated and inhibit excitatory input to the DLS and to the nAc. Strychnine-induced disinhibition of glutamatergic transmission was insensitive to the muscarinic receptor inhibitor scopolamine (10 μM), inhibited by the nicotinic acetylcholine receptor antagonist mecamylamine (10 μM) and blocked by GABAA receptor inhibitors, suggesting that tonically activated glycine receptors depress excitatory input to the striatum through modulation of cholinergic and GABAergic neurotransmission. As an end-product example of striatal GABAergic output in vivo we measured dopamine release in the DLS and nAc by microdialysis in the awake and freely moving rat. Reversed dialysis of bicuculline (50 μM in perfusate) only increased extrasynaptic dopamine levels in the nAc, while strychnine administered locally (200 μM in perfusate) decreased dopamine output by 60% in both the DLS and nAc. Our data suggest that GABAA and glycine receptors are tonically activated and modulate striatal transmission in a partially subregion-specific manner

Further characterization of the GlyT-1 inhibitor Org25935 : anti-alcohol, neurobehavioral, and gene expression effects

The glycine transporter-1 inhibitor Org25935 is a promising candidate in a treatment concept for alcohol use disorder targeting the glycine system. Org25935 inhibits ethanol-induced dopamine elevation in brain reward regions and reduces ethanol intake in Wistar rats. This study aimed to further characterise the compound and used ethanol consumption, behavioral measures, and gene expression as parameters to investigate the effects in Wistar rats and, as pharmacogenetic comparison, Alko-Alcohol (AA) rats. Animals were provided limited access to ethanol in a two-bottle free-choice paradigm with daily drug administration. Acute effects of Org25935 were estimated using locomotor activity and neurobehavioral status. Effects on gene expression in Wistar rats were measured with qPCR. The higher but not the lower dose of Org25935 reduced alcohol intake in Wistar rats. Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies). Neurobehavioral effects by Org25935 differed between the strains (AA-rats towards sedation). Org25935 did not affect gene expression at the mRNA level in the glycine system of Wistar rats. The data indicate a small therapeutic range for the anti-alcohol properties of Org25935, a finding that may guide further evaluations of the clinical utility of GlyT-1 inhibitors. The results point to the importance of pharmacogenetic considerations when developing drugs for alcohol-related medical concerns. Despite the lack of successful clinical outcomes, to date, the heterogeneity of drug action of Org25935 and similar agents and the unmet medical need justify further studies of glycinergic compounds in alcohol use disorder.Peer reviewe

Development of a diet quality index assessing adherence to the Swedish nutrition recommendations and dietary guidelines in the Malmö Diet and Cancer cohort.

OBJECTIVE: To develop a diet quality index (DQI) that assesses adherence to the Swedish nutrition recommendations (SNR) and the Swedish dietary guidelines (SDG). DESIGN: A cross-sectional study within the Malmö Diet and Cancer (MDC) cohort. A diet history method collected dietary data, a structured questionnaire lifestyle and socio-economic information, and anthropometric data were collected by direct measurements. The index (DQI-SNR) included six components: SFA, PUFA, fish and shellfish, dietary fibre, fruit and vegetables, and sucrose. SETTING: Malmö, Sweden. SUBJECTS: Men (n 4525) and women (n 8491) of the MDC cohort enrolled from September 1994 to October 1996. RESULTS: For participants with high DQI-SNR scores, nutrient and food intakes were close to recommendations. However, most of the study population exceeded the recommended intake for SFA (98 %) and few reached recommended intakes for dietary fibre (24 %), fruit and vegetables (32 %), vitamin D (18 %) and folate (2 %). A high DQI-SNR score was positively associated with age, physical activity, not smoking, past food habit change, education and socio-economic status. Individuals with high scores were more likely to have a diabetes diagnosis or experienced a cardiovascular event. CONCLUSIONS: Results suggest that the DQI-SNR is a useful tool for assessing adherence to the SNR 2005 and the SDG in the MDC cohort. No index has previously been developed with the aim of evaluating adherence to the current dietary recommendations in Sweden. Further validation of the DQI-SNR, and evaluation of its utility, is needed

Genetic variation in the fat mass and obesity-associated gene (FTO) in association with food preferences in healthy adults.

Earlier studies have indicated that the fat mass and obesity-associated gene (FTO) is not only associated with BMI and weight but also with appetite and dietary intake

A diabetes-predictive amino acid score and future cardiovascular disease.

AimsWe recently identified a metabolic signature of three amino acids (tyrosine, phenylalanine, and isoleucine) that strongly predicts diabetes development. As novel modifiable targets for intervention are needed to meet the expected increase of cardiovascular disease (CVD) caused by the diabetes epidemic, we investigated whether this diabetes-predictive amino acid score (DM-AA score) predicts development of CVD and its functional consequences.Methods and resultsWe performed a matched case-control study derived from the population-based Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC), all free of CVD. During 12 years of follow-up, 253 individuals developed CVD and were matched for age, sex, and Framingham risk score with 253 controls. Amino acids were profiled in baseline plasma samples, using liquid chromatography-tandem mass spectrometry, and relationship to incident CVD was assessed using conditional logistic regression. We further examined whether the amino acid score also correlated with anatomical [intima-media thickness (IMT) and plaque formation] and functional (exercise-induced myocardial ischaemia) abnormalities. Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for incident CVD in subjects belonging to quartiles 2, 3, and 4 was 1.27 (0.72-2.22), 1.96 (1.07-3.60), and 2.20 (1.12-4.31) (P(trend) = 0.010), respectively, after multivariate adjustment. Increasing quartile of the DM-AA score was cross-sectionally related to carotid IMT (P(trend) = 0.037) and with the presence of at least one plaque larger than 10 mm(2) (P(trend) = 0.001). Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for inducible ischaemia in subjects belonging to quartiles 2, 3, and 4 was 3.31 (1.05-10.4), 4.24 (1.36-13.3), and 4.86 (1.47-16.1) (P(trend) = 0.011), respectively.ConclusionThis study identifies branched-chain and aromatic amino acids as novel markers of CVD development and as an early link between diabetes and CVD susceptibility

Nuclear EMC Effect in a Statistical Model

A simple statistical model in terms of light-front kinematic variables is used to explain the nuclear EMC effect in the range $x \in [0.2,~0.7]$, which was constructed by us previously to calculate the parton distribution functions (PDFs) of the nucleon. Here, we treat the temperature $T$ as a parameter of the atomic number $A$, and get reasonable results in agreement with the experimental data. Our results show that the larger $A$, the lower $T$ thus the bigger volume $V$, and these features are consistent with other models. Moreover, we give the predictions of the quark distribution ratios, \emph{i.e.}, $q^A(x) / q^D(x)$, $\bar{q}^A(x) / \bar{q}^D(x)$, and $s^A(x) / s^D(x)$, and also the gluon ratio $g^A(x) / g^D(x)$ for iron as an example. The predictions are different from those by other models, thus experiments aiming at measuring the parton ratios of antiquarks, strange quarks, and gluons can provide a discrimination of different models.Comment: 26 latex pages, 3 figure

Microarray Analysis of Thyroid Stimulating Hormone, Insulin-Like Growth Factor-1, and Insulin-Induced Gene Expression in FRTL-5 Thyroid Cells

To determine which genes are regulated by thyroid stimulating hormone (thyrotropin, TSH), insulin and insulin-like growth factor-1 (IGF-1) in the rat thyroid, we used the microarray technology and observed the changes in gene expression. The expressions of genes for bone morphogenetic protein 6, the glucagon receptor, and cyclin D1 were increased by both TSH and IGF-1; for cytochrome P450, 2c37, the expression was decreased by both. Genes for cholecystokinin, glucuronidase, beta, demethyl-Q 7, and cytochrome c oxidase, subunit VIIIa, were up-regulated; the genes for ribosomal protein L37 and ribosomal protein L4 were down-regulated by TSH and insulin. However, there was no gene observed to be regulated by all three: TSH, IGF-1, and insulin molecules studied. These findings suggest that TSH, IGF-1, and insulin stimulate different signal pathways, which can interact with one another to regulate the proliferation of thyrocytes, and thereby provide additional influence on the process of cellular proliferation