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Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3–10mg/kg) did not produce alcohol-like stimulus effects. However, pretreatment with LY379268 (1 and 3mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1g/kg). Systemic LY379268 (3mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6μg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3μg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1μg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.
Drugs of abuse share the common attribute that they produce distinct subjective or interoceptive effects. In both humans and animals, these interoceptive drug effects can serve as discriminative stimuli, such that the subject uses these interoceptive cues to distinguish between drug and non-drug conditions. In addition to reinforcement processes, these discriminative stimulus effects represent a major controlling process of drug seeking behavior (Stolerman, 1992; Wise et al, 2008). To date, there is a growing interest in the role of metabotropic glutamate receptors, subtypes 2 and 3 (mGlu2/3), in modulating drug taking and seeking behavior. For example, systemic administration of mGlu2/3 receptor agonists has been shown to inhibit cocaine and nicotine self-administration (Baptista et al, 2004; Adewale et al, 2006; Liechti et al, 2007). In relation to alcohol, systemic mGlu2/3 receptor activation can reduce alcohol self-administration (Backstrom and Hyytia, 2005; Sidhpura and Weiss, 2010; but see Rodd et al, 2006) and relapse-like behavior (Rodd et al, 2006; Zhao et al, 2006; Sidhpura and Weiss, 2010). However, the potential role of mGlu2/3 receptors in regulating the discriminative stimulus effects of alcohol has not been examined.
mGlu2/3 receptors are members of the group II family of mGluRs. These Gi-coupled receptors function as autoreceptors; regulating presynaptic neurotransmitter release (Baskys and Malenka, 1991; Liu et al, 1993; Macek et al, 1996; Marek et al, 2000; Molinaro et al, 2009; Farazifard and Wu, 2010). As such, activation of mGlu2/3 receptors decreases the synaptic availability of glutamate, allowing for 'refinement' of glutamatergic neurotransmission (Schoepp, 2001; Pinheiro and Mulle, 2008). Given the functional role of mGlu2/3 receptors in modulating glutamate release and that the discriminative stimulus effects of alcohol are generally characterized by processes that reduce/inhibit glutamatergic neurotransmission (Kostowski and Bienkowski, 1999), such that N-methyl--aspartic acid (NMDA) antagonists and γ-aminobutyric acid type A (GABAA)-positive modulators produce alcohol-like discriminative stimulus effects (Jarbe and McMillan, 1983; Schechter et al, 1993; Ator et al, 1993; Bienkowski et al, 1997; Hundt et al, 1998; Grant et al, 2000; Shelton and Grant, 2002; Vivian et al, 2002; Helms et al, 2009), we hypothesized that mGlu2/3 receptors may have a modulatory role in the expression of the discriminative stimulus effects of alcohol. Further support for this hypothesis comes from studies showing that mGlu2/3 receptors are highly expressed in limbic brain regions (Petralia et al, 1996; Ohishi et al, 1998; Ferraguti and Shigemoto, 2006) known to modulate the discriminative stimulus effects of alcohol, such as the nucleus accumbens and the amygdala (Hodge and Aiken, 1996; Hodge and Cox, 1998; Hodge et al, 2001; Besheer et al, 2003).
Accordingly, the purpose of this study was to examine the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. Male Long-Evans rats were trained to discriminate between a moderate dose of alcohol (1g/kg) and water administered orally by gavage (IG) on a well-characterized two lever drug discrimination task. We first examined whether systemic pharmacological activation of mGlu2/3 receptors by LY379268, a selective mGlu2/3 receptor agonist (Monn et al, 1999), produces alcohol-like discriminative stimulus effects and/or modulates the discriminative stimulus effects of alcohol. Next, we sought to identify whether mGlu2/3 receptor activation is associated with changes in neuronal activity in specific brain regions as measured by c-Fos immunoreactivity (IR) using immunohistochemistry techniques. Finally, guided by the anatomical specificity of those results, discrimination-trained rats were implanted with bilateral cannulae aimed at the amygdala and nucleus accumbens (anatomical control) for site-specific LY379268 administration to directly assess the functional role of mGlu2/3 receptor activation within these regions in modulating the expression of the discriminative stimulus effects of alcohol.
Male Long-Evans rats (Harlan Sprague Dawley, Indianapolis, IN) were individually housed in Plexiglas cages. Before training, male rats were weighed and handled daily. Food intake was restricted to approximately 16g of food/day to maintain body weight (325–340g). Water was available ad libitum in the home cage unless noted. The colony room was maintained on a 12-h light/dark cycle. Experiments were conducted during the light cycle (between 0800 and 1100 hours). Animals were under continuous care and monitoring by veterinary staff from the Division of Laboratory Animal Medicine at UNC-Chapel Hill. All procedures were conducted in accordance with the NIH Guide to Care and Use of Laboratory Animals and institutional guidelines.
Rats were trained to lever press on a fixed ratio 1 (FR1) schedule of sucrose (10% (w/v)) reinforcement in operant conditioning chambers (Med Associates, Georgia, VT). A single lever (left or right) was present on alternating training days as the FR schedule was gradually increased to FR10. Alcohol discrimination training began after stabilization of response rates on both levers with <10% daily variation in total responses.
Alcohol (1g/kg) or water was administered IG before daily training sessions (M-F). Immediately following alcohol or water, rats were placed in the chambers for a 10-min timeout period. Next, the house light was illuminated and both levers were introduced, signaling commencement of the 15-min session. Training days varied on a double alternation schedule (water, water, alcohol, alcohol…). Completion of 10 responses on the alcohol-appropriate lever (eg, left lever) resulted in the presentation of the sucrose solution. Likewise, completion of 10 responses on the water-appropriate lever (eg, right lever) resulted in sucrose delivery. Responses on the inappropriate lever were recorded, but produced no programmed consequences. Water- and alcohol-associated levers were randomly assigned and counterbalanced across animals. Testing began when the accuracy criteria were met: the percentage of appropriate lever responses before the first reinforcer, and during the entire session was >80% for at least 8 out of the 10 consecutive days.
Test sessions were similar to training sessions except that they were 2min in duration (after 10-min delay), and 10 responses on either lever resulted in sucrose delivery. Reinforcement was delivered to examine the effects of treatments on overall response rates (internal measure of nonspecific motor effects). Test sessions were interspersed with training sessions if performance during 3 of 4 previous training sessions met accuracy criteria.
An alcohol dose substitution curve was determined before testing of LY379268 to ensure alcohol stimulus control. Cumulative dosing procedures (Hiltunen and Jarbe, 1989; Hodge et al, 2001; Besheer et al, 2009) were used for all testing sessions (excluding microinjection studies). To determine a cumulative alcohol dose response curve (0.1, 0.3, 1.0, 1.7g/kg), rats initially received 0.1g/kg alcohol and were placed in the chamber for a 10-min delay period followed by a 2-min test session. After the session, rats received a subsequent alcohol administration of 0.2g/kg (0.3g/kg cumulative dose) and another delay/test session. This procedure was repeated with two subsequent administrations of 0.7g/kg alcohol, which are additive to produce the stated dose range. Thus, testing of the entire dose curve was completed in ~48min. No more than two test sessions were conducted per week.
Cumulative doses of LY379268 (0.3, 1, 3, 10mg/kg, i.p.; n=10) were tested to determine whether mGlu2/3 receptor activation produced alcohol-like stimulus effects. Doses within this range have been reported to be effective at reducing alcohol self-administration and seeking behavior (Backstrom and Hyytia, 2005; Rodd et al, 2006; Sidhpura and Weiss, 2010). Water/alcohol administration was withheld during these tests.
At 2 weeks following the agonist substitution test, a cumulative alcohol substitution test (0.1, 0.3, 1.0, 1.7g/kg) was performed to determine whether mGlu2/3 receptor activation altered the discriminative stimulus effects of alcohol. LY379268 (0, 1, 3mg/kg) was administered at 10min before the first alcohol dose of the cumulative alcohol substitution test. LY379268 doses were tested according to a randomized within subjects design.
Experimentally naive male Long-Evans rats were divided into two groups and administered saline (i.p.) or LY379268 (3mg/kg; i.p.; n=5/group). Approximately, at 110min after the injection, rats were anesthetized and brains were extracted after transcardial perfusion. Tissue was sliced into 40μm sections and stored (−20°C) until further processing. Sections were immunolabeled by rabbit anti-c-Fos antibody (1:20000 dilution; Calbiochem) using a biotinylated secondary anti-rabbit antibody conjugated to an avidin–biotin complex (Vector ABC kit, Vector Laboratories). c-Fos-IR was visualized by diaminobenzidine solution (Polysciences, Warrington, PA; see Supplementary Materials and Methods).
c-Fos-IR was visualized using an Olympus CX41 light microscope (Olympus America, Center Valley, PA). IR was quantified with image analysis software (Bioquant Nova; R&M Biometric, Nashville, TN) using a digital camera (Regita model, QImaging, Burnaby, BC) interfaced to a computer (Dell, Round Rock, TX). The microscope, camera, and software were background corrected and normalized to preset light levels to ensure fidelity of data acquisition. c-Fos-IR pixel count measurements were calculated from a circumscribed field (eg, brain region) and divided by the area of the region and expressed as c-Fos-positive pixels/mm2. Analysis was conducted by a researcher blind to the treatment conditions. Data were acquired from at least three sections/brain region/animal for c-Fos-IR and analyses were averaged to obtain one value per subject. The regions examined were the amygdala (central nucleus (CeA); basal lateral nucleus (BLA); lateral dorsal nucleus (LaDL); −1.80 to −2.50 AP) and nucleus accumbens (shell and core; +1.70 to +1.00 AP; Paxinos and Waton, 1998).
Stereotaxic surgery was performed in discrimination-trained rats (n=12). Two sets of bilateral guide cannulae (26-gauge; Plastics One, Roanoke, VA) were implanted to terminate 2mm above the nucleus accumbens (core) and the amygdala (CeA). The coordinates for the nucleus accumbens and amygdala were AP +1.7, ML +1.5mm, DV −5.5mm, and AP −1.9, ML +4.2, −6.5 DV (from skull), respectively (Paxinos and Waton, 1998). We made no attempt to functionally distinguish specific sub-nuclei of the accumbens (eg, core vs shell) or amygdala (eg, CeA, BLA, or LaDL) based on evidence that suggests that the distance of drug diffusion after microinjection could possibly be larger than the distance between each sub-nuclei (Perez de la Mora et al, 2006). Rats were allowed 1 week for recovery before resuming alcohol discrimination training.
Site-specific bilateral microinjections were made with 1.0μl Hamilton syringes connected to 33-gauge injectors (Plastics One, Roanoke, VA) extending 2mm below the guide cannulae. A pump (Harvard Apparatus, Natick, MA) delivered a volume of 0.5μl/side for 1min. The injector remained in place for 1.5min after injections to allow for diffusion. LY379268 was micro-infused into the amygdala (0, 0.3, 3, 6μg/0.5μl/side) or nucleus accumbens (0, 0.3, 1, 3μg/0.5μl/side). After the diffusion period, rats received a single alcohol dose (1g/kg, IG) and were placed in the chamber for a test session (similar to the systemic dosing test sessions, with the exception that rats experienced a single test). For the first four tests, all rats received a sham injection and a vehicle injection in the nucleus accumbens and a sham injection and vehicle injection in the amygdala. After initial tests, a single LY379268 and alcohol dose (1g/kg) combination was randomly tested in each brain region during each session. Cannulae placements were verified following microinjection experiments (see Supplementary Materials and Methods).
Alcohol (95% (w/v); Pharmco-AAPER, Shelbyville, KY) was diluted in distilled water to 20% (v/v) and administered IG. Alcohol volume was varied to achieve doses of 0.1, 0.3, 1, and 1.7g/kg. (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268; Tocris, Ellisville, MI) and was dissolved in 0.9% saline and injected at a volume of 1ml/kg (i.p.). LY379268 is a systemically active potent agonist of group II mGlu receptors and devoid of agonist or antagonist activity at ionotropic glutamate receptors, mGlu1a, mGlu5a, or mGlu7 receptors (Monn et al, 1999). For microinfusion studies, LY379268 was dissolved in artificial cerebral spinal fluid.
Response accuracy was expressed as a percentage of alcohol-appropriate responses on delivery of the first reinforcer. Response rate (responses/min) was analyzed for the entire session and served as a measure of locomotor ability/drug efficacy. Complete substitution for alcohol was defined as >80% alcohol-appropriate responding. Data from rats that did not complete an FR10 during test sessions were excluded from response accuracy analysis, but included in the response rate analysis. Response accuracy and response rate data were analyzed by one or two-way repeated measures (RM) analysis of variance (ANOVA) with Tukey post hoc comparisons. c-Fos-IR was analyzed using Student's t-tests to compare treatment groups within brain regions. Significance was declared at p0.05.
For each rat tested in the discrimination experiments, alcohol discriminative stimulus control was evaluated first by testing a range of cumulative alcohol doses before mGlu2/3 receptor agonist testing. Analyses are representative from all rats in each of the three discrimination experiments (n=22). Alcohol-appropriate responding was significantly increased in a dose-dependent manner after cumulative alcohol administration (Figure 1a; F(3,60)=38.221, p<0.001), with 1.7g/kg fully substituting (>80%) for the alcohol training dose (ie, producing stimulus properties similar to the training dose). The 1.0g/kg alcohol dose (training dose) generally produces >90% alcohol-appropriate responding during regular training sessions, but tends to produce roughly 60% alcohol-appropriate responding during the cumulative dosing procedure (Hodge et al, 2001; Besheer et al, 2010). There were no significant changes in response rate throughout cumulative alcohol testing (Figure 1b; p=0.076).
The first experiment was aimed at determining if activation of group II mGlu receptors by LY379268 produced alcohol-like discriminative stimulus effects (ie, alcohol substitution; >80% alcohol-appropriate responding). The cumulative LY379268 dose range (0.3–10mg/kg, i.p.) did not substitute for alcohol in rats trained to discriminate 1g/kg alcohol from water (p=0.412; one-way RM ANOVA). The mean (±SEM) percent alcohol-appropriate responding at each cumulative LY379268 dose was as follows: 1.0±3.0 (0.3mg/kg); 0.0±0.0 (1mg/kg); 1.0±3.0 (3mg/kg); 2.1±6.0 (10mg/kg). Furthermore, LY379268 also did not alter response rate (p=0.883; one-way RM ANOVA). Mean (±SEM) response rate (total responses/min) at each cumulative LY379268 dose was as follows: 56.0±9.7 (0.3mg/kg); 53.2±10.9 (1mg/kg); 54.1±15.8 (3mg/kg); 51.7±14.7 (10mg/kg). These data show that LY379268 does not produce alcohol (1g/kg)-like stimulus effects.
The next experiment was conducted to assess the role of mGlu2/3 receptor activation in modulating the discriminative stimulus properties of alcohol. A significant main effect of alcohol dose (F(3,27)=60.62, p<0.001), and a significant interaction (F(6,50)=2.41, p=0.04) were observed. A main effect of LY379268 dose was not found (p=0.31). Post hoc comparisons showed a significant reduction in alcohol-appropriate responding by LY379268 (1 and 3mg/kg, i.p.) at 1.0g/kg alcohol (p<0.001), suggesting that mGlu2/3 receptor activation blunted the interoceptive effects of the alcohol training dose (Figure 2a). Overall, LY379268 altered response rate as evidenced by a significant main effect of LY379268 dose (F(2,18)=5.48, p=0.01); however, none of the doses differed from vehicle, suggesting that the reduction in alcohol-appropriate responding (at 1g/kg alcohol) was not due to nonspecific alterations in response rate. There was also a significant main effect of alcohol dose (F(3,27)=3.406, p=0.032). These main effects were likely driven by general reductions in response rate at the highest LY379268 and alcohol dose (3mg/kg LY379268+1.7g/kg alcohol), as 3 of the 10 rats did not respond; however, a significant interaction was not observed (Figure 2b).
Manipulation of metabotropic glutamate receptors has been associated with altered expression of c-Fos (Kaatz and Albin, 1995; Kearney et al, 1997; Zhao et al, 2006; Besheer et al, 2009), a member of a family of immediate early gene transcription factors that is commonly used as a biomarker for mapping neuronal activity (Besheer et al, 2008; Cole et al, 1989; Morgan et al, 1987; Olive et al, 2001). Furthermore, the nucleus accumbens and the amygdala are critically involved in modulating the discriminative stimulus effects of alcohol (Hodge and Aiken, 1996; Hodge and Cox, 1998; Besheer et al, 2003). Therefore, we sought to determine whether the activation of mGlu2/3 receptors is associated with changes in neuronal activity within these regions. Using c-Fos as a marker for neuronal activity, we assessed c-Fos-IR after systemic administration of LY379268. Pretreatment with LY379268 (3mg/kg, i.p.) produced significant increases in c-Fos IR (positive pixels/mm2) in the BLA (Figure 3a, b and c; p=0.035), CeA (Figure 3d, e and f; p=0.014), and LaDL (Figure 3g, h and i; p=0.028). Interestingly, c-Fos-IR in the core and shell of the nucleus accumbens was not significantly altered by LY379268 (Figure 3j, k and l; core (p=0.875), shell (p=0.245)). These data suggest that the activation of mGlu2/3 receptors is associated with increased neuronal activity within the amygdala but not the nucleus accumbens, and this increased activity may contribute to mGlu2/3 receptor modulation of the discriminative stimulus effects of alcohol.
Using data observed in the c-Fos IR experiment as a guide for neuroanatomical selectivity, cannulae were implanted in the amygdala and nucleus accumbens (anatomical control) for site-specific microinjection of LY379268 to examine functional and neuroanatomical specificity of mGlu2/3 receptor modulation of the discriminative stimulus effects of alcohol. Intra-amygdala LY379268 (6μg) produced a significant reduction in alcohol-appropriate responding relative to vehicle treatment (Figure 4a; F(3,25)=4.761, p=0.009), and did not alter response rate (Figure 4b; p=0.273). Figure 4c illustrates approximate amygdala cannulae placement. In contrast, intra-accumbens infusion of LY379268 (0–3μg/0.5μl/side) did not significantly alter alcohol-appropriate responding (Figure 4d; p=0.182). It should be noted that only one of the nine rats responded on the alcohol-appropriate lever when the 3μg dose of LY379268 was microinjected into the accumbens, therefore, there is only one value represented for that data point. Accordingly, LY379268 significantly reduced the response rate (Figure 4e; F(3,23)=10.881, p<0.001), with significant reductions observed at the highest dose (3μg) relative to vehicle (p<0.001). Figure 4f illustrates approximate nucleus accumbens cannulae placement. These data suggest that activation of mGlu2/3 receptors in the amygdala, but perhaps not the nucleus accumbens, inhibits the discriminative stimulus effects of alcohol. In addition, these two brain regions show differential sensitivity to the motor impairing effects of LY379268.
These results show for the first time that the group II metabotropic glutamate receptors have a functional role in modulating the discriminative stimulus properties of alcohol. First, we show that systemic mGlu2/3 receptor activation by LY379268 does not produce alcohol-like stimulus effects. Second, systemic LY379268 administration reduced alcohol-appropriate responding, suggesting a blunting of the interoceptive effects of alcohol following mGlu2/3 receptor activation. Further, systemic mGlu2/3 receptor activation increased neuronal activity within the amygdala, and not the nucleus accumbens, as measured by c-Fos IR. These findings led us to target mGlu2/3 receptors in the amygdala to determine functional involvement of these receptors in the expression of the discriminative stimulus effects of alcohol. Accordingly, activation of mGlu2/3 receptors by site-specific microinjections of LY379268 in the amygdala reduced alcohol-appropriate responding, confirming functional neuroanatomical control over the discriminative stimulus properties of alcohol. In contrast, intra-accumbens mGlu2/3 receptor activation (anatomical control) did not significantly alter the discriminative stimulus effects of alcohol, but produced a dramatic reduction in response rate (ie, motor impairment) at the highest tested dose. In summary, these data suggest that the amygdala may be a key target region in mGlu2/3 receptor modulation of the interoceptive effects of alcohol and may be important for the development of mGlu2/3 receptor pharmacotherapeutics for alcohol use disorders.
This study is the first to show that systemic activation of mGlu2/3 receptors does not generalize to the stimulus effects of alcohol, which is consistent with past studies that examined the role of Group I mGlu receptors in modulating the discriminative stimulus effects of alcohol (Besheer and Hodge, 2005; Besheer et al, 2009). These findings are somewhat surprising because of the fact that most compounds that reduce excitatory neurotransmission (ie, NMDA antagonists, GABAA agonists) typically substitute for investigator and/or self-administered alcohol in discrimination tasks (Grant and Colombo, 1993; Hodge and Aiken, 1996; Hodge and Cox, 1998; Besheer et al, 2003; Shelton, 2004; Besheer and Hodge, 2005). The difference in the lack of substitution for alcohol may be attributable to interactions between alcohol and the different receptor subtypes. Alcohol alters NMDA and GABAA receptor function through direct interaction with these fast action ion channel receptors (Majewska, 1988; Dildy and Leslie, 1989; Weight et al, 1991; Sapp and Yeh, 1998; Criswell et al, 2003). In contrast, mGlu receptors signal through slower intricate G-protein signaling cascades that are well characterized for their relatively modest role in modulating excitatory neurotransmission (Ferraguti and Shigemoto, 2006), allowing for modulation of alcohol effects without generalizing to the stimulus effects of alcohol. Future experimentation examining the role of other mGlu receptor subtypes in alcohol discrimination will be required to validate this hypothesis. It could also be argued that the LY379268 doses tested were not high enough to elicit alcohol-like stimulus effects because there were no changes in behavior observed across tested doses. Indeed, the highest dose did not significantly alter response rate (Figure 2b), but acute doses of LY379268 higher than 10mg/kg produce profound motor impairing effects (Cartmell et al, 2000) and may have nonspecific actions at other receptors (Monn et al, 1999; Seeman and Guan, 2008; but see Fell et al, 2009; Zysk et al, 2011), which would potentially complicate the interpretation of results; therefore, higher doses were not tested in this study.
By contrast, when tested in combination with alcohol, systemic administration of LY379268 significantly reduced alcohol-appropriate responding by nearly 50% without altering the rate of responding, suggesting that activation of mGlu2/3 receptors blunts the interoceptive effects of alcohol. Several studies have shown that systemic administration of mGlu2/3 receptor agonists reduce the reinforcing effects of alcohol and relapse-like behavior in rodents (Backstrom and Hyytia, 2005; Rodd et al, 2006; Sidhpura and Weiss, 2010). This study presents a possible behavioral mechanism that may account, in part, for the efficacy of such compounds in modifying alcohol-drinking behaviors in animal models. That is, reported reductions in alcohol self-administration may be related to alterations in the interoceptive effects of the self-administered/consumed alcohol. It will be interesting for future experiments to directly address this possibility. Interestingly, systemic LY379268 did not reduce alcohol-appropriate responding at a 1.7g/kg dose of alcohol. Alcohol has actions at multiple cellular and molecular targets (Vengeliene et al, 2008), therefore, it is possible that a higher dose of alcohol may further stimulate other receptor or signaling systems, thereby reducing the efficacy of mGlu2/3 receptor activation in blunting the discriminative stimulus effects of a higher dose of alcohol (Grant, 1999). Further, given that these animals had considerable exposure to the alcohol-training dose (1g/kg), exposure to higher alcohol doses could produce stronger stimulus effects that are more difficult to alter with pharmacological manipulation. Future studies using a higher alcohol-training dose (ie, 2g/kg) may reveal differences in mGlu2/3 receptor modulation across different alcohol doses.
In an effort to identify neuroanatomical involvement of mGlu2/3 receptors in modulating the interoceptive effects of alcohol, we assessed IR of the early immediate gene transcription factor, c-Fos, as an index of neuronal activity to examine response of limbic brain regions following mGlu2/3 receptor agonist administration. Our focus was on the nucleus accumbens and amygdala given that these are two primary regions known to regulate the discriminative stimulus effects of alcohol (Hodge and Aiken, 1996; Hodge and Cox, 1998; Hodge et al, 2001; Besheer et al, 2003). We showed that systemic LY379268 pretreatment increased c-Fos IR in sub-nuclei of the amygdala, with no change in neuronal activity in the nucleus accumbens of naive rats. These findings are consistent with those of Zhao et al. (2006) after systemic administration of LY379268 in Wistar rats. The observation of increased c-Fos IR after systemic administration seems paradoxical given that a compound that reduces overall glutamate activity and cellular excitability, such as LY379268, would be predicted to decrease neuronal activity. These data suggest that LY379268 may be acting through a postsynaptic mechanism or by interacting with GABA neurons to induce changes in neuronal activity. As such, an explanation for our findings of increased c-Fos IR in the amygdala following systemic LY379268 administration is that mGlu2/3 receptor activation may be altering neuronal activity through a postsynaptic mechanism, whereby activation of postsynaptic mGlu2/3 receptors reduces excitatory neurotransmission. Alternatively, LY379268 could be inducing disinhibition (or reducing GABA inhibition) by reducing glutamate release into synapses that signal through a network of GABAergic interneurons that regulate excitatory neurotransmission within the amygdala. Indeed, systemic administration of a structurally similar mGlu2/3 receptor agonist (LY354740) has been shown to induce c-Fos expression in GABAergic neurons (Swanson et al, 2005). Whether the two mGlu2/3 receptor subtypes differentially mediate cellular excitability among different neuronal cell types has yet to be investigated. Regardless of the underlying mechanism, our finding demonstrates that sub-nuclei of the amygdala show a response to mGlu2/3 receptor activation, and also suggests a possible anatomical target for the modulatory effects of mGlu2/3 receptor activation on the expression of the discriminative stimulus effects of alcohol.
Functional involvement of intra-amygdala mGlu2/3 receptors was confirmed as activation of these receptors inhibited expression of the discriminative stimulus effects of alcohol (1g/kg). Interestingly, mGlu2/3 receptor activation in the nucleus accumbens did not alter alcohol-appropriate responding, except at a dose that produced a profound reduction in response rate (see later). This functional brain regional dissociation is reflected in the c-Fos-IR findings, in which systemic LY379268 treatment increased neuronal activity in the amygdala but not the nucleus accumbens. This data pattern suggests that amygdala-specific activation of mGlu2/3 receptors reduces sensitivity to the interoceptive cues of alcohol. An explanation for this reduction in sensitivity is that intra-amygdala mGlu2/3 receptor activation resulted in excitation (as discussed above) that blunted the interoceptive effects of the alcohol or interacted with the alcohol to make it less 'alcohol-like'. This could also explain the reduction in alcohol-appropriate responding following systemic LY379268 administration, and is consistent with c-Fos activation in the amygdala. Further, the reductions in alcohol-appropriate responding following systemic administration may be modulated, at least in part, by mGlu2/3 receptors in the amygdala given the similar data pattern after mGlu2/3 receptors administration directly into this region, and not the nucleus accumbens. It is interesting that the highest dose of LY379268 (6μg) was necessary to reduce alcohol-appropriate responding. This dose is indeed higher than that previously reported in microinjection studies using LY379268 (Besheer et al, 2010; Uejima et al, 2007). It may be that repeated alcohol exposure, as used in the present study, induces changes in mGlu2/3 receptor density particularly within the amygdala, thus requiring a higher dose of the agonist to alter behavior. Alternatively, this high localized dose of LY379268 may have had off-target actions at other receptors such as dopamine (D2) receptors (Seeman and Guan, 2008; but see Fell et al, 2009).
An alternative explanation to decreased sensitivity to the interoceptive effects of alcohol is that mGlu2/3 receptor activation interfered with the expression of the learned association. That is, the interoceptive effects of alcohol serve as a discriminative stimulus when the animal has learned that the drug state sets the occasion on which responses on a specific lever are reinforced. Therefore, mGlu2/3 receptor activation may have interfered with the expression of the learned association in the amygdala, but not the nucleus accumbens. Indeed, the amygdala has been well characterized for its role in conditioned associations (Gallagher and Holland, 1994; LeDoux, 2003; Maren, 2005; Zimmerman et al, 2007), and mounting evidence suggests that this region has an important role in modulating associations between drugs of abuse and stimuli such as internal or environmental cues (Schroeder et al, 2008; See et al, 2003; Theberge et al, 2010). It will be interesting for future experiments to examine the expression and function of mGlu2/3 receptors in the amygdala during different stages of discrimination learning (ie, acquisition vs maintenance) to determine whether learning the discrimination induces changes in mGlu2/3 receptors.
In addition to differential brain regional c-Fos response to mGlu2/3 receptor activation, and functional involvement in the expression of the discriminative stimulus effects of alcohol, the amygdala, and nucleus accumbens also demonstrated differential sensitivity to the motor impairing effects of LY379268. That is, a lower LY379268 dose (3μg) caused profound reductions in response rate when injected into the nucleus accumbens, whereas the amygdala was relatively insensitive to motor impairing effects as a twofold higher dose (6μg) did not alter response rate. Previous work has shown motor-impairing effects after systemic mGlu2/3 receptor agonist administration (Cartmell et al, 2000; Winter et al, 2004; Backstrom and Hyytia, 2005) and intra-accumbens administration (Besheer et al, 2010). Taken together, these data suggest that the nucleus accumbens may have a contributing role in the reported motor impairing effects induced by mGlu2/3 receptor agonists. Interestingly, in this study, systemically administered LY379268 did not alter response rate or c-Fos IR when administered alone. These results are in contrast to the significant motor impairment evident following intra-accumbens administration of LY379268, suggesting dissociation between global glutamatergic pathways or neural circuits that may be affected following systemically and those specifically altered following intra-accumbens administration of the mGlu2/3 receptor agonist. In addition, this differential sensitivity to the motor impairment following systemic and local administration of LY379268 and that of the nucleus accumbens and the amygdala may be attributable to reduced activity from nucleus accumbens efferent projections to the globus pallidus, a key neuroanatomical structure for coordinated locomotor function (Mogenson et al, 1983).
This study shows that the interoceptive effects of a moderate alcohol dose are blunted by activation of mGlu2/3 receptors in the amygdala and that mGlu2/3 receptor activation does not produce alcohol-like effects. Although the specific interaction between interoceptive effects/subjective effects of drugs to reinforcement processes is not yet known, it is interesting to note that mGlu2/3 receptor activation reduces alcohol self-administration (Backstrom and Hyytia, 2005). The lack of substitution for alcohol following mGlu2/3 receptor activation in our study suggests that reported reductions in self-administration are likely not due to the agonist producing alcohol-like effects, and the possibility exists that mGlu2/3 receptor activation may blunt the interoceptive effects of the consumed alcohol. Interestingly, previous work has shown no specific changes in alcohol self-administration behavior following mGlu2/3 receptor activation in the nucleus accumbens (Besheer et al, 2010). This is consistent with findings in this work showing lack of intra-accumbens involvement of mGlu2/3 receptors in modulating the interoceptive effects of alcohol.
To date, activation of mGlu2/3 receptors has been shown to reduce drug self-administration, relapse to drug-seeking, as well as inhibit the discriminative stimulus effects of PCP, and LSD (Baptista et al, 2004; Winter et al, 2004; Bossert et al, 2006; Peters and Kalivas, 2006; Lu et al, 2007; Hao et al, 2010; Jin et al, 2010), and as demonstrated by this work, alcohol. As such, mGlu2/3 receptors may be an efficacious target for the development of therapeutics for the treatment of addiction (Kenny and Markou, 2004; Heidbreder and Hagan, 2005). Moreover, mGlu2/3 receptor agonists are also generating interest for their potential role in treating multiple psychiatric disorders (Imre, 2007; Patil et al, 2007; Yasuhara and Chaki, 2010), such as depression and anxiety; two disorders that are often co-morbidly expressed in alcoholics (Schuckit and Hesselbrock, 1994; Hasin et al, 2005). In addition, delineating the specific role of each receptor subtype (2 and 3, separately) would be advantageous for drug development, and with the recent emergence of selective mGlu2 and mGlu3 receptor positive modulators, future work may provide some additional insight to the contributions of activity at mGlu2 or 3 receptors in modulating the discriminative stimulus effects of alcohol and reinforcement processes.
This work was supported in part by funds from the National Institutes of Health AA016009 (JB), AA014983 (CWH), ABMRF/The Foundation for Alcohol Research (JB), and by the Bowles Center for Alcohol Studies.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Intentional and Unintentional Contaminants in Food and Feedby Fadwa Al-Taher, Lauren Jackson, Jonathan DeVries
Pub. Date: 01/19/2010
Publisher: American Chemical Society
Assurance of the safety and quality of foods requires the constant vigilance of scientists (and others) in the food supply chain to the potential presence of contaminants. Most frequently, contaminants are naturally incurred, e.g. mycotoxins resulting from mold growth, minerals of concern from soils in which the food is grown, and pathogenic microbes. Scientists
Assurance of the safety and quality of foods requires the constant vigilance of scientists (and others) in the food supply chain to the potential presence of contaminants. Most frequently, contaminants are naturally incurred, e.g. mycotoxins resulting from mold growth, minerals of concern from soils in which the food is grown, and pathogenic microbes. Scientists worldwide have developed programs and analytical methods to minimize the negative impacts of naturally occurring contaminants on humankind. More insidious perhaps, is the intentional adulteration of foods by addition of non-inherent materials (either as a substitution for an authentic component, or simple addition) for economic gain, i.e. increasing the perceived, and thus the sales value of the food. Often these substitutions do not result in a food safety issue per se (there may be nutrition impact); however, numerous instances have surfaced wherein the economic adulteration resulted in a negative safety impact to the food supply. Melamine is an example of a macroscale adulterant, used to increase the analytically derived protein quantity of a food protein source. In as much as melamine will equate to roughly 400% protein utilizing current analytical technologies used for trade, adding small amounts along with other non-proteinaceous materials can result in an adulterated protein ingredient or product meeting the full certificate of analysis claims. Sudan dyes are an example of a microscale adulterant, added in small quantity to ingredients such as paprika or dried chili peppers to enhance the color, and thus the perceived value of the ingredient. This book defines or highlights some of the issues with natural contamination and economic adulteration and the response of the food community to these issues to minimize negative impacts to the food supply.
Product Details
- 9780841269798
- Publisher:
- American Chemical Society
- Publication date:
- 01/19/2010
- Series:
- ACS SYMPOSIUM Series, #1020
- Pages:
- 304
- Product dimensions:
- 6.20(w) x 9.10(h) x 0.80(d)
Table of Contents
1. Overview Chapter
Fadwa Al-Taher
2. U.S. Food and Drug Administration's Program for Chemical
Contaminants in Food
Mike Bolger, Paul South, C. Murray, Lauren Robin, G. Wood, Henry Kim and Nega Beru
3. Microbial contamination of fresh produce
Susanne E. Keller
4. Nanoscale materials in foods: existing and potential sources
Bernadene A. Magnuson
5. Renal toxicity of pet foods contaminated with melamine and related compounds
William H. Tolleson
6. Mycotoxins of concern in imported grains
Dojin Ryu and Lloyd B. Bullerman
7. Effect of heat-processed foods on acrylamide formation
Fadwa Al-Taher
8. Furan in thermally processed foods
Patricia Nyman
9. What chemists need to know about very low levels of chemicals in food
Richard W. Lane
10. Effects of pasteurization on detection and toxicity of the beans from Abrus precatorius
Eric AE. Garber
11. Detection and confirmation of food allergen using mass spectrometric techniques: Characterization of allergens in hazelnut using ESI and MALDI Mass Spectrometry
Dorcas Weber, Gustavo Polenta, Benjamin P.-Y. Lau, and Samuel Benrejeb Godefroy
12. Inactivation of microbial contaminants in fresh produce
Brendan A. Niemira, Bassam Annous, Xuetong Fan, Ching-Hsing Liao, and Joseph Sites
13. CARVER + Shock: Risk Assessment Tool
Phillip Pohl, Eric Lindgren, Cecelia Williams, Malynda Aragon, Jeffrey Daneels, Robert Browitt, Madison Link, Regina Hunter, Don Kautter, Jon Woody, Amy Barringer, Dave Acheson, Cory Bryant, Fred Shank, and Sarah Davis
14. Dealing with intentional and unintentional contaminants in meat and poultry products regulated by the USDA/FSIS
Kerry L. Dearfield and Suzanne Rigby
15. Lead in Food: The Neo-classical contaminant
Michael E. Kashtock
16. Achieving total food protection: Benefits from integrating food safety and food defense programs
David K. Park
Author Index
Subject Index
Customer Reviews
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Tag Archives: teacher collaboration.
Collaborative Teaching: Addressing ESL Teacher Concerns
Twelve years ago, I was interested in how collaborative teaching might work for our ESL program. I had read about ESL teachers who were "pushing into" the general education classroom to collaborate with classroom teachers and wanted to see for myself. … Continue reading
Posted in TESOL Blog Tagged as collaborative teaching, elementary education, elementary ESL, ESL in mainstream, evergreen, Judie Haynes, teacher collaboration. 2 Comments


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I was very surprised to see that the State Board of Education has hired Mid-continent Research for Education and Learning (McRel) to compare Nebraska's standards to the latest fad in education, the Common Core State Standards.
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Critic Reviews for Cannes Man
All Critics (8) | Fresh (4) | Rotten (4) | DVD (1)
Though some of the bits are funny, this is a film that would probably work for an insider in ways that might go right past an outsider.
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No excerpt available.
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Audience Reviews for Cannes Man
This movie is about a director that finds a man in Cannes turns into a producer introducing to movie stars during the Cannes Film Festival. The movie is boring but has great cameos by various actors Johnny Depp, John Malvoich(?), Chris Penn, James Brolin etc That is the only good part about the movie. I gave it 50 for Johnny and Jim they were funny. Clip with Johnny and Jim http://www.youtube.com/watch?v=VXhvW4Z9VDk
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Engine problem
2002 Kia Spectra 4 cyl Two Wheel Drive Automatic 129100 miles
I have 2002 Kia Spectra GS with 129100 miles. As a precuation I am planning to change the Timming Belt. Could you please tell me how much it will cost me?
Tuesday, February 12th, 2008 AT 2:30 PM


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You guys are probably wondering why I haven't been posting many sounds for the last month well number one so ...
First stage of an archeological dig
Digging in the Snow with a Zoom H2
Rustling a small pile of leaves with my foot.
These are the sounds recorded by cooking utensils such as pots, pans .... They are made of metal and wood ...
clattering metal objects
The sound of metal scraping against metal.
The clang and ring of metal striking metal.
The clang and ring of metal striking metal.
Recordings of different percussive sounds from abandoned small wave power plant. Tascam DR-100.
A pack of 22 Metallic Sounds. All sounds are High Quality Synthesized Metallic sounds
smaller metal bowl hit with small metal stick. Higher pitched ring.
vibrating metal
A puntual sound of the water. It is relaxing.
hitting a watering can made of plastic


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$9.99"Sunshine, you're my baby and I'm your only mother. You must mind the one taking care of you, but she's not your mama." Ashley Rhodes-Courter spent nine years of her life in fourteen different foster homes, living by those words. As her mother spirals out of control, Ashley is left clinging to an unpredictable, dissolving relationship, all the while getting pulled deeper and deeper into the foster
$8.99In the sequel to the New York Times bestselling memoir Three Little Words, Ashley Rhodes-Courter expands on life beyond the foster care system, the joys and heartbreak with a family she's created, and her efforts to make peace with her past.Ashley Rhodes-Courter spent a harrowing nine years of her life in fourteen different foster homes. Her memoir, Three Little Words, captivated audiences
$3.99A heartbreaking and shocking short story from foster carer Rosie Lewis. Toddler Charlie falls from the second floor window of his tower block home while his mother is busy shooting up in their dirty council flat. Laying alone on a pile of rubbish until concerned neighbours hear him whimpering, Charlie is taken to hospital by police officers who are unable to rouse his mother. With a gash to his
A True Story of Five Siblings Who Survived an Unspeakable Childhood on Long IslandRegina's Calcaterra memoir, Etched in Sand, is an inspiring and triumphant coming-of-age story of tenacity and hope. Regina Calcaterra is a successful lawyer, New York State official, and activist. Her painful early life, however, was quite different. Regina and her four siblings survived an abusive and painful childhood only to find themselves faced with the challenges of the foster-care system
Scarlett's Secret: A real-life short story by Casey WatsonBestselling author and foster carer Casey Watson tells the shocking and deeply moving true story of two sisters who carry a terrible secret. This is a first taste of the 'Unit' series: several stories about 'difficult' children Casey helped during her time as a behaviour manager at her local comprehensive. Casey doesn't know what to expect when seventeen-year-old twins Scarlett and Jade join her
The True Story of a Polygamous Church WifeIn the early 1970s an innocent teenager who had led a sheltered life was forced to leave her family and enter into a polygamous, abusive, and deviant relationship with a man called the Prophet. In 2008, nearly 40 years later, she fled his religious sect. Property is not a misnomer. It accurately depicts how the women in the sect were treated. Carol Christie reveals the degradation, abuse, and
$8.89Four extraordinary true stories ... Bobby and Micky, six and four, controlled from beyond the grave by their evil father ... Mina, seventeen, who has Downs Syndrome, desperate to be like everyone else, falling into the hands of men who abuse her trust ... Sylvie, a fourteen-year-old mother being pimped by her father ... Twins Larry and Francey, ten, scarcely human after an upbringing of
My Sister and I: We Are SurvivorsThe true life story of two little girls: Deena, age 4 and Starla, age 5, who become the sexual objects of a deranged stepfather and his sons and their friends througout their childhood and their teenage years. The story follows the girls until they are finally able to move away from home and escape the vile attention of the sexual perverts. The story also examines the effects on the two females as
A Last Kiss for Mummy: A teenage mum, a tiny infant, a desperate decisionBestselling author and foster carer Casey Watson tells the heartbreaking true story of a teenage mother and baby in need of a safe and loving home. At fourteen, Emma is just a child herself – and one who's never been properly mothered. She has been in foster care several times already and when she discovered she was pregnant, and refused to have an abortion, her mother threw her out of the house.
$6.99The latest title from the internationally bestselling author and foster carer Cathy Glass. Beth is a sweet-natured child who appears to have been well looked after. But it isn't long before Cathy begins to have concerns that the relationship between Beth and her father is not as it should be. Little Beth, aged 7, has been brought up by her father Derek after her mother left when she was a toddler.
$5.99"Y. That perfect letter. The wishbone, fork in the road, empty wineglass. The question we ask over and over. Why? . . . My life begins at the Y." So opens Marjorie Celona's highly acclaimed and exquisitely rendered debut about a wise-beyond-her-years foster child abandoned as a newborn on the doorstep of the local YMCA. Swaddled in a dirty gray sweatshirt with nothing but a Swiss Army knife tucked
$9.99A new memoir from Sunday Times and New York Times bestselling author Cathy Glass, now with an exclusive preview of Cathy's inspiring new title, Please Don't Take My Baby, coming out on April 25th. Eight-year-old Aimee was on the child protection register at birth. Her five older siblings were taken into care many years ago. So no one can understand why she was left at home to suffer for so long.


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I am creating slides with combo-boxes. I get what I want when I run the codes of each slide individually in debug mode.
I want to write a macro which will run all the subs on all the slides when I run the presentation? Should I use the Call function?


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Photo Details
This picture is of General Charles A. Nason,who was in the Civil War. He was born in 1822 and died in 1900,both in Hampton Falls,New Hampshire. He is buried a long with his wife(Mary Perkins)and most of his children in The Nason Family Cememtery in Hampton Falls.
at Hampton Fals, Rockingham, New Hampshire USA


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Change Location
ACE Fit Share
Fit Life Articles
Change means pushing ourselves beyond our comfort zone and entering into unfamiliar territory. Let's explore five tools for breaking a major life change down into smaller, more manageable, parts.
It can feel daunting trying to squeeze in one more thing into an already overcrowded schedule, but establishing and committing to a yoga practice does not have to require a lot of time each day. Learn how you can reap the many benefits of a yoga practice, even if you only...
Summer is just around the corner, which means now is the time to start getting in shape for it. Whether you want to tone your body or simply be fit enough to enjoy fun summer activities like biking, swimming and hiking, weight training is one of the best ways to accomplish...


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Jump Design / Following
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BenobaidNeuman Productions London
We are Benobaid Neuman Productions, a London based music and sound production company. We're a team of Composers, Producers and Sound designers. we work along side each other creatively and technically. As an all-in-one production team we are beneficial to directors as the producers, sound…
Hey Im a freelance motion designer based in London, working in all aspects of 2D and 3D animation. www.jamesbrocklebank.co.uk
ALCANAUTHA Studio Plus France (alsace)
DSLR Film Maker, Photograffer & motion designer Join our Beyond ALCANAUTHA facebook profil to stay updated: http://www.alcanautha.com http://www.facebook.com/alcanautha.studio
Anthony Elliott Huddersfield, UK
Maker of short videos and a fair bit of time-lapse. My blog: www.aenimated.co.uk After being employed as a time-lapse engineer for a few years, I started up on my own: www.constructfilms.co.uk
Lee Jacobs London
Art Director at Jump Design & Direction, London. Lee has worked in motion graphics for twelve years. From humble beginnings and pixelated masterpieces at Teletext he left a junior role to take up residence at Deluxe Digital Studios. Swiftly achieving the position of Senior Designer, and with a…
Tokyo o'Clock Barcelona
For most people there is never enough time. However, we are not like most people. We don't sleep, we don't eat, we don't stop until the job is done. We work twenty-four hours a day, around the clock and around the globe to bring you artistic solutions with purpose and meaning. This…
Albert Bauer Studios PRO Hamburg / Munich, Germany
Albert Bauer Studios offers unparalleled expertise in the field of creative image design and processing for both print and online applications. Based in Hamburg and Munich, experienced CGI artists, image editors and photographers are committed to bringing even the most challenging ideas to fruition…
Ali Bin Madhi Saudi Arabia
Abdulrahman Shihab QATAR
Digital Artist, Photographer & Filmmaker, Interested in Documentary Films I Hope I Will Be Pro In 3D Motion Graphics World & VFX Follow Me On Twitter: @bo_shihab
Matuus Šun Steff Gaal Seychelles
art direction, motion design & interactive development
Artillery is an award winning design studio. We specialise in pushing the creative boundaries across all design disciplines including branding, animation and motion graphics. Our strengths lie within a process of working with our quality in-house talents and a core of external specialists which means…
Louis du Mont Plus London
Hi, I'm Louis. I'm a digital artist based in London. Personal: www.louisdumont.com Twitter: twitter.com/louisdumont Photos: flickr.com/2create Studio: www.weareformation.com Also working on a CG / VFX short film: www.visitingshort.com
Nuno Barbosa Plus Portugal
Director/Motion Designer firstname.lastname@example.com 2014 - Vimeo Staff Pick https://vimeo.com/channels/staffpicks/113000956 2012 - Winner of "Best in Event Award" in "Creative Macau - Sound & Image Challenge" 2012 - Winner of "Rode Rockumentary International Film Competition" 2012…
Visuala Lab specializes in the art of storytelling through video and motion graphics. VL based in Warsaw, Poland.
Rosie Skinner London
Motion graphics designer at MTV, London. www.cargocollective.com/rosieskinner https://twitter.com/rosie_skinner_
Kojo Boateng London
Kojo Boateng is currently Design Director at ITN, the UK's leading provider of independent broadcast news. He leads an award winning team in creating environments for ITN's ground-breaking virtual reality system and oversees the design for all ITV News programming for the UK's biggest…
Miguel Rato Plus London, UK
I'm a Freelance Art Director / Motion Designer & Director at TRAJECTORY. Always on the look for exciting projects to work on and smart people to collaborate with! In the past I have been working with names like; FutureDeluxe, Axis Animation, EA (Electronic Arts), MPC, Spov, BLIND, Found…
GeeFX® Studios Plus London, UK
GeeFX® Studios is a full service moving image design studio with a long history in motion graphics, CGI & visual effects, we create high quality affordable visual solutions across a variety of platforms at very competitive rates. We offer a wide range of creative solutions depending on your requirements.
Browse FollowingFollowing
When you follow someone on Vimeo, you subscribe to their videos, receive updates about them in your feed, and have the ability to send them messages.
Choose what appears in your feed using the Feed Manager.


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Vinitaly is a 4 day event being held from 9th April to the 12th April 2017 in Verona, Italy. This event showcases product from Meat, Poultry & Seafood, Food & Beverage, Wine & Spirits industries.
Visitors Attending
onwumere sebastian emeka
Executive Director at Del Star Global Resources Ltd
Abuja, Nigeria
Stefano Novelli
Perugia, Italy
gabriele angelucci
Rimini, Italy
Megan Ann
Port St Lucie at Registered Nurse
Port Saint Lucie
Amaning Isaac
Marketing Manager at Teekept Travel And Tour
Kumasi, Ghana
Robert Crapanzano
President at The Thronton Park Wine Club
Orlando, United States Of America
Map & Directions
Venue to be announced
Verona, ItalyGet Directions
Featured Hotels in Verona
From EUR 107
From EUR 71.25
From EUR 90
From EUR 140
Exhibitor Profile
Vinitaly plays host to more than 4164 exhibiting companies, looking to promote a vast range of rich and exotic varieties of wines, spirits and other alcoholic beverages. Abruzzo Malvasia, Alcamo Grillo, Barbaresco Riserva and Botticino are some of the most renowned varieties of wine that are displayed here. Canavese Rosso, Carso Terrano, Franciacorta and Gabiano wines are showcased during the event as well. Garda Cabernet, Irpinia Bianco, Lamezia Rosato and Lugana wines are exhibited at the show as well, along with a host of other wine types and brands. The list of exhibitors at the show features several eminent companies, including CABERT S.p.A. and BRACCO.
Other Related Events
Aug 30
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Oct 07
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Verona, Italy


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realmagick.com The shrine of knowledge.
Sari Bangladesh Saris
- It's a wrap!
- The sari is not exclusive to India; it is worn in Bangladesh, Nepal and Sri Lanka too. Of course the manner ...
- Jamdani factory owner arrested on charge of making teen work while in chains
- Police have arrested the owner of a Jamdani sari factory at Narayanganj on charges of tying up a teenaged worker with chains and torturing him for 15 days. ... He would make him work on the saris with the chain tied to his feet for 15 days.
- Mehak Chalal: I can't handle generation leaps in shows
- For her entry sequence, the actress had to wear a flimsy white sari and bathe under the waterfall. "The water was very cold.
- Saree-torial splendour: Here's the first-ever saree flash mob
- Flash mob by trendy, elegant Saree wearing urban women conducted by an organistaion Devditi at Select City Mall, Saket on Tuesday, October 27, in New Delhi, India. (Waseem Gashroo/HT Photo) ...
Sari Bangladesh Saris is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Sari Bangladesh Saris books and related discussion.
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Kelly Thiebaud and Bryan Craig have been engaged since 28th Jun 2015. [view couple]
Kelly Hager Thiebaud (born on August 28, 1982) is an American actress best known for her portrayal of Dr. Britt Westbourne on ABC's General Hospital. She has also been in several films including Hostel: Part III and Grace Unplugged....
Connect any celebrity with Kelly Thiebaud to see how closely they are linked... romantically!
she have an arabic middle name cool


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Researchers at the University of Pennsylvania conducted a series of medical tests on patients who speak in tongues. The study yielded surprisingly positive results. Watch the video below to learn about the science behind glossolalia.
Draw closer to God. Experience the presence of the Holy Spirit every month as you read Charisma magazine. Sign up now to get Charisma for as low as $1 per issue.
Dare to go deeper in your faith. Our "Life in the Spirit" devotional takes you on a journey to explore who the Holy Spirit is, how to interact with Him, and how He works in your life. Are you ready to go deeper?


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The Army's Medical Communications for Combat Casualty Care – better known as MC4 – has a new leader.
Lt. Col. William Geesey relinquished his role as product manager for the MC4' s Product Management Office to Lt. Col. Danny Morton during a change of charter ceremony at Fort Detrick, Md.
Geesey leaves MC4 as the longest-tenured product manager for MC4 since its inception in 1999. Among his many accomplishments leading the center, Geesey spearheaded a telehealth initiative that digitally connects remote soldiers with mental-health specialists, for which he earned a place among the Federal 100 winners of 2012.
Geesey will stay with the Army, but details of his next assignment haven't been released yet.
Morton, who previously served as chief of staff at the U.S. Army Medical Materiel Agency, plans to expand use and engagement with MC4 systems, enhance user training and readiness, and continue focus on system quality and capabilities to benefit deployed soldiers worldwide.
Posted by Camille Tuutti on Apr 20, 2012 at 12:11 PM
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In the latest issue: grid security, agile development, BYOD and more!
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The latest version of the Defense Department-wide Enterprise Service Management Framework places more emphasis on managing IT risk.
Despite GSA's efforts to accelerate the FedRAMP approval process, the lack of agency reciprocity puts the program's central goals at risk.
Got some early-career colleagues who are doing great things in federal IT? Nominate them for FCW's 2016 Rising Star awards.
The agency software inventories required under the draft category management policy will be treasure maps that lead to efficient, effective, streamlined buying and unprecedented savings.
As experts warned of the "dire" threats posed by outdated federal technology, lawmakers grilled top feds, debated workforce issues and inched closer to backing a $3.1 billion fix-it fund.
The agency is making strides in developing and deploying border technologies but still has some weaknesses.
Agencies have spent almost $23 billion on legacy IT over the past three years, according to reports to Congress. Is a revolving fund the answer?
The United Kingdom will go live with its governmentwide digital identity platform, GOV.UK Verify, in the coming days. The U.S. government will need a little more time.
What contracting officer representatives really think is needed to fix contract management.
I would like to contact Lt. colonel William Gessey...I was his high school teacher.
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text:
Ratings based on 3 Verified Reviews
They paid and stayed. We double-checked.
5.0 Room cleanliness
5.0 Service & staff
5.0 Room comfort
5.0 Hotel condition
Expedia Verified ReviewsThey paid and stayed. We double-checked.
by MARCO ANTONIO from Boituva
100% THE BEST IN B&BPosted Feb 12, 2016 on Hotels
GIUSEPPE, obrigado por tudo ! fantástico e único foram a qualidade e o conforto do TownHouse Fata Morgana! 100% The best !
by A verified traveler from Richboro, PA
Outstanding B & BPosted Jun 4, 2015
Pros: Everything was great, there is no kitchen so Giuseppe takes you out to breakfast in the morning at any time that you choose.
Cons: Not an improvement but guests should know that it is a second floor and not handicap accessible.
Location: Location is great. Reggio is on beach, town of old traditional Italian culture. Tell Giuseppe what you want to do/eat, he will tell you where to go.
My daughters and I stayed here for three nights prior to my 20 year old starting a month study abroad program in Reggio. Facility was beautiful, probably the best shower in all of Italy. Very clean, well maintained, comfortable. But the best is part is the host, Giuseppe. He is like your favorite cousin, tour guide and source of information. He will tell you everything that you need to know and answer any questions you may have with out being intrusive. I felt very comfortable leaving my daughter knowing that she has a friend in Reggio should she need anything.
by William from Phoenix
Reggio B&BPosted May 17, 2015 on Hotels
Giuseppe owner and manager was most accommodating. pricey but nice. Near train station and good shopping area/ restaurants


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FREE SHIPPING on orders of $85 or more
An excerpt from www.HouseOfNames.com archives copyright © 2000 - 2016
Origins Available: English, German
The name Cobian is tied to the ancient Anglo-Saxon culture of England. It comes from the given name Jacob.
The surname Cobian was first found in Lincolnshire, where they held a family seat from ancient times.
Only recently has spelling become standardized in the English language. As the English language evolved in the Middle Ages, the spelling of names changed also. The name Cobian has undergone many spelling variations, including Cobbin, Cobbing, Cobon, Cobin, Cobyn, Cobben, Cobenn, Coblyn, Coblin and many more.
This web page shows only a small excerpt of our Cobian research. Another 246 words (18 lines of text) covering the years 1202, 1273, 1298, 1345, and 1773 are included under the topic Early Cobian History in all our PDF Extended History products and printed products wherever possible.
More information is included under the topic Early Cobian Notables in all our PDF Extended History products and printed products wherever possible.
To escape the unstable social climate in England of this time, many families boarded ships for the New World with the hope of finding land, opportunity, and greater religious and political freedom. Although the voyages were expensive, crowded, and difficult, those families that arrived often found greater opportunities and freedoms than they could have experienced at home. Many of those families went on to make significant contributions to the rapidly developing colonies in which they settled. Early North American records indicate many people bearing the name Cobian were among those contributors:
Cobian Settlers in United States in the 19th Century
Cobian Settlers in United States in the 20th Century
Other References
The Cobian Family Crest was acquired from the Houseofnames.com archives. The Cobian Family Crest was drawn according to heraldic standards based on published blazons. We generally include the oldest published family crest once associated with each surname.
This page was last modified on 24 February 2016 at 14:03.
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"Barkan can play with all the tension and expressive dissonance of Neil Young and Crazy Horse with the advantage of being a more sensitive improviser."
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"On Flightless Bird: "Barkan courageously underplays his expert guitar on this effort. It's about the songs. The spacious ensemble arrangements foreground Barkan's dry, intimate vocals: a top crust of curmudgeon that fails to cover the world of feeling underneath.""
"On his new album Flightless Bird he manages to create a set of songs that echo with the restless, free spirit of jazz, but which are also firmly anchored by their Americana roots."
"This is not guitar work like, say, Satriani or Vai, no ruthless flurry of notes here. Rather, a much more restrained and tasteful exploration of the fretboard... It flies in the face of the current crop of popular stuff, speed pop and overproduced chum that currently deadens the airwaves. Well worth hunting out.""