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What a joy this Bloomsbury classic proved to be. The story revolves around a young man living a precarious existence in New York in the s. The entire narrative is told in the second person employing a voice that is by turns self-deprecating and pathetic. There is no way you will be able to get everything in this article verified, and also there is no graceful way to admit failure. But this is the s. There is no internet, no smartphones. For our poor old narrator, who somehow exaggerated his ability to speak French on his resume, there are dozens of phone calls to make to Paris to verify certain facts. It would at least be a relief if you could tell yourself that this was your best shot. You feel like a student who is handing in a term paper that is part plagiarism, part nonsense and half finished. The writer was counting on the Verification Department to give authority to his sly observations and insidious generalisations. This is not cricket on his part, but it is your job that is on the line. Most of the lightning-paced narrative comprises a series of set pieces, most of which are very funny indeed, but the story is not all humour and lightness. Underpinning our narrator lurching from one crisis to the next are deeper issues relating to our need to fit in, to be accepted by our peers and society as a whole without fear of judgement. Yes, this is a book set in New York in the s, but forget any reviews you might have seen which paint Bright Lights, Big City as a portrait of excess or rich people doing bad things. This is a black comedy about a something trying to find his way in the world, not always making the right decisions and paying the price along the way. There are a lot of painful realisations in Bright Lights, Big City , all rounded out by a redemptive, satisfying ending. I am a book obsessive who has been charting my reading life online since the early s. View all posts by kimbofo. Like you I had pigeon-holed this book in my mind. I read it a couple of years ago in the run up to a trip to New York …. Wonderful novel , beautifully written. Like Liked by 1 person. I will definitely re-read it at some point. So cleverly written. Like Like. One for a reread sometime for sure. The follow-up is a bit lighter I seem to recall set in Japan, some martial arts? He seems to be in semi-retirement? The s. Cheers, Poppy. I like your enthusiasm, Kim. And I find encouraging that after so many years of reviewing you still find books that appeal so strongly to you. Thanks for the review. Thanks Danielle. This site uses Akismet to reduce spam. Learn how your comment data is processed. Subscribe now to keep reading and get access to the full archive. Type your email…. Continue reading. Skip to content November 29, September 4, kimbofo. Fiction — hardcover; Bloomsbury; pages; Going off the rails The story revolves around a young man living a precarious existence in New York in the s. It is, of course, all down hill from there… Heartbreaking reasons for a life falling apart at the seams Most of the lightning-paced narrative comprises a series of set pieces, most of which are very funny indeed, but the story is not all humour and lightness. Share this:. Like Loading Published by kimbofo. Next post 5 books to read for Diverse December. Be interested in the short story collections… Like Liked by 1 person. Thanks for the recommendation. I will have to investigate further… Like Like. Absolute Bargain! Thanks for the review Like Like. Pingback: My favourite books of Reading Matters. Pingback: 8 great novels written in the second person — Reading Matters. Pingback: 17 intriguing novellas you can read in a day or an afternoon — Reading Matters. I'd love to know what you think, so please leave a comment below Cancel reply. Discover more from Reading Matters Subscribe now to keep reading and get access to the full archive. Type your email… Subscribe. Comment Reblog Subscribe Subscribed. Reading Matters. Sign me up. Already have a WordPress. Log in now. Loading Comments Email Required Name Required Website.

‘Bright Lights, Big City’ by Jay McInerney

How can I buy cocaine online in Serre Chevalier

Official websites use. Share sensitive information only on official, secure websites. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. The current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. The neurokinin 1 NK1 receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown. We sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant CJ, , in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride NaCl solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption. The present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers. Obesity-related pathology is an alarming public health problem worldwide. Homeostatic control systems precisely regulate body weight and adiposity in a restrictive food environment \[1\]. However, non-homeostatic factors, such as palatability and motivation, override these systems when a sedentary lifestyle is combined with accessibility of palatable and calorically dense foods or natural reinforcers \[1\]. In fact, the current obesity epidemic is suggested to be partly driven by over-consumption of natural reinforcers such as sugar \[2\] — \[6\]. Uncontrolled over-consumption of natural reinforcers share characteristics with drug addiction. Additionally, there is overlap between brain regions regulating seeking and self-administration of substances of abuse and those regulating motivational and reinforcing aspects of foraging and intake of natural reinforcers \[9\] — \[15\]. For example, natural reinforcers, including sucrose, activate neurons in the ventral tegmental area VTA. Conversely, VTA lesions selectively reduce sucrose consumption \[16\]. Furthermore, sucrose consumption increases dopamine release in the nucleus accumbens \[17\] , a brain area exhibiting opiate-like activation following excessive sugar intake \[18\]. Finally, recent neuroimaging studies have discovered neuroadaptations in obese individuals that mimic those in cocaine addicted individuals \[14\] , \[19\] , \[20\]. The common molecular substrates underling the motivation to consume natural reinforcers and drugs of abuse are largely unknown. However, the endogenous opioid system is one possible candidate \[15\]. An interaction between sugar consumption and the opioid system is supported by cross-tolerance \[21\] , \[22\] and cross-dependence \[23\] — \[25\] between sucrose consumption and opiates. In addition, both sugar and ethanol intake is decreased by the opioid antagonist naltrexone \[26\] — \[28\]. Recently it has been suggested that the neurokinin 1 NK1 -receptor system, and its endogenous ligand substance P SP , interacts with the opioid receptor systems to regulate reward related behaviors. Furthermore, NK1-receptor knock-out mice are insensitive to the rewarding properties of morphine \[34\] , \[35\]. NK1-receptor knock-out mice fail to develop a preference for morphine, using the conditioned place preference paradigm, and self-administer morphine at lower levels than wild-type controls \[35\]. Additionally, recent series of preclinical and clinical experiments identified the NK1-receptor as a novel therapeutic target for alcohol use disorders AUDs \[36\]. The preclinical studies showed that NK1-receptor knockout mice decreases voluntary ethanol consumption and increased sensitivity to sedative effects of ethanol \[36\]. In the clinical setting, the NK1-receptor antagonist LY suppressed alcohol craving and improved overall well-being in recently detoxified AUD patients \[36\]. The role of NK1-receptor system in AUDs is further supported by a study showing that polymorphisms of the NK1-receptor are significantly associated with the development of AUDs in Caucasian individuals \[37\]. The involvement of the opioid system in rewarding properties of both sucrose and drugs of abuse, together with the interaction between the opioid and the NK1-receptor system in reward related behaviors led us to the hypothesis that the NK1-receptor system may play a role in appetitive behaviors. To further elucidate the role of the NK1-receptor system in the regulation of consumption of natural reinforcers and ethanol, we evaluated the efficacy of a clinically safe and selective NK1-receptor antagonist, ezlopitant CJ, \[38\] , \[39\] to decrease sucrose and ethanol consumption and seeking. Ezlopitant has previously been investigated in clinical trials as a potential therapy for pain, chemotherapy-induced emesis and irritable bowel syndrome \[40\] , \[41\]. The present study gives further support to the hypothesis that the NK1-receptor system might be a novel therapeutic target for addictive disorders. The effect of the NK1-receptor antagonist, ezlopitant on sucrose and ethanol operant self-administration was evaluated in Long-Evans rats that had a stable level of ethanol or sucrose responding on a FR3 schedule. The effect of ezlopitant on the incentive motivation to respond for sucrose and ethanol was evaluated in Long-Evans rats that had achieved a stable level of ethanol or sucrose responding on a FR3 schedule. One sucrose animal was excluded from analysis because of low breakpoint responding following vehicle treatment and one ethanol animal was excluded from analysis due to lack of responding during regular FR3 sessions. Post hoc analysis showed that all doses of ezlopitant significantly decreased sucrose intake compared to vehicle at the 6 hour time point Figure 3A. In addition, there was an overall main effect on the preference for ethanol over water at both time points \[6hrs: F 3. However, ezlopitant treatment failed to induce a significant decrease in ethanol consumption compared to vehicle B. To examine the possibility that ezlopitant inhibited operant self-administration and consumption of ethanol and sucrose through a general effect on locomotor behavior, we administrated ezlopitant or vehicle to two different groups of Long Evans rats. To evaluate if the marked ezlopitant-induced decrease in sucrose compared to ethanol intake was dependent on the high caloric value of the sucrose solution, we tested the effect of the compound on a 0. Ezlopitant treatment had an overall main effect on voluntary consumption of 0. To further evaluate ezlopitant's selectivity for sweet solutions, we tested the effect of the NK1-receptor antagonist on water and salty NaCl solution intake, respectively. There were no significant difference in water or 0. Emerging evidence indicates that the NK1-receptor system is involved in reinforcing mechanisms of drugs of abuse including alcohol. The present study gives further support for a role of the NK1-receptor system in appetitive behaviors, as the NK1-receptor antagonist, ezlopitant, inhibits SP binding in rat membranes and decreases both sucrose and ethanol self-administration without decreasing water or salty solution consumption or inhibiting general locomotor activity. In the present study, the NK1-receptor antagonist ezlopitant is effective in attenuating both sucrose and ethanol intake in rodents. Somewhat surprisingly, ezlopitant more potently inhibited sucrose consumption when compared to ethanol in all drinking models used. While the addictive properties of ethanol are well established for review see \[10\] , \[49\] , evidence for food or sugar addiction has been largely based on anecdotal evidence. However, some people claim that they feel compelled to eat sweet foods, similar to how an alcoholic might crave alcohol \[9\] and it has recently been shown that natural reinforcers stimulate the same neural systems and reward mediating neurotransmitters including dopamine, acetylcholine and opioids as ethanol for review see: \[9\] , \[10\]. Furthermore, emerging evidence indicate that sucrose is addictive in rodents \[9\] , \[18\] , \[23\] , \[50\]. Several stages of addiction, for example bingeing \[51\] , withdrawal \[9\] , \[23\] , \[52\] , craving \[53\] — \[55\] and cross-sensitization to amphetamine and cocaine \[56\] , \[57\] , can all be induced following intermittent excessive sugar intake. Finally, the reinforcing properties of sugar are supported by a recent study showing that sweetened solutions can surpass cocaine reward, even in drug-sensitized and -addicted rats \[58\]. Additionally, the amygdala, which expresses high levels of NK1-receptors, plays a role in the motivational aspects of alcohol drinking behaviors \[59\]. Thus, LY might attenuate craving by suppression of pathologically elevated activity in the amygdala \[36\]. Furthermore, MOR and NK1-receptors are co-expressed in amygdala neurons \[60\] which is an important area for the NK1-receptor's involvement in the motivational aspects of morphine reward \[29\]. The present results support this hypothesis. In the operant self-administration paradigm, the rats were trained on a fixed ratio FR3 schedule to obtain an sucrose or ethanol reward and following establishment of stable baseline responding were challenged using a PR schedule. This paradigm is thus used as a measure of the motivation to seek the reward \[61\]. Ezlopitant was more effective in inhibiting sucrose and ethanol under FR3 operant conditions than in a two-bottle-choice setting where the reward is freely available. Importantly, the decreases in operant behaviors on both fixed and PR schedules were more dramatic in the sucrose-trained animals when compared to the ethanol-trained animals. Because, ezlopitant had no effect on general locomotor activity and NK1-receptor antagonists act as antidepressants in rodents \[62\] , the possibility that the ezlopitant-induced decreased activity in the operant self-administration paradigm could be a result of decreased general activity or anhedonia is minimal. Furthermore, ezlopitant significantly attenuated intake of the non-caloric sweetener saccharin, but had no effect on water and salty solution consumption. These results indicate that NK1-receptors play an important role in appetitive responding for sweet solutions, regardless of caloric value, and may regulate the motivational aspects of consumption of ethanol and sweetened solutions. The present study shows that ezlopitant treatment significantly decreases ethanol consumption in rats, supporting a study showing that NK1-receptor knock-out mice have markedly lower ethanol consumption than wild-type controls \[36\]. One possible explanation is that higher doses of the NK1-receptor antagonist are needed to attenuate ethanol consumption in mice than rats. This is supported by a study indicating that a near-complete inactivation of NK1-receptors is needed to suppress ethanol consumption in mice \[36\]. These results indicate a species difference in the sensitivity to the behavioral response following NK1-receptor antagonism. The exact mechanism by which the NK1 receptor antagonist, ezlopitant decreases sucrose and ethanol intake remains unclear. There is strong evidence that both sucrose and ethanol stimulate the brain reward system through endogenous opioids see for example \[10\] , \[11\] , \[13\]. The effectiveness of ezlopitant in attenuating sucrose and ethanol consumption indicates there may also be an interaction between NK1-receptors and the endogenous opioid system in reward-related behaviors, but this possibility remains to be determined. In conclusion, the present study demonstrates that the NK1-receptor antagonist, ezlopitant, decreases sucrose and ethanol consumption and seeking in three different drinking models, giving further support of an involvement of the NK1-receptor system in AUDs and other reward-related behaviors. A clinical study is possible as ezlopitant is known to be safe in human subjects \[40\] , \[41\]. The animals were acclimatized to the individual housing conditions and handling before the start of the experiments. All animals in the two-bottle-choice experiments were maintained on a 12 hour reversed light-dark cycle lights off at 10 am and rats in the operant self-administration and locomotor experiments were maintained on a regular 12 hour light-dark cycle lights on at 7 am. Food and water were available ad libitum , except during initial training in the operant self-administration paradigm, as described below. The experiments contained herein comply with the current laws of the United States of America. Both groups were kept on a fixed ratio 3 schedule of reinforcement FR3; three active lever presses required for 0. Thus, each rat served as its own control. The PR ratio method is as described by \[43\]. Briefly, the PR session was initiated by presentation of a compound cue extension of the levers, illumination of the stimulus light over the active lever, tone sounding, and illumination of a raised dipper cup filled with alcohol or sucrose. After the compound cue, responding proceeded under a PR schedule that was the same for alcohol and sucrose rats. The PR schedule of reinforcement was determined by the equation. Briefly, after the compound cue, rats could lick the dipper cup, press a lever, or do nothing. If rats licked first, a PR schedule of reinforcement of 1, 1, 2, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, 17, 20, 22, 25, 28, 32, 36, 40, 45, 50, etc. If rats pressed first, a PR of 1, 2, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, 17, 20, 22, 25, 28, 32, 36, 40, 45, 50, etc. If the rat chose to do nothing, a 20 s timeout period occurred, and the rat was re-cued with the compound cue for up to 20 iterations. For the few rats that required re-cue, one or two re-cues were sufficient to elicit a response. Breakpoint was defined as the number of presses contained in the last, successfully completed ratio in either a 1 hr session or after 15 min of non-responding, whichever came first. Null responses, where an animal completed the required number of lever presses but did not lick to receive the reinforcer, were not counted toward the breakpoint. Ezlopitant-PR tests were performed on Tuesdays and Fridays in a Latin square design with regular FR3 sessions performed the other three days a week. All fluids were presented in ml graduated glass for rats or ml plastic cylinders for mice , with stainless steel drinking spouts inserted through two grommets in front of the cage. Bottles were weighed 6 and 24 hours for rats and 2 hours for mice after the fluids were presented, and measurements were taken to the nearest 0. After 24 hours the ethanol bottle was replaced with a second water bottle that was available for the next 24 hours. This pattern was repeated on Wednesdays and Fridays. The rats had unlimited access to water over the weekend after the 24 hour measurement was taken on Saturday morning. When rats had maintained stable baseline drinking levels for 12 weeks, administration of ezlopitant began. The effect of ezlopitant on consumption of water and salty solution, respectively, was evaluated in the same group Long-Evans rats given intermittent-access to 0. Following the last ezlopitant-saccharin test occasion, the saccharin was removed and the rats were given continuous-access to two bottles of water. The treatment was repeated and reversed between animals 48hrs later. Thus, each animal served as its own control. After the last ezlopitant-water test occasion, the rats were given intermittent-access to one bottle of 0. Two bottles of water were available at all other times. Following stable baseline consumption during six-seven weeks 30—38 drinking sessions, 5. The DID method was also used as a model of sucrose consumption. Horizontal locomotor activity was monitored at ms throughout the sessions. The study was run in 4 daily 2-hour-sessions as described previously \[47\]. In brief, after habituation of boxes Day 1 and injections Day 2 and 3 testing was conducted on Day 4. After 60 minutes, a single injection of the assigned treatment was given, subsequently, the session continued for an additional 60 minutes. Data was collected across the entire 2-hour-session and recorded as distance traveled in cm. Single drug dose-response curve of Substance P SP -stimulated 0. The NK1-receptor antagonist, ezlopitant CJ, \[ 2S,3S-cis diphenylmethyl -N-\[ 2-methoxy,5-isopropylphenyl methyl\]azabicyclo-\[2. The compound was prepared in saline immediately before each injection. All injections were given as an acute i. Statistical analysis was performed using GraphPadPrism software. The locomotor, water- and NaClbottle-choice data were analyzed with Student's t-test. Data from in vitr o functional binding assays were analyzed by non-linear regression with a sigmoidal curve with variable slope to determine EC 50 and IC 50 values. We thank Pfizer Inc for providing ezlopitant for these studies. Competing Interests: The authors have declared that no competing interests exist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. As a library, NLM provides access to scientific literature. PLoS One. Find articles by Pia Steensland. Find articles by Jeffrey A Simms. Find articles by Carsten K Nielsen. Find articles by Joan Holgate. Find articles by Jade J Bito-Onon. Find articles by Selena E Bartlett. Silvana Gaetani : Editor. Received Mar 25; Accepted Aug 9; Collection date Open in a new tab. Similar articles. Add to Collections. 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How can I buy cocaine online in Serre Chevalier