Glutamatergic Modulation of Cue-Induced Drug-Seeking Behavior in the Rat

The characteristics of drug addiction include compulsive drug use despite negative consequences and re-occurring relapses, returns to drug use after a period of abstinence. Therefore, relapse prevention is one of the major challenges for the treatment of drug addiction. There are three main factors capable of inducing craving for drugs and triggering relapse long after cessation of drug use and dissipation of physical withdrawal signs: stress, re-exposure to the drug, and environmental stimuli (cues) that have been previously associated with drug use. The neurotransmitters dopamine and glutamate have been implicated in the modulation of drug-seeking behavior. The aim of this project was to examine the role of glutamatergic neurotransmission in relapse triggered by conditioned drug-associated stimuli. The focus was on clarifying whether relapse to drug seeking can be attenuated by blockade of glutamate receptors. In addition, as the nucleus accumbens has been proposed to participate in the modulation of drug-seeking behavior, the effects of glutamate receptor blockade in this brain structure on cue-induced relapse were investigated. The studies employed animals models in which rats were trained to press a lever in a test cage to obtain alcohol or intravenous cocaine. Drug availability was paired with distinct olfactory, auditory, or visual stimuli. This phase was followed by extinction training, during which lever presses did not result in the presentation of the drug or the drug-associated stimuli. Extinction training led to a gradual decrease in the number of lever presses during test sessions. Relapse was triggered by presenting the rats with the drug-associated stimuli in the absence of alcohol or cocaine. The drug-associated stimuli were alone capable of inducing resumption of lever pressing and maintaining this behavior during repeated testing. The number of lever presses during a session represented the intensity of drug-seeking and relapse behavior. The results suggest that glutamatergic neurotransmission is involved in the modulation of drug-seeking behavior. Both alcohol and cocaine relapse were attenuated by systemic pretreatment with glutamate receptor antagonists. However, differences were found in the ability of ionotropic AMPA/kainate and NMDA receptor antagonists to regulate drug-seeking behavior. The AMPA/kainate antagonists CNQX and NBQX, and L-701,324, an antagonist with affinity for the glycine site of the NMDA receptor, attenuated cue-induced drug seeking, whereas the competitive NMDA antagonist CGP39551 and the NMDA channel blocker MK-801 were without effect. MPEP, an antagonist at metabotropic mGlu5 glutamate receptors, also decreased drug seeking, but its administration was found to lead to conditioned suppression of behavior during subsequent treatment sessions, suggesting that MPEP may have undesirable side effects. The mGluR2/3 agonist LY379268 and the mGluR8 agonist (S)-3,4-DCPG decreased both cue-induced relapse to alcohol drinking and alcohol consumption. Control experiments showed however that administration of the agonists was accompanied by motor suppression limiting their usefulness. Administration of the AMPA/kainate antagonist CNQX, the NMDA antagonist D-AP5, and the mGluR5 antagonist MPEP into the nucleus accumbens resulted also in a decrease in drug-seeking behavior, suggesting that the nucleus accumbens is at least one of the anatomical sites regulating drug seeking and mediating the effects of glutamate receptor antagonists on this behavior.Alkoholi- ja huumeriippuvuudelle on tyypillistä pakonomainen tarve käyttää päihdettä ja toistuvat retkahtamiset raittiiden kausien jälkeen. Stressi, päihteelle altistuminen ja päihteen käyttöön liittyneet ehdollistuneet ärsykkeet voivat aiheuttaa voimakkaan ja hallitsemattoman päihteen himon ja retkahtamisen kauankin päihteen käytön ja fyysisten vieroitusoireiden loputtua. Näin ollen tehokas päihderiippuvuuden hoito edellyttää paitsi päihteiden akuuttien vaikutusmekanismien selvittämistä myös retkahtamisen neurobiologian tuntemista. Dopamiini ja glutamaatti ovat pääasialliset päihdehakuista käyttäytymistä säätelevät hermovälittäjäaineet. Tutkimuksen tarkoituksena oli selvittää glutamatergisen hermovälityksen merkitystä aistiärsykkeiden laukaisemassa retkahtamisessa. Erityisesti pyrittiin selvittämään, voidaanko retkahtamisalttiutta vähentää glutamaattireseptoreiden salpauksella. Lisäksi tutkittiin retkahtamiskäyttäytymisen kannalta tärkeänä pidetyn accumbens-aivotumakkeen merkitystä aistiärsykkeiden laukaisemassa päihdehakuisessa käyttäytymisessä. Tutkimuksissa käytettiin koe-eläinmalleja, joissa rotat opetettiin annostelemaan itselleen alkoholia tai kokaiinia koehäkissä olevaa vipua painamalla. Päihteiden saatavuuteen yhdistettiin valo-, ääni- tai tuoksuärsykkeitä. Opetusta seuranneen ekstinktiovaiheen aikana päihdettä ei ollut saatavilla eikä koehäkissä ollut aistiärsykkeitä. Tällöin vivun painaminen vähitellen lakkasi palkinnon puuttuessa. Retkahtaminen laukaistiin altistamalla rotat päihteiden vaikutuksiin yhdistyneille aistiärsykkeille. Tällöin vivun painaminen alkoi uudelleen, vaikka alkoholia tai kokaiinia ei ollut testitilanteessa saatavilla. Vivunpainallusten määrä retkahtamistestissä mittasi retkahtamisalttiutta ja päihdehakuisuutta. Tulokset osoittavat, että glutamaterginen hermovälitys säätelee päihdehakuista käyttäytymistä. Sekä alkoholi- että kokaiiniretkahtamista voitiin vähentää systeemisesti annostelluilla glutamaattireseptoriantagonisteilla. Ionotrooppisten glutamaatti-antagonistien vaikutus riippui kuitenkin reseptorityypistä sekä sitoutumiskohdasta reseptorissa. AMPA/kainaattiantagonistit CNQX ja NBQX sekä NMDA-reseptorin glysiinikohtaan sitoutuva antagonisti L-701,324 vähensivät retkahtamista. Sen sijaan kompetitiivisella NMDA-antagonisti CGP39551:llä ja NMDA-reseptorin kanavasalpaaja MK-801:llä ei ollut vaikutusta retkahtamisalttiuteen. mGluR5-tyypin metabotrooppinen glutamaattireseptoriantagonisti MPEP vähensi päihdehakuista käyttäytymistä, mutta lääkeaineen annostelulla oli myös ehdollistuneita, rottien vivunpainamista alentavia pitkäaikaisvaikutuksia. mGluR2/3-agonisti LY379268 ja mGluR8-agonisti (S)-3,4-DCPG vähensivät sekä alkoholin juomista että aistiärsykkeiden laukaisemaa retkahtamista, mutta molemmat agonistit heikensivät myös motorista suorituskykyä. Ei-toivotut sivuvaikutukset tulevat todennäköisesti estämään lääkeaineiden hyötykäytön. AMPA/kainaattiantagonisti CNQX, NMDA-antagonisti D-AP5 ja mGluR5-antagonisti MPEP vähensivät kokaiiniretkahtamista myös aivojen accumbens-tumakkeeseen annosteltuna. Tämä viittaa siihen, että accumbens-tumake on yksi aivoalueista, joiden kautta glutamaattireseptoriantagonistien retkahtamista hillitsevät vaikutukset välittyvät

Dopaminergic modulation of reward-guided decision making in alcohol-preferring AA rats

R**esults from animal gambling models have highlighted the importance of dopaminergic neurotransmission in modulating decision making when large sucrose rewards are combined with uncertainty. The majority of these models use food restriction as a tool to motivate animals to accomplish operant behavioral tasks, in which sucrose is used as a reward. As enhanced motivation to obtain sucrose due to hunger may impact its reward-seeking effect, we wanted to examine the decision-making behavior of rats in a situation where rats were fed ad libitum. For this purpose, we chose alcohol-preferring AA (alko alcohol) rats, as these rats have been shown to have high preference for sweet agents. In the present study, AA rats were trained to self-administer sucrose pellet rewards in a two-lever choice task (one pellet vs. three pellets). Once rational choice behavior had been established, the probability of gaining three pellets was decreased over time (50%, 33%, 25% then 20%). The effect of D-amphetamine on decision making was studied at every probability level, as well as the effect of the dopamine D-1 receptor agonist SKF-81297 and D-2 agonist quinpirole at probability levels of 100% and 25%. D-Amphetamine increased unprofitable choices in a dose-dependent manner at the two lowest probability levels. Quinpirole increased the frequency of unprofitable decisions at the 25% probability level, and SKF-82197 did not affect choice behavior. These results mirror the findings of probabilistic discounting studies using food-restricted rats. Based on this, the use of AA rats provides a new approach for studies on reward-guided decision making. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Amphetamine primes enhanced motivation toward uncertain choices in rats with genetic alcohol preference

Comorbidity with gambling disorder (GD) and alcohol use disorder (AUD) is well documented. The purpose of our study was to examine the influence of genetic alcohol drinking tendency on reward-guided decision making behavior of rats and the impact of dopamine releaser D-amphetamine on this behavior. In this study, Alko alcohol (AA) and Wistar rats went through long periods of operant lever pressing training where the task was to choose the profitable of two options. The lever choices were guided by different-sized sucrose rewards (one or three pellets), and the probability of gaining the larger reward was slowly changed to a level where choosing the smaller reward would be the most profitable in the long run. After training, rats were injected (s.c.) with dopamine releaser D-amphetamine (0.3, 1.0 mg/kg) to study the impact of rapid dopamine release on this learned decision making behavior. Administration of D-amphetamine promoted unprofitable decision making of AA rats more robustly when compared to Wistar rats. At the same time, D-amphetamine reduced lever pressing responses. Interestingly, we found that this reduction in lever pressing was significantly greater in Wistar rats than in AA rats and it was not linked to motivation to consume sucrose. Our results indicate that conditioning to the lever pressing in uncertain environments is more pronounced in AA than in Wistar rats and indicate that the reinforcing effects of a gambling-like environment act as a stronger conditioning factor for rats that exhibit a genetic tendency for high alcohol drinking.Peer reviewe

The κ-opioid receptor antagonist JDTic decreases ethanol intake in alcohol-preferring AA rats

Studies suggest that the kappa-opioidergic system becomes overactivated as ethanol use disorders develop. Nalmefene, a currently approved treatment for ethanol use disorders, may also elicit some of its main effects via the kappa-opioidergic system. However, the exact role of kappa-opioid receptors on regulating ethanol intake and contribution to the development of ethanol addiction remains to be elucidated. The aim of the present study was to clarify the role of accumbal kappa-opioid receptors in controlling ethanol intake in alcohol-preferring Alko Alcohol (AA) rats. Microinfusions of the long-acting and selective kappa-opioid receptor antagonist JDTic (1-15 mu g/site) were administered bilaterally into the nucleus accumbens shell of AA rats voluntarily consuming 10% ethanol solution in the intermittent, time-restricted two-bottle choice access paradigm. JDTic (10 mg/kg) was also administered subcutaneously. Both the acute and long-term effects of the treatment on ethanol intake were examined. As a reference, nor-BNI (3 mu g/site) was administered intra-accumbally. Systemically administered JDTic decreased ethanol intake significantly 2 days and showed a similar trend 4 days after administration. Furthermore, intra-accumbally administered JDTic showed a weak decreasing effect on ethanol intake long-term but had no acute effects. Intra-accumbal administration of nor-BNI tended to decrease ethanol intake. The results provide further evidence that kappa-opioid receptors play a role in controlling ethanol intake and that accumbal kappa-opioid receptors participate in the modulation of the reinforcing effects of ethanol. Furthermore, the results suggest that kappa-opioid receptor antagonists may be a valuable adjunct in the pharmacotherapy of ethanol use disorders.Peer reviewe

Screening for potential undiagnosed Gaucher disease patients : Utilisation of the Gaucher earlier diagnosis consensus point-scoring system (GED-C PSS) in conjunction with electronic health record data, tissue specimens, and small nucleotide polymorphism (SNP) genotype data available in Finnish biobanks

Background: Autosomal recessive Gaucher disease (GD) is likely underdiagnosed in many countries. Because the number of diagnosed GD patients in Finland is relatively low, and the true prevalence is currently not known, it was hypothesized that undiagnosed GD patients may exist in Finland. Our previous study demonstrated the applicability of Gaucher Earlier Diagnosis Consensus point-scoring system (GED-C PSS; Mehta et al., 2019) and Finnish biobank data and specimens in the automated point scoring of large populations. An indicative point -score range for Finnish GD patients was determined, but undiagnosed patients were not identified partly due to high number of high-score subjects in combination with a lack of suitable samples for diagnostics in the assessed biobank population. The current study extended the screening to another biobank and evaluated the feasibility of utilising the automated GED-C PSS in conjunction with small nucleotide polymorphism (SNP) chip genotype data from the FinnGen study of biobank sample donors in the identification of undiagnosed GD patients in Finland. Furthermore, the applicability of FFPE tissues and DNA restoration in the next-generation sequencing (NGS) of the GBA gene were tested. Methods: Previously diagnosed Finnish GD patients eligible to the study, and up to 45,100 sample donors in Helsinki Biobank (HBB) were point scored. The GED-C point scoring, adjusted to local data, was automated, but also partly manually verified for GD patients. The SNP chip genotype data for rare GBA variants was visually assessed. FFPE tissues of GD patients were obtained from HBB and Biobank Borealis of Northern Finland (BB). Results: Three previously diagnosed GD patients and one patient previously treated for GD-related features were included. A genetic diagnosis was confirmed for the patient treated for GD-related features. The GED-C point score of the GD patients was 12.5-22.5 in the current study. The score in eight Finnish GD patients of the previous and the current study is thus 6-22.5 points per patient. In the automated point scoring of the HBBPeer reviewe

Importance of GluA1 Subunit-Containing AMPA Glutamate Receptors for Morphine State-Dependency

Peer reviewe

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets

Epitranscriptomics of Ischemic Heart Disease - The IHD-EPITRAN Study Design and Objectives

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m(6)A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m(6)A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m(6)A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.</p

Harrasta terveellisesti ja turvallisesti itsepuolustuslajeja

TIIVISTELMÄ Arras, Pia & Bäckström, Daniela. Harrasta terveellisesti ja turvallisesti itsepuolustuslajeja. Helsinki, syksy 2012, 45 s., 2 liitettä. Diakonia-ammattikorkeakoulu, Diak Etelä Helsinki. Hoitotyön koulutusohjelma, sairaanhoitaja (AMK). Opinnäytetyö käynnistettiin Helsingin itsepuolustuskoulun kanssa. Yhteisen hankkeen taustalla ovat samat mielenkiinnon kohteet ja havaittu tarve ensiaputaitojen kehittämiseen. Työelämälähtöisen opinnäytetyön tavoitteena oli tuottaa käytännöllinen ensiapuopas 7-11-vuotiaiden lasten itsepuolustuslajeja ohjaaville opettajille. Opas vahvistaa myös opettajien osaamista lasten ja nuorten terveyden edistämisen alueella. Työn tarkoituksena oli lasten liikuntavammojen ehkäiseminen ja hoito sekä liikunnan tärkeyden huomioiminen. Opinnäytetyö sisältää teoreettisen osan terveyden edistämisestä sekä produktion. Raportissa myös kuvataan prosessin eri vaiheet. Opinnäytetyössä käytetään itsepuolustuslajien valmentajan sijasta nimitystä opettaja, koska tämä oli yhteistyötahomme käytäntö. Käytämme Helsingin itsepuolustuskoulusta nimitystä Hipko, koska tätä nimitystä kyseisestä yrityksestä käytetään yleisimmin. Produktion sisältöä suunniteltiin yhdessä Hipkon kanssa. Aineistoa kerättiin oppaaseen kirjallisuuskatsauksen pohjalta samalla paneutuen alan ajankohtaisiin tutkimuksiin ja kehittämistarpeisiin. Asiantuntijahaastattelut toteutettiin yksilöhaastattelun muodossa. Produktio tuli Hipkon saleille opettajien käyttöön. Produktin arvioinnin suorittivat Hipkon lapsia ohjaavat opettajat vastaamalla arviointilomakkeeseen. Arvioinnin perusteella muutimme kieliasua varmempaan sanakäyttöön. Kuviakin toivottiin lisää, mutta tässä emme olleet samaa mieltä. Mielestämme kuvia oli havainnollistamiseen tarpeeksi. Produktin tavoitteena oli, että opettajat saisivat tietoa ensiavun antamisesta liikuntavamman sattuessa. Opas on myös opettajien opiskeltavissa ja vammojen sattuessa helpon luettavuutensa takia helposti käytettävissä. Saamamme palautteen mukaan opas on opettajilla kovassa käytössä, kun he käyvät läpi omia ajantasaisia ensiaputaitojaan. Opasta käytetään myös lasten opetusmateriaaleissa. Opasta säilytetään Hipkon saleilla. Olemme oppineet lisää terveellisistä elämäntavoista sekä siitä, kuinka tärkeää terveyden edistäminen on. Olemme oppineet lisää lapsen kehitysprosessista ja terveellisten elämäntapojen vaikutuksesta lapsen kasvuun. Olemme saaneet laajan näkemyksen liikuntavammoista ja niiden ensiavusta. Olemme myös oppineet, millaisia ensiaputaitoja opettajilla tällä hetkellä on. Asiasanat: urheiluvammat, lapset, ensiapu, oppaatABSTRACT Arras, Pia and Bäckström, Daniela. First Aid Guide for Instructors of Martial Arts of Children. 43p.,2 appendices. Language: Finnish. Helsinki, Spring 2012. Diaconia University of Applied Sciences. Degree Programme in Nursing. Degree: Nurse. The objective of this thesis was to produce a practical first aid guide book for martial arts’ instructors training children. The thesis focused on the prevention of children’s injuries when doing martial arts. In addition, the thesis consists of health promotion, treatment of sport injuries and the importance of sports for children. The content of this thesis was produced in partnership with the Helsinki School of Martial Arts, Hipko. As for method, we interviewed 3 specialists of Martial Arts three times at their gym. We gathered the interviews and made a summary of the answers. We also used scientific articles, surveys and literature processing our topic. The target group was the instructors coaching children from the age of 7 to 11. Conclusions indicate that instructors need more training in first aid and support in preventing injuries, such as in health promotion. This means for example instructing children how to eat healthy, what is the right amount of exercise for a child and how important sleeping is for a developing child. The product was released as a paper version at the gym of Hipko and is used by instructors monthly. We reserved feedback which was positive. They thought the guide book was diverse and easy to read. It could have contained more pictures. In the future we recommend studies about the instructors skills in first aid

Personality traits measured at baseline can predict academic performance in upper secondary school three years late

The aim of the present study was to explore the ability of personality to predict academic performance in a longitudinal study of a Swedish upper secondary school sample. Academic performance was assessed throughout a three-year period via final grades from the compulsory school and upper secondary school. The Big Five personality factors (Costa & McCrae, 1992) - particularly Conscientiousness and Neuroticism - were found to predict overall academic performance, after controlling for general intelligence. Results suggest that Conscientiousness, as measured at the age of 16, can explain change in academic performance at the age of 19. The effect of Neuroticism on Conscientiousness indicates that, as regarding getting good grades, it is better to be a bit neurotic than to be stable. The study extends previous work by assessing the relationship between the Big Five and academic performance over a three-year period. The results offer educators avenues for improving educational achievement