Browsing by Subject "morfiini"
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(2018)The nucleus accumbens (NAc) is located in the ventral striatum and plays a critical role in drug addiction. NAc receives dopaminergic projections from ventral tegmental area (VTA) which is activated after administration of various abused drugs. Activation of VTA increases the release of dopamine in NAc. Increased dopamine levels induce the release of acetylcholine from striatal cholinergic interneurons. These cholinergic interneurons have been related to the development of addiction and other emotion-related disorders such as depression. Previous studies have shown that a lesion of cholinergic interneurons led to an increase in morphine-induced conditioned place preference in mice. Moreover, an activation of cholinergic interneurons by designer receptors (DREADD) has reduced food consumption motivated by food restriction. The purpose of this study was to investigate whether accumbal cholinergic interneurons mediate alcohol- and morphine-induced conditioned place preference and locomotor activity. The activation of cholinergic interneurons was controlled using DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology. DREADDs are G protein-coupled receptors. Cellular function and activation can be modulated by these receptors. DREADDs are activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Fluorescent protein, mCherry, is attached to DREADDs so that the expression of receptors in brain tissue can be observed. Cre-spesific adeno-associated viruses (AAV) with DREADD gene were injected bilaterally to the nucleus accumbens of ChATcre mice in stereotactic surgery. The effects of alcohol and morphine were tested with conditioned place preference procedure. Mice were divided to three groups after DREADDs: activating receptor Gq (n = 10), inhibiting receptor Gi (n = 9) and control mC (n = 9). There were both male and female mice in every group. Alcohol did not induce conditioned place preference in any group. The locomotor activity of mice significantly increased after alcohol injection compared to saline injection. However, cholinergic interneurons had no effect on the increased locomotor activity. Morphine-induced conditioned place preference was expressed in every group but there were no significant differences between DREADDs and control group when the first 15 minutes and the whole 30 minutes of the place preference test was analysed. Though, Gq-receptor seemed to decrease the place preference compared to control group when the place preference test was observed in five minute intervals. Morphine also significantly increased the locomotor activity of mice, but there were no differences between the groups. Sex had no influence on the place preference, but female mice were more active than male mice during the alcohol conditioning and the alcohol place preference test. The locomotor activity of female mice also increased more than the activity of male mice after morphine injection. The effect of accumbal cholinergic interneurons on alcohol-induced conditioned place preference remained unclear. Activation of cholinergic interneurons suppressed morphine-induced conditioned place preference compared to control group but not enough so that the effect could be seen during the whole place preference test. The mice were same in the morphine test as in the alcohol test so the mice were conditioned to alcohol before morphine and therefore the results of morphine-induced conditioned place preference are not reliable.
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(2020)Osa keskushermostoon vaikuttavista lääkkeistä on riippuvuutta aiheuttavia ja päihteinä käytettyjä. Tämä on olennaista huomioida jo ennen uusien lääkkeiden markkinoille tuloa. Lisäksi on tärkeää yrittää ymmärtää yhä paremmin jo käytössä olevien, mutta väärinkäytettyjen lääkkeiden toimintaa. Erityisesti Yhdysvaltojen tämänhetkinen opioidiepidemia on nostanut esille tällä hetkellä käytössä olevien opioidien haittavaikutukset. Lääkkeen riippuvuuspotentiaalia voidaan mitata monilla eri tavoin. Ehdollistettu paikkahakuisuus (CPP) mittaa tutkittavan aineen palkitsevia ominaisuuksia ja perustuu klassiseen ehdollistumiseen. Menetelmä on hyvin vakiintunut ja soveltuu käytettäväksi eri eläinlajeilla. Menetelmää ei kuitenkaan ole validoitu ihmisillä, ja on syytä huomata, että todellisuudessa ehdollistumistapahtumat voivat olla monimutkaisempia. Tarkastelen tutkielmassani keskushermostoon vaikuttavan lääkeainekandidaatti ganaxolonen väärinkäyttöpotentiaalia ehdollistetun paikkahakuisuuden avulla. Tutkimuksessa käytettiin poistogeenisiä hiiriä, joilta puuttuu toimiva GABAA –reseptorin δ-alayksikkö, sekä villityypin hiiriä. Paikkahakuisuuden sijaan ganaxolonen havaittiin aiheuttavan paikka-aversiota villityypin hiirillä, mutta ei poistogeenisillä hiirillä. Täten vaikuttaa siltä, että lääkkeellä ei luultavasti ole väärinkäyttöpotentiaalia. Lisäksi tutkin samanlaisilla hiirillä morfiinin vaikutusta kivuntuntemiseen. Tässä tutkimuksessa havaitsin, että kyseiset poistogeeniset hiiret olivat herkempiä morfiinin kipua vähentävälle vaikutukselle kokeessa, joka mittaa kipureaktioita spinaalitasolla, mutta supraspinaalireaktioita mittaavassa kokeessa eroa ei havaittu. Lisäksi poistogeenisillä hiirillä ei havaittu paikkahakuisuutta morfiinin suhteen. Tätä tietoa voidaan mahdollisesti myöhemmin hyödyntää kehitettäessä tehokkaampia kipulääkkeitä tai lääkeyhdistelmiä, joilla olisi pienempi riippuvuuspotentiaali.
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(2010)Glutamate is the principal excitatory neurotransmitter in the central nervous system. Glutamatergic neurotransmission plays a central role in the development and maintenance of drug addiction. Glutamate interacts with other neurotransmitters such as dopamine in the actions concerning addiction. During the development of drug addiction, plastic changes in the neuronal connections related to memory and learning occur for example in the amount of synapses and in the efficacy of their action. Glutamatergic AMPA receptor and especially its GluA1 subunit are thought to be included in the neurobiological mechanisms related to drug addiction. Compulsive drug craving and relapses to drug use after a period of abstinence are central problems among people suffering drug addiction. Conditioned place preference is a technique that is used to study motivational properties of drugs in experimental animals. The aim of this master's thesis was to examine the importance of glutamatergic AMPA receptor GluA1 subunit in the morphine-induced place preference and in its extinction and reinstatement behaviour. Locomotor activity of mice was studied during all the phases of experiment. Glutamatergic AMPA receptor GluA1 subunit-deficient (GluA1-/-) and their control (wildtype) mice, based on C57BL/6J mouse strain, were used in the experiments. During the conditioning phase, the mice were trained to associate the effects of morphine (20 mg/kg) with a specific environment. After conditioning, the extinction with morphine paired conditioning environment was assessed by giving saline (0,9 % NaCl solution) to mice. The extinction phase was followed by reinstatement test, in which mice were given morphine (20 mg/kg). The seeking of animals with morphine paired conditioning environment described drug-seeking during different phases of experiment. GluA1-/- mice were more hyperactive when placed in the testing environment compared to the wildtype mice. However, the morphine-induced locomotor activity did not differ between genotypes. Locomotor activity of both genotypes was sensitized equally in consequence of repeated morphine exposures. Morphine induced place preference in both genotypes. Furthermore, the extinction of morphine place preference happened in both genotypes. However, the results of reinstatement test differed partly between genotypes. The place preference was reinstated by morphine in wildtype mice, but not in GluA1-/- mice, when using repeated testing extinction method. Instead of place preference, wildtype mice exhibited place aversion, when extinction method was saline conditioning. As a result of these experiments, extinction method can have an impact on the results of reinstatement test and conclusions cannot be done on the importance of GluA1 subunit in morphine reinstatement. In conclusion, the results of place preference experiments support the conception that GluA1 subunit is not significant in morphine conditioning. However, based on these experiments, GluA1 subunit is not important in morphine extinction, as one might assume on the basis of literature. GluA1 subunit may have an importance in morphine reinstatement, although the results of reinstatement test were partly contradictory.
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(2021)I arbetet undersöktes nivån på vilken ämnena S-ketamin, norketamin och 6- hydroxynorketamin hämmar molekylen UDP-glukuronosyltransferas 2B7, som är det enzym som ligger huvudsakligen bakom metabolisationen av morfin till morfinets glukuronidationsprodukter. Morfin är en opioid, som har många biverkningar och därför är det viktigt att undvika stora morfindoser. Syftet med undersökningen är att hitta läkemedel, som kan administreras tillsammans med morfin för att minska mängden morfin som krävs för smärtlindring. Undersökningen grundar sig på att simulera mänskans biologiska miljö genom inkubation i rätta förhållanden med hjälp av enzymer, som härstammar från mänskolevern. Resultaten var att S-ketamin, norketamin och 6-hydroxynorketamin hämmar metabolisationen av morfin. S-ketamin var det mest potenta ämnet. Resultaten ger en insikt om att i vidare undersökningar torde S-ketamin få ett större värde över de två andra undersökta ämnen. Om dessa resultat korrelerade kliniskt, skulle patienter möjligtvis få samma smärtlindring med en mindre morfindos.
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(2021)I arbetet undersöktes nivån på vilken ämnena S-ketamin, norketamin och 6- hydroxynorketamin hämmar molekylen UDP-glukuronosyltransferas 2B7, som är det enzym som ligger huvudsakligen bakom metabolisationen av morfin till morfinets glukuronidationsprodukter. Morfin är en opioid, som har många biverkningar och därför är det viktigt att undvika stora morfindoser. Syftet med undersökningen är att hitta läkemedel, som kan administreras tillsammans med morfin för att minska mängden morfin som krävs för smärtlindring. Undersökningen grundar sig på att simulera mänskans biologiska miljö genom inkubation i rätta förhållanden med hjälp av enzymer, som härstammar från mänskolevern. Resultaten var att S-ketamin, norketamin och 6-hydroxynorketamin hämmar metabolisationen av morfin. S-ketamin var det mest potenta ämnet. Resultaten ger en insikt om att i vidare undersökningar torde S-ketamin få ett större värde över de två andra undersökta ämnen. Om dessa resultat korrelerade kliniskt, skulle patienter möjligtvis få samma smärtlindring med en mindre morfindos.
Now showing items 1-5 of 5