Browsing by Subject "conditioned place preference"

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  • Miettinen, Ville (Helsingin yliopisto, 2020)
    Pedunculopontine tegmental nucleus (PPTg) has been connected to many different brain functions. Lesions in this region have been demonstrated to have effects on drug related behavior, learning and locomotion. Furthermore, glutamatergic projections to VTA have been found in earlier studies. VTA is one of the most important brain regions related to feeling of reward. Thus, it is plausible that glutamatergic cells are the ones that are responsible for these alterations in drug related behaviour. Additionally, there are efferents to basal ganglia and regions related to them, which indicates that PPTg is likely to possess some functions related to locomotion. The aim of this study was to explore what kind of differences in food consumption, spontaneous locomotion, morphine induced locomotion and morphine induced conditioned place preference result from modulation of activity of the glutamatergic neurons of the PPTg in mice. In this study DREADD-method was used. This method allowed for both excitation and inhibition of the neurons. This method involves injection viral vector stereotactically to the desired brain region, which leads to expression of artificial receptor in specific type of neurons. These receptors can then be activated by injecting clozapine-Noxide(CNO) intraperitoneally. There were two test groups, one got receptor that activates the neuron when activated, other got one that inhibits the neuron. Control group got receptor that does not react to CNO. In the tests conducted, there was no difference in the amount of food consumed or distance moved spontaneously. In the conditioned place preference experiment, there was no significant difference in distance moved between groups. However, both of the test groups expressed weaker preference to the morphine-paired environment when compared to the control group. This could be explained by reinforcing effects of morphine being mediated through glutamatergic neurons of the PPTg.
  • Kinnunen, Marja (Helsingfors universitet, 2015)
    Histamine is a monoamine structured signal molecule, which takes part in many functions of living organisms. It was first found in brain approximately 70 years ago. Neuronal histamine regulates for example biological rhythms, energy metabolism and thermoregulation. In the 1980's, H3-receptor was recognized in the brain. Neuronal histamine regulates functions of other transmitters for example gamma-aminobutyric acid, glutamate, acetylcholine, noradrenaline and dopamine. Currently, the interactions of histamine and dopamine are not well characterized. Though, it is known that histaminergic fibers innerviate almost every dopaminergic area of the brain. There are also several H3-receptors in the striatum and in the limbic system. These brain areas are important for the rewarding effect of dopamine. The aim of the experimental part of this Master's thesis was to examine the location of histaminergic and dopaminergic nervous systems in mouse brain by using immunohistochemistry. Primary antibodies that were produced in rabbit (anti-histamine (HA)) and in mouse (anti-tyrosine hydroxylase (TH)), and secondary anti-rabbit and anti-mouse anti-bodies, that were produced in goat and conjugated with fluorophores, were used in the study. The samples were imaged with a confocal microscope. The primary aim was to find out, in which addiction related brain areas, histamine and dopamine cells and fibers are located and how they are situated in relation to each other. H3-receptor antagonists have been shown to decrease the consumption and rewarding effect of alcohol in animal models. Therefore, it was examined if non-imidazole structured H3-receptor antagonist also inhibits the rewarding effect of amphetamine, and if it decreases the locomotor activity induced by amphetamine. JNJ-39220675, a neutral antagonist of H3-receptor, and behavioral paradigm of conditioned place preference (CPP) were used in the experiment. CPP was also used to find out if D2-receptor agonist quinpirole cause reward or aversion. The effect of JNJ-39220675 on quinpirole's place preference and change in locomotor activity was also investigated. The interactions of these two pharmacological ligands were also examined in a separate locomotor activity experiment. C57BL/6J mice were used in all experiments. The results show that there are possible synaptic connections of histaminergic and dopaminergic system in substantia nigra, supramammillary nucleus, dorsomedial hypothalamic area and ventral periaqueductal grey area. Also, histaminergic nerve fibers innerviate to the dorsal striatum, which regulates motor functions, and to the ventral striatum, which is a part of the rewarding system of the brain. Hence, it is possible that histamine regulates the actions of dopa-mine in these brain areas. The behavioral experiments showed that JNJ-39220675 inhibits acutely increased locomotor activity caused by amphetamine, and decreases desensitation of decreased locomotor action caused by repeated dose of quinpirole. However, JNJ-39220675 did not have any effect on the rewarding effect of amphetamine, which causes strong sensitization. Also, JNJ-39220675 did not have an effect on quinpirole's aversive action. It remains to be seen, if H3-receptor is a potential target for new medicines in the treatment of different brain diseases and addiction in the future.
  • Kääntä, Kari (Helsingin yliopisto, 2023)
    Psykedeelejä tutkitaan tällä hetkellä aktiivisesti uudenlaisena hoitomuotona erilaisten psykiatristen sairauksien hoidossa. Vallitseva tieteellinen käsitys on, että klassiset psykedeelit eivät aiheuta riippuvuutta. Kahdessa tutkimuksessa klassisista psykedeeleistä lysergihapon dietyyliamidin (LSD) on kuitenkin havaittu aiheuttavan paikkaehdollistumaa rotilla. Paikkaehdollistuman muodostumista pidetään yhtenä riippuvuutta aiheuttavan aineen tunnusmerkeistä. Aivojen palkkiojärjestelmän toiminta on paikkaehdollistuman muodostumisessa merkittävässä osassa. Lisäksi paikkaehdollistumaan ja palkkiojärjestelmään liitettyjen aivoalueiden on havaittu aktivoituvan LSD:n annostelun seurauksena. Tutkimuksessamme tarkastelimme LSD:n kerta-annostelun ja toistetun annostelun vaikutusta c-Fos-proteiinin ilmentymiseen palkkiojärjestelmään liittyvillä aivoalueilla hiirillä. Hiiret (n=12) oli jaettu kolmeen neljän hiiren ryhmään. Kontrolliryhmä sai päivittäin suolaliuosinjektion ja LSD:n kerta-annostelun ryhmässä hiiret saivat kahdeksantena päivänä LSD-injektion (0,1 mg/kg i.p.). Toistetun annostelun ryhmässä hiiret saivat suolaliuos- ja LSD-injektiot vuoropäivinä. Hiirten aivoista tehtiin jääleikkeet, joista tarkasteltiin palkkiojärjestelmään ja paikkaehdollistumaan liittyviä aivoalueita. C-Fos-proteiinin ilmentyminen saatiin näkyviin immunohistokemiallisella värjäyksellä. Tutkimuksessamme nähtiin tilastollisesti merkitsevä ero ventraalisen tegmentumin alueen c-Fos-aktiivisuudessa LSD:n kerta-annostelun ja toistetun annostelun ryhmien välillä, jossa toistetun annostelun ryhmässä aktiivisuus oli korkeampi. Tämä löydös on kyseenalainen, koska toistetun annostelun ryhmän tulos ei kuitenkaan merkitsevästi eronnut kontrolliryhmän c-Fos-aktiivisuudesta. Muiden aivoalueiden osalta käsittelyryhmien välillä ei havaittu tilastollisesti merkitseviä eroja. Käytettyjen positiivisten ja negatiivisten kontrollien tulokset haastavat tutkimuksen tulosten luotettavuuden, mikä voi osittain selittyä havaituilla teknisillä ongelmakohdilla.
  • Ojala, Katja (Helsingfors universitet, 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.
  • Kiiskinen, Tuomo; Korpi, Esa R.; Aitta-aho, Teemu (2019)
    Extinction and reinstatement of morphine-induced conditioned place preference were studied in glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor GluA1 subunit-deficient mice (global GluA1-KO mice). In line with previous findings, both acquisition and expression of conditioned place preference to morphine (20 mg/kg, subcutaneously) were fully functional in GluA1 KO mice compared with wild-type littermate controls (GluA1-WT), thus enabling the study of extinction. With a 10-session extinction paradigm, the GluA1 KO mice showed complete extinction similar to that of the GluA1-WT mice. Morphine-induced reinstatement (10 mg/kg, subcutaneously) was detected in both mouse lines. GluA1 KO mice moved more during all the phases of the experiment, including the place conditioning trials, extinction sessions, and place preference tests. The results suggest that the GluA1 subunit may be dispensable or prone to compensation at the neural circuitries delineating extinction and reinstatement. The GluA1 KO mice show altered long-term between-session habituation, which extends longer than previously anticipated.