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Browsing by Subject "H3-reseptori"

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  • Aaltonen, Linda (2015)
    Parkinson's disease is a neurodegenerative disease where the nigrostriatal dopaminergic cells die gradually causing severe motor symptoms. Current treatment of the disease relieves the symptoms but does not affect the progression of the disease, nor does it have a neuroprotective effect. The most important drug for the treatment of Parkinson's disease is L-dopa, the precursor of dopamine. With long-term use, L-dopa loses its efficacy and patients start to get adverse effects. The most significant adverse effects are abnormal involuntary movements called dyskinesias. In the literature review of this thesis Parkinson's disease and its treatment is briefly described. Review focuses on the description of the brain cholinergic and histaminergic systems and their receptors along with the available studies about cholinergic and histaminergic neurotransmission in Parkinson's disease 6-hydroxydopamine (6-OHDA) rodent model. The experimental part of this thesis consisted of two different set of experiments and in both of these the dopamine neurons were destroyed unilaterally by injecting 6-OHDA into the striatum. The aim of the first experiment was to examine histamine H3-receptor antagonist JNJ-39220675 and α7-nicotinic receptor agonist PHA-543613, and their combination therapy effects on motor function and the concentrations of striatal neurotransmitters in hemiparkinsonian mice. Effects on motor function were studied two and four weeks after the 6-OHDA injection with cylinder test, the D-amphetamine-induced rotations, and the inverted grid test. After behavioral tests, mice were sacrificed and striatal neurotransmitter concentrations were determinated by HPLC. The aim of the second experiment was to examine if nicotine can relieve L-dopa-induced dyskinesias. In this experiment 6-OHDA was injected at two sites into the striatum, which was intended to produce more extensive destruction of dopaminergic neurons than in the first experiment. The extent of the lesion by 6-OHDA was verified before starting chronic L-dopa treatments with cylinder test. One month after the 6-OHDA injection, five mice were sacrificed and their striatum and substantia nigra sections were measured for destruction of dopaminergic neurons by immunohistochemical TH-staining. Chronic L-dopa treatment with benserazide was started 49‚àí63 days after the 6-OHDA injection. At the same time, mice were divided into two groups. Half of them got normal drinking water and half got nicotine water. During the chronic L-dopa treatment, development of dyskinesias was observed once a week by video tracking. The cylinder test was also done once again after starting the L-dopa treatment. In the first experiment, H3-receptor antagonist JNJ-39220675 showed promising results in improving motor function. Mice used the impaired (contralateral) paw more in the cylinder test and rotated less to the ipsilateral side in the D-amphetamine-induced rotation test than control animals two weeks after the 6-OHDA injection. Combination therapy also reduced the ipsilateral rotations but in the cylinder test it had no effect two weeks after 6-OHDA injection. Because the asymmetry in behavioural tests were caused by destroying dopaminergic neurons, balancing of the motor skills can result from decreased levels of dopamine in the intact side or from increased dopamine levels or stronger dopaminergic postsynaptic transmission in the lesion side. The results four weeks after 6-OHDA injection are not reliable because the striatal samples showed that dopamine concentrations in the lesion side were very close to that of the intact side indicating recovery from the lesion. In the second experiment, mice developed dyskinesias which were decreased with nicotine treatment. Mice also used the contralateral side paw less indicative of loss of dopamine neurons. In agreement, TH-immunostaining confirmed significant loss of TH-positive neurons. Based on these findings, the 6-OHDA injection site, the selected drug doses, and the experimental design seem to fit the evaluation of dyskinesias. The occurrence of dyskinesias and nicotine's effect on them was seen strongest in the body movements. Dyskinesias in forelimbs were minor, but the nicotine treatment decreased them also.
  • Vanhanen, Jenni (2010)
    Histamine is an important neurotransmitter in peripheral as well as in central nervous system. Histaminergic neurons modulate various functions such as sleep-wake cycle, energy metabolism, memory and pain. In addition the brain histaminergic system has been shown to play a role in reinforcement, addiction and addiction related behaviors. After finding the H3 receptor in 1980s it was realised how essential the neuronal histamine is in modulating several central nervous system (CNS) disorders. H3 receptor modulates the synthesis and release of histamine. Furthermore it modulates the release of various other neurotransmitters, such as serotonin, noradrenalin, dopamine, glutamate, γ-aminobutyric acid (GABA) and acethylcoline. The H3 receptor is predominantly expressed in the brain and therefore it is an attractive target for various CNS indications. For more than a decade H3 receptor has gained the interest of many pharmaceutical companies. Several H3 receptor ligands, mainly antagonists or inverse agonists, have been assessed in preclinical as well as in clinical studies. So far there are not enough clinical data on the safety and efficacy of H3 receptor ligands, but there is a strong possibility that H3 receptor antagonists will be used in the treatment of various important disorders, including narcolepsy, schizophrenia and cognitive disorders. Earlier in our research group it was shown that H3 receptor ligands play a major role in ethanol related behaviors. These observations were confirmed in the practical part of this Master's thesis. H3 receptor modulates ethanol stimulation as well as ethanol reinforcement. Both H3 receptor antagonists, ciproxifan and JNJ-10181457 were able to inhibit ethanol-evoked conditioned place preference (CPP). This means they were able to inhibit ethanol reward and reinforcement. Ciproxifan also increased ethanol stimulation. Immepip on the other hand did not alter ethanol-evoked CPP, but it totally inhibited the stimulation of locomotor activity by ethanol. The dopaminergic system regulates both reward and motor functions. The postsynaptic H3 receptors have been shown to be able to heteromerize with both dopamine D1- and D2- receptors in striatum. The formed heteromers modulate dopaminergic neurotransmission in vitro, which may lead to alterations in behavior in vivo. It is therefore possible that the responses we have seen on a behavioral level in this Master's thesis project are due to interactions between histaminergic and dopaminergic systems in striatal areas. The H3 receptor is an interesting target in the drug development of various CNS disorders. The responses seen in this Master's thesis project also indicate that the blockade of H3 receptor inhibit ethanol reward and reinforcement. In conclusion, these findings indicate that H3 receptor antagonists could possibly have therapeutic potential in treating ethanol addiction.