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Browsing by Subject "nAChR"

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  • Nousiainen, Sini (2016)
    Parkinson's disease is a progressive neurodegenerative disease where dopaminergic neurons die in the substantia nigra pars compacta. Dopamine depletion induces typical parkinsonian motor symptoms which are treated by the golden standard medication levodopa and compounds enhancing the effect of levodopa. However in 4-6 years after the initiation of the chronic levodopa therapy abnormal involuntary movements (AIMs, also called levodopa-induced dyskinesia, LID) often develop and can notably worsen the quality of life. The most effective treatment for LID is deep brain stimulation (DBS), but as an invasive method its use is rare and not suitable for all patients. To date the only effective therapy for LID with marketing authorisation is amantadine. The disadvantage of amantadine is loss of efficacy which might appear less than a year after the initiation of medication. The pathophysiology of LID is a diverse phenomenon and includes dysfunctions in several different neurotransmitter systems both in the basal ganglia and in surrounding brain areas. The role of nicotinic acetylcholine receptors (nAChRs) in the pathophysiology of LID has been studied recently. Both nicotine and several nicotine-like agents have been shown to alleviate LID in preclinical studies and nicotine itself has been tested in a clinical phase II study as a potential LID medication. Of various different nAChR subtypes, the α7 receptor seems to be a potential option for future therapy of LID. It has been shown that α7 nAChR knock out mice display an increase in LID suggesting that this nicotinic receptor subtype has an inhibitory impact on the development of LID. Other studies have confirmed this view by showing that a selective α7 nAChR agonist (ABT-107) alleviates LID in primates and is neuroprotective for dopaminergic neurons in rats. Based on these observations, the aim of this study was to examine the effect of a novel α7 nAChR agonist (AZD0328) on LID in a 6-OHDA mouse model of Parkinson's disease. C57BL/6J female mice (n=17) were injected unilaterally 6-OHDA solution (3 µg) into the right medial forebrain bundle (MFB). Degeneration of dopaminergic neurons was detected two weeks after the 6-OHDA injection by measuring the motor performance in rotating rod with accelerated speed and with amphetamine-induced rotametry (2.5 mg/kg, i.p.). In the beginning of the chronic treatment, levodopa (4.5 mg/kg, s.c.) was administered twice daily for four days and then continued once daily (from Mon to Sun) to the end of the experiments. Levodopa treatment had been ongoing for 10 days before the first testing of drug effects. The pretreatment (AZD0328 0.06, 0.19, 1.9 mg/kg or 0.9 % saline, s.c.) was given 30 minutes before levodopa. The study was conducted using a within subject design so that each mouse received all four treatments on four test days during three weeks. Mice were videorecorded for 1 minute 20, 40, 60, 80 and 100 minutes after the levodopa injection was given. After the last recording day mice were killed under anesthesia via perfusion fixation and brains were collected for immunohistochemical staining to measure the extent of degeneration of dopaminergic neurons. 54 % of mice who survived from surgery (13/17) were dyskinetic (n=7). AZD0328 alleviated axial dyskinesia statistically significantly 40 minutes after levodopa injection but the statistical analysis did not reveal which of the doses was the most effective. The pretreatment with AZD0328 did not affect orolingual or forepaw dyskinesia. A potential mechanism of AZD0328 in alleviating LID might be the desensitization of α7 nAChRs which would happen only at very low doses. This means that LID are only attenuated when receptors are temporarily activated and then immediately gradually inactivated. The doses used in this study might have only activated the α7 nAChRs which might explain why no clear alleviation of LID was observed. On the other hand, the acute treatment may also be insufficient to develop desensitization. Additional studies are needed to investigate the effects of chronic administration of AZD0328 on LID in mice.
  • Meijer, Juri (2012)
    Smoking is one of the major causes for premature deaths worldwide. Tobacco smoke contains nicotine, which activates the nicotinic acetylcholine receptors (nAChR) expressed by the human body. nAChRs are part of the cholinergic system and its endogenous neurotransmitter is acetylcholine. The nAChRs are excitatory and the often regulate the release of other neurotransmitters. Nicotine is one of the most addicting compounds known. The rewarding effects of nicotine are mediated through the activation of the mesolimbic dopamine pathway. The mesolimbic pathway is triggered also by the compounds activating the endogenous opioid system thus mediating the rewarding effects and opioid addiction. The nicotine - opioid interactions have been widely studied. It is observed that majority of opioid abusers and patients receiving opioid replacement therapy are smokers. It has been also detected that nicotine releases endogenous opioid peptides in vivo in the brain regions mediating both addiction and analgesia. In addition, the rewarding effect of nicotine attenuates in opioid receptor knock-out rodents. Furthermore, it has been observed that nicotine's rewarding effects can be reduced with opioid receptor antagonists. In order to prevent smoking's negative effects the use opioid antagonists for smoking cessation has been clinically researched with poor results. Many of the opioids in clinical use have diverse and direct interaction with the nAChRs in vitro. E.g. it has been observed that methadone and morphine have an effect on the function of the nAChRs. This may explain partially the smoking behaviour of replacement therapy patients. Opioids are prescribed mainly for the treatment of moderate to intense pain. Nicotine is too found to be analgesic in vivo but in humans its analgesic effect has been questionable. In the experimental part of thesis binding and functional interactions with human's α4β2-nAChR expressed by SH-EP1-hα4β2 cell line was researched with clinically commonly used opioids codeine, oxycodone and tramadol. Competitive binding was studied using [3H]-epibatidine binding assay and the functional effects were studied using 86Rb+-efflux assay. The results suggest that oxycodone and tramadol act as weak competitive antagonists of α4β2-nAChR in vitro in concentrations that are clinically irrelevant. According to the results, however, codeine acts as positive allosteric modulator of α4β2-nAChR potentiating the effects of nicotine in micromolar concentrations. The effect is similar to galantamine, used in treatment of Alzheimer's disease. The clinical relevance of codeine's potentiating nicotine's effect on the function of α4β2-nAChR cannot be estimated according to the results from these studies. Therefore, in order to confirm the results experiments with codeine need to be done in vivo using e.g. α4- and β2-knock-out mice in order to clarify α4β2-nAChR's role in the analgesic and rewarding effects of codeine. However, the results from the experimental part provide valuable information on the interactions of nicotine and opioids. Results from studies conducted with α4β2-nAChRs have not been published enough to determine the importance of the phenomenon in i.a. drug addiction and analgesia.