Eylem Seç
Investigation of striatal delta opioid and NMDA receptor-mediated transmission in Parkinson's disease and dyskinesia
Başlık:
Investigation of striatal delta opioid and NMDA receptor-mediated transmission in Parkinson's disease and dyskinesia
Yazar:
Hallett, Penelope J., author.
ISBN:
9780438085435
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (353 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
Parkinson's disease is a movement disorder caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Subsequent alterations in the activity of basal ganglia nuclei are implicated in the production of parkinsonian symptoms. Symptomatic treatments for Parkinson's disease rely predominantly on the dopamine-replacing agent levodopa. However repeated administration of levodopa results in side-effects, particularly levodopa induced dyskinesia (LID), and alternative approaches are necessary to manage or prevent these complications. Administration of the delta opioid receptor agonist, SNC80, has previously been reported to exert anti-parkinsonian actions in experimental Parkinson's disease. The role of delta-1 and delta-2 receptor subtypes in mediating this action was investigated by behavioural analysis in the reserpine-treated rat following systemic administration of the delta-1 and delta-2 receptor subtype antagonists, BNTX and naltriben, administered in conjunction with SNC80. Both antagonists were able to block the anti-parkinsonian actions of SNC80, suggesting that neither delta-1 nor delta-2 subtypes of delta opioid receptors alone are responsible for mediating the actions of SNC80. In order to investigate further the role of delta opioid receptors in Parkinson's disease, receptor autoradiography was employed, using [3H]naltrindole, a ligand selective for delta-opioid receptors. Alterations in the binding of delta opioid receptors in the basal ganglia and associated regions were investigated in the reserpine-treated rat and MPTP-lesioned macaque models of Parkinson's disease. Increased binding in premotor cortex, sensorimotor striatum and associative striatum were detected rostrally in reserpinised rats, however, no alteration in binding was found at any region measured in MPTP-lesioned animals, nor in MPTP-lesioned animals with dyskinesia. This suggests that abnormalities in delta opioid receptor transmission in parkinsonism do not lie at the receptor level and that alterations in downstream signalling, G-protein coupling or receptor dimerisation may instead be involved. Abnormalities of striatal NMDA receptor transmission were investigated in animal models of Parkinson's disease and LID. The effect of increasing concentrations of glutamate on binding of the NMDA channel blocker [3H]MK-801 was investigated in extensively-washed striatal membranes prepared from reserpine-treated rats. No change in the EC50 of glutamate to stimulate NMDA receptors was detected. However, the maximal level of specific [3H]MK-801 binding was significantly increased in membranes prepared from reserpine-treated rats compared to vehicle-treated rats suggesting increased activatability of NMDA receptors in parkinsonism. The function of NMDA receptors is influenced by their interactions with associated intracellular proteins and by the number and type of subunits forming NMDA receptors. In situ hybridisation was utilised to determine striatal mRNA expression of the NMDA receptor synapse-associated protein, PSD-95, in parkinsonian and dyskinetic MPTP-lesioned macaques. No significant alteration in striatal PSD-95 mRNA expression was detected. In order to detect striatal NMDA receptor subunit abundance, immunoblotting for NMDA receptor subunits NR1, NR2A and NR2B was carried out in striatal subcellular fractions prepared from parkinsonian and dyskinetic MPTP-lesioned macaques. NR2B subimit abundance in parkinsonian animals was decreased, and NR2A abundance in dyskinetic animals was increased in synaptosomal membranes, suggesting that abnormal NMDA receptor fimction in Parkinson's disease may be reflected in altered receptor composition of synaptic NMDA receptors. These studies highlight the importance of delta opioid and NMDA transmission in Parkinson's disease and LID and illustrate novel approaches to the development of new therapeutic strategies, either by targeting delta opioid receptor subtypes; using subtype-selective NMDA receptor antagonists; or by reversing the delivery of specific NMDA receptor subunits to the synapse.
Notlar:
School code: 1543
Konu Başlığı:
Tüzel Kişi Ek Girişi:
Mevcut:*
Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(686961.1) | 686961-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
On Order
Liste seç
Bunu varsayılan liste yap.
Öğeler başarıyla eklendi
Öğeler eklenirken hata oldu. Lütfen tekrar deneyiniz.
:
Select An Item
Data usage warning: You will receive one text message for each title you selected.
Standard text messaging rates apply.