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  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Journal of neurology 247 (2000), S. II36 
    ISSN: 1432-1459
    Schlagwort(e): Key Words AMPA receptor ; Medium spiny neuron ; NMDA ; receptor ; Phosphorylation ; Signal transduction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Motor dysfunction produced by the chronic non-physiological stimulation of dopaminergic receptors on striatal medium spiny neurons is associated with alterations in the sensitivity of glutamatergic receptors, including those of the N-methyl-D-aspartate (NMDA) subtype. Functional characteristics of these ionotropic receptors are regulated by their phosphorylation state. Lesioning the nigrostriatal dopamine system of rats induces parkinsonian signs and increases the phosphorylation of striatal NMDA receptor subunits on serine and tyrosine residues. The intrastriatal administration of certain inhibitors of the kinases capable of phosphorylating NMDA receptors produces a dopaminomimetic motor response in these animals. Treating parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the serine and tyrosine phosphorylation of specific NMDA receptor subunits. Again, the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases alleviates the motor complications. NMDA receptor antagonists, including some non-competitive channel blockers, act both palliatively and prophylactically in rodent and primate models to reverse these levodopa-induced response alterations. Similarly, in clinical studies dextrorphan, dextromethorphan, and amantadine have been found to be efficacious against motor complications. Recent observations in animal models further indicate that certain amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists alleviate, while others exacerbate, these complications. Thus, it appears that the denervation or intermittent stimulation of striatal dopaminergic receptors differentially activates signal transduction pathways in medium spiny neurons. These in turn modify the phosphorylation state of ionotropic glutamate receptors and consequently their sensitivity to cortical input. These striatal changes contribute to symptom production in Parkinson’s disease, and their prevention or reversal could prove useful in the treatment of this disorder.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
    ISSN: 1432-2072
    Schlagwort(e): Dopamine ; Kappa opioids ; Spiradoline ; Catalepsy ; Grooming ; Stereotypies
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Striatal dynorphin-containing neurons receive dopaminergic inputs from the substantia nigra pars compacta and project primarily to the substantia nigra pars reticulata and entoped uncular nucleus. These neurons mainly express dopamine (DA) D1 receptors and thus dynorphin system stimulation might be expected largely to influence D1 receptor agonist or antagonist effects on motor function. It is well known the interaction existing between DA D1 and D2 drugs in the induction of behavioral effects. However, the effects of dynorphin on selective D1 and D2 DA agonist and antagonist-induced behaviors have not yet been investigated. Administration of the kappa agonists spiradoline (0.5, 1 and 5 mg/kg) or U50,488H (1, 10 and 25 mg/kg) decreased non-stereotyped grooming induced by the selective D1 agonist SKF38393. This effect was inhibited by the non-selective opioid receptor antagonist naloxone (20 mg/kg) and by the selective kappa antagonist nor-binaltorphimine (nor-BNI, 20 mg/kg). Stereotypies induced by the selective D2 agonist quinpirole were decreased by spiradoline (1 and 5 mg/kg) and by U50,488H (1, 10 and 25 mg/kg), while jerking movements of a type associated with increased D2 receptor and decreased D1 receptor stimulation emerged. Kappa agonist effects were inhibited by the prior administration of SKF38393 (10 mg/kg); these inhibitory effects were blocked by prior administration of the D1 antagonist SCH23390 (5 mg/kg). Naloxone reversed the effects of both kappa agonists on quinpirole-induced stereotypies. Kappa agonists increased D1 antagonist-induced catalepsy, but had no effect on D2 antagonist-induced catalepsy. Naloxone and nor-BNI inhibited this effect. These results suggest that the motoric effects of D1 receptor antagonists in part reflect stimulation of striatal dynorphin containing efferents.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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