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  • 20 mg/kg  (1)
  • Kappa opioids  (1)
  • Key Words AMPA receptor  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Antiparkinsonian and antidyskinetic activity of drugs targeting central glutamatergic mechanisms (2000)
    Springer
    Journal of neurology 247 (2000), S. II36 
    Details
    ISSN: 1432-1459
    Keywords: Key Words AMPA receptor ; Medium spiny neuron ; NMDA ; receptor ; Phosphorylation ; Signal transduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00007759
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Effects of kappa receptor agonists on D1 and D2 dopamine agonist and antagonist-induced behaviors (1996)
    Springer
    Psychopharmacology 123 (1996), S. 215-221 
    Details
    ISSN: 1432-2072
    Keywords: Dopamine ; Kappa opioids ; Spiradoline ; Catalepsy ; Grooming ; Stereotypies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02246181
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Tolerance to a suprathreshold dose of L-Dopa in MPTP mice: effects of glutamate antagonists (1999)
    Springer
    Journal of neural transmission 106 (1999), S. 283-300 
    Details
    ISSN: 1435-1463
    Keywords: Keywords: C57 Bl/6 mice ; MPTP ; suprathreshold ; L-Dopa ; 20 mg/kg ; chronic injections ; tolerance ; NMDA antagonists ; MK-801 ; CGP 40116 ; reinstatement ; synergism ; parkinsonism.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Three experiments were performed to study the development and manipulation of tolerance to a suprathreshold dose of L-Dopa (20 mg/kg, s.c.) in MPTP-treated and control (saline-injected) C57 Bl/6 mice. The motor activity reinstatement effect of this dose of L-Dopa upon MPTP-treated mouse behaviour deteriorated from the 13th injection (Test Day 8) of L-Dopa onwards and reached basal level (i.e. no stimulatory effects of the drug) by the 16th administration (Test Day 10). Administration of L-Dopa to control mice reduced locomotor and rearing activity throughout the tolerance development period (Test Days 1–12) during the first hour after injection, and then increased locomotor activity during the second hour. The effects of combining either a noncompetitive, MK-801, or a competitive, CGP 40116, glutamate antagonist with L-Dopa, following tolerance development, were assessed in MPTP mice on the 23rd day of L-Dopa administration (Test Day 13). MK-801 (0.1 mg/kg, s.c.) reinstated the locomotory and rearing behaviour induced by L-Dopa; CGP 40116 did so also to a greater extent in the dose range 0.01 to 0.03 mg/kg. These results indicate that MPTP-treated mice continue to offer a useful parkinsonian model also for the examination of different aspects of the "wearing-off" phenomenon of L-Dopa tolerance and in particular the putative glutamatergic involvement. The clinical consequences may be far-reaching for the utility of L-Dopa in Parkinson's disease, whether the effects demonstrated be of a reinstatement or synergistic na-ture, once therapeutically adequate glutamate antagonists are more readily available.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007020050158
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    Paper (German National Licenses)
    Fulltext
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