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Activity of serotonin 5-HT1A receptor 'biased agonists' in rat models of Parkinson's disease and l-DOPA-induced dyskinesia.

Iderberg, Hanna LU ; McCreary, A C; Varney, M A; Cenci Nilsson, Angela LU and Newman-Tancredi, A (2015) In Neuropharmacology 93. p.52-67
Abstract
Serotonin 5-HT1A receptor agonists reduce l-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714... (More)
Serotonin 5-HT1A receptor agonists reduce l-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714 abolished l-DOPA-induced AIMs even at very low doses (0.02-0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of l-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the l-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of l-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested. Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and l-DOPA dose-sparing effects in PD patients. (Less)
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author
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type
Contribution to journal
publication status
published
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in
Neuropharmacology
volume
93
pages
52 - 67
publisher
Elsevier
external identifiers
  • pmid:25645393
  • wos:000353729900006
  • scopus:84922741840
ISSN
1873-7064
DOI
10.1016/j.neuropharm.2015.01.012
language
English
LU publication?
yes
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0ecf3320-1799-4717-adf6-4639e9c2436b (old id 5145615)
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http://www.ncbi.nlm.nih.gov/pubmed/25645393?dopt=Abstract
date added to LUP
2015-03-03 16:43:54
date last changed
2017-10-01 03:33:14
@article{0ecf3320-1799-4717-adf6-4639e9c2436b,
  abstract     = {Serotonin 5-HT1A receptor agonists reduce l-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714 abolished l-DOPA-induced AIMs even at very low doses (0.02-0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of l-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the l-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of l-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested. Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and l-DOPA dose-sparing effects in PD patients.},
  author       = {Iderberg, Hanna and McCreary, A C and Varney, M A and Cenci Nilsson, Angela and Newman-Tancredi, A},
  issn         = {1873-7064},
  language     = {eng},
  pages        = {52--67},
  publisher    = {Elsevier},
  series       = {Neuropharmacology},
  title        = {Activity of serotonin 5-HT1A receptor 'biased agonists' in rat models of Parkinson's disease and l-DOPA-induced dyskinesia.},
  url          = {http://dx.doi.org/10.1016/j.neuropharm.2015.01.012},
  volume       = {93},
  year         = {2015},
}