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Activity of serotonin 5-HT(1A) receptor 'biased agonists' in rat models of Parkinson's disease and L-DOPA-induced dyskinesia.
Neuropharmacology. 2015 Jun; 93:52-67.N

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.

Authors+Show Affiliations

Basal Ganglia Pathophysiology Unit, Dept. Experimental Medical Sciences, Lund University, Sweden. Electronic address: Hanna.Iderberg@med.lu.se.Brains On-Line BV, Groningen, The Netherlands.Neurolixis Inc., Dana Point, CA 92629, USA.Basal Ganglia Pathophysiology Unit, Dept. Experimental Medical Sciences, Lund University, Sweden. Electronic address: Angela.Cenci_Nilsson@med.lu.se.Neurolixis Inc., Dana Point, CA 92629, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25645393

Citation

Iderberg, H, et al. "Activity of Serotonin 5-HT(1A) Receptor 'biased Agonists' in Rat Models of Parkinson's Disease and L-DOPA-induced Dyskinesia." Neuropharmacology, vol. 93, 2015, pp. 52-67.
Iderberg H, McCreary AC, Varney MA, et al. Activity of serotonin 5-HT(1A) receptor 'biased agonists' in rat models of Parkinson's disease and L-DOPA-induced dyskinesia. Neuropharmacology. 2015;93:52-67.
Iderberg, H., McCreary, A. C., Varney, M. A., Cenci, M. A., & Newman-Tancredi, A. (2015). Activity of serotonin 5-HT(1A) receptor 'biased agonists' in rat models of Parkinson's disease and L-DOPA-induced dyskinesia. Neuropharmacology, 93, 52-67. https://doi.org/10.1016/j.neuropharm.2015.01.012
Iderberg H, et al. Activity of Serotonin 5-HT(1A) Receptor 'biased Agonists' in Rat Models of Parkinson's Disease and L-DOPA-induced Dyskinesia. Neuropharmacology. 2015;93:52-67. PubMed PMID: 25645393.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activity of serotonin 5-HT(1A) receptor 'biased agonists' in rat models of Parkinson's disease and L-DOPA-induced dyskinesia. AU - Iderberg,H, AU - McCreary,A C, AU - Varney,M A, AU - Cenci,M A, AU - Newman-Tancredi,A, Y1 - 2015/01/31/ PY - 2014/09/11/received PY - 2015/01/08/revised PY - 2015/01/13/accepted PY - 2015/2/4/entrez PY - 2015/2/4/pubmed PY - 2016/1/2/medline KW - 5-HT KW - 5-HT(1A) receptor KW - 6-OHDA rat model of PD KW - Biased agonist KW - Dopamine, serotonin KW - Parkinson's disease KW - l-DOPA KW - l-DOPA-Induced dyskinesia SP - 52 EP - 67 JF - Neuropharmacology JO - Neuropharmacology VL - 93 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/25645393/Activity_of_serotonin_5_HT_1A__receptor_'biased_agonists'_in_rat_models_of_Parkinson's_disease_and_L_DOPA_induced_dyskinesia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(15)00028-3 DB - PRIME DP - Unbound Medicine ER -