Characterizing the differential roles of striatal 5-HT1A auto- and hetero-receptors in the reduction of l-DOPA-induced dyskinesia.

Abstract

l-DOPA remains the benchmark treatment for Parkinson's disease (PD) motor symptoms, but chronic use leads to l-DOPA-induced dyskinesia (LID). The serotonin (5-HT) system has been established as a key modulator of LID and 5-HT1A receptors (5-HT1AR) stimulation has been shown to convey anti-dyskinetic effects. However, 5-HT1AR agonists often compromise clinical efficacy or display intrinsic side effects and their site(s) of actions remain debatable. Recently, highly selective G-protein biased 5-HT1AR agonists, F13714 and F15599, were shown to potently target 5-HT1A auto- or hetero-receptors, respectively. The current investigation sought to identify the signaling mechanisms and neuroanatomical substrates by which 5-HT1AR produce behavioral effects. In experiment 1, hemi-parkinsonian, l-DOPA-primed rats received systemic injections of vehicle, F13714 (0.01 or 0.02mg/kg), or F15599 (0.06 or 0.12mg/kg) 5min prior to l-DOPA (6mg/kg), after which LID, motor performance and 5-HT syndrome were rated. Both compounds significantly reduced LID, without affecting motor performance, however, acute administration of F13714 significantly induced 5-HT syndrome at anti-dyskinetic doses. In experiment 2, we elucidated the role of striatal 5-HT1AR in the effects of F13714 and F15599. Hemi-parkinsonian, l-DOPA-primed rats received bilateral intra-striatal microinjections of either F13714 (0, 2 or 10μg/side) or F15599 (0, 10 or 30μg/side) 5min prior to systemic l-DOPA (6mg/kg). Intra-striatal effects mimicked systemic effects, suggesting that striatal 5-HT1AR sub-populations play an important role in the anti-LID and pro-5-HT syndrome profiles of F13714 and F15599. Finally, in experiment 3, we examined the effects of F13714 and F15599 on D1 receptor (D1R) agonist-induced dyskinesia by administering either compound 5min prior to SKF 38393 (2mg/kg). While F13714 resulted in a mild delay in D1R-mediated dyskinesia, F15599 had no effect. Collectively these data suggest that the F-series compounds articulate their anti-LID effects through activation of a diverse set of striatal 5-HT1A hetero-receptor populations.

• Authors: Samantha M Meadows, Nicole E Chambers, Melissa M Conti, Sharon C Bossert, Crystal Tasber, Eitan Sheena, Mark Varney, Adrian Newman-Tancredi, Christopher Bishop
• Journal: Experimental neurology (Exp Neurol) Vol. 292 Pg. 168-178 (06 2017) ISSN: 1090-2430 [Electronic] United States
• PMID: 28342749 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• 3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methyl-6-methylaminopyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
• 3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
• Aminopyridines
• Antiparkinson Agents
• Piperidines
• Pyrimidines
• Receptor, Serotonin, 5-HT1A
• Serotonin
• Levodopa

Topics

• Aminopyridines (pharmacology)
• Animals
• Antiparkinson Agents (pharmacology)
• Corpus Striatum (drug effects, metabolism)
• Dyskinesia, Drug-Induced (drug therapy)
• Levodopa (pharmacology)
• Male
• Motor Activity (drug effects)
• Neostriatum (drug effects, metabolism)
• Parkinson Disease (drug therapy)
• Piperidines (pharmacology)
• Pyrimidines (pharmacology)
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (drug effects, metabolism)
• Serotonin (metabolism)