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

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

  • Exp Neurol. 2017 Jun;292:168-178. doi: 10.1016/j.expneurol.2017.03.013.
Samantha M Meadows 1,  Nicole E Chambers 2,  Melissa M Conti 3,  Sharon C Bossert 4,  Crystal Tasber 5,  Eitan Sheena 6,  Mark Varney 7,  Adrian Newman-Tancredi 8,  Christopher Bishop 9
Affiliations

Affiliations

  • 1 Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: smeadow3@binghamton.edu.
  • 2 Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: nchambe4@binghamton.edu.
  • 3 Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: mconti2@binghamton.edu.
  • 4 Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: sbosser1@binghamton.edu.
  • 5 Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: ctasber1@binghamton.edu.
  • 6 Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: esheena1@binghamton.edu.
  • 7 Neurolixis Inc., Dana Point, CA 92629, USA. Electronic address: mvarney@neurolixis.com.
  • 8 Neurolixis Inc., Dana Point, CA 92629, USA. Electronic address: anewmantancredi@neurolixis.com.
  • 9 Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: cbishop@binghamton.edu.
PMID: 28342749 DOI: 10.1016/j.expneurol.2017.03.013
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.

Keywords

Biased agonist; LID; Microinjection; Neuropharmacology; Parkinson's disease; Serotonin 1A receptor; Serotonin syndrome; Striatum.

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