Characterizing the differential roles of striatal 5-HT1Aauto- and hetero-receptors in the reduction of l-DOPA-induced dyskinesia.
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-HT1Areceptors (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-HT1Aauto- 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 D1receptor (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-HT1Ahetero-receptor populations.
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: smeadow3@binghamton.edu.
Samantha M
SM
Meadows
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: nchambe4@binghamton.edu.
Nicole E
NE
Chambers
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: mconti2@binghamton.edu.
Melissa M
MM
Conti
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: sbosser1@binghamton.edu.
Sharon C
SC
Bossert
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: ctasber1@binghamton.edu.
Crystal
C
Tasber
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: esheena1@binghamton.edu.
Eitan
E
Sheena
Neurolixis Inc., Dana Point, CA 92629, USA. Electronic address: mvarney@neurolixis.com.
Mark
M
Varney
Neurolixis Inc., Dana Point, CA 92629, USA. Electronic address: anewmantancredi@neurolixis.com.
Adrian
A
Newman-Tancredi
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: cbishop@binghamton.edu.
Christopher
C
Bishop
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
C119079:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methyl-6-methylaminopyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; C524188:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; D000631:Aminopyridines; D000978:Antiparkinson Agents; D010880:Piperidines; D011743:Pyrimidines; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D007980:Levodopa
Biased agonist; LID; Microinjection; Neuropharmacology; Parkinson's disease; Serotonin 1A receptor; Serotonin syndrome; Striatum