Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats.
Dopamine (DA) replacement therapy with l-DOPA is the standard treatment for Parkinson's disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as L-DOPA-induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. However neither the persistence nor the mechanism(s) of these effects have been investigated. Therefore the current endeavor sought to mimic a prolonged regimen of SERT inhibition in L-DOPA-primed and -naïve hemi-parkinsonian rats. Rats received 3 weeks of daily co-treatment of the selective 5-HT reuptake inhibitors (SSRIs) citalopram (0, 3, or 5 mg/kg) or paroxetine (0, 0.5, or 1.25 mg/kg) with L-DOPA (6 mg/kg) during which AIMs and motor performance were monitored. In order to investigate potential mechanisms of action, tissue levels of striatal monoamines were monitored and the 5-HT(1A) receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in L-DOPA-primed and -naïve subjects, respectively, without interfering with motor performance. Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in L-DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT(1A) receptors while maintaining L-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels.
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: costock1@binghamton.edu.
Corinne Y
CY
Ostock
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: dlinden1@binghamton.edu.
David
D
Lindenbach
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: agolden1@binghamton.edu.
Adam A
AA
Goldenberg
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: ekampto1@binghamton.edu.
Elias
E
Kampton
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: rdelliso@binghamton.edu.
Rich
R
Dell'isola
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: akatzma1@binghamton.edu.
Aaron C
AC
Katzman
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
D000818:Animals; D015283:Citalopram / Q000008:administration & dosage / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D017374:Paroxetine / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*
D015283:Citalopram; D004298:Dopamine; D007980:Levodopa; D016627:Oxidopamine; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors
3,4-dihydroxyphenylacetic acid; 5-HIAA; 5-HT; 5-HT(1A) receptor; 5-hydroxyindoleacetic acid; 6-OHDA; 6-hydroxydopamine; AIMs; ALO; Abnormal involuntary movements; Axial, limb and orolingual; Benserazide; DA; DAT; DL-serine 2-(2,3,4-trihydroxybenzyl) hydrazine hydrochloride; DMSO; DOPAC; Dimethyl sulfoxide; Dopamine; Dopamine transporter; FAS; Forepaw adjusting steps test; HPLC; High performance liquid chromatography; LID; MFB; Medial forebrain bundle; N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt; NE; Norepinephrine; PD; Parkinson's disease; SERT; SSRI; Selective 5-HT reuptake inhibitor; Selective serotonin reuptake inhibitor; Serotonin; Serotonin transporter; WAY100635; l-DOPA-induced dyskinesia