title: Monoamine transporter contributions to l-DOPA effects in hemi-parkinsonian rats.
abstract: l-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to abnormal involuntary movement or dyskinesia (LID) development. Although poorly understood, dyskinetic mechanisms involve a complex interaction between the remaining dopamine system and the semi-homologous serotonin and norepinephrine systems. Serotonin and norepinephrine transporters (SERT and NET, respectively) have affinity for dopamine uptake especially when dopamine transporters (DAT) are scant. Monoamine reuptake inhibitors have been reported to modulate l-DOPA's anti-parkinsonian effects, but DAT, SERT, and NET's contribution to dyskinesia has not been well delineated. The current investigation sought to uncover the differential expression and function of DAT, SERT, and NET in the l-DOPA-treated hemi-parkinsonian rat. Protein analysis of striatal monoamine transporters in unilateral sham or 6-hydroxydopamine-lesioned rats treated with l-DOPA (0 or 6 mg/kg) showed lesion-induced DAT loss and l-DOPA-induced gain in SERT:DAT and NET:DAT ratios in lesioned rats which positively correlated with dyskinesia expression, suggesting functional shifts among monoamine transporters in the dyskinetic state. SERT blockade with citalopram (3, 5 mg/kg) reduced LID while DAT and NET blockade with GBR-12909 (5, 10 mg/kg) and nisoxetine (5, 10 mg/kg), respectively, mildly exacerbated dyskinesia expression. Transporter inhibition did not significantly alter l-DOPA's ability to reverse motor deficit. Overall, DA and DAT loss with l-DOPA treatment appear to precipitate gain in SERT and NET function. Strong correlations with LID and direct behavioral comparisons of selective transporter blockade reveal novel implications for SERT, DAT, and NET as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Conti
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Meadows
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Melikhov-Sosin
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lindenbach
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Hallmark
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Werner
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA. Electronic address: cbishop@binghamton.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bishop
mesh_terms: D000818:Animals; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D007980:Levodopa
keywords: Dopamine transporter; Dyskinesia; Norepinephrine transporter; Parkinson's disease; Serotonin transporter; l-DOPA