title: Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics in vivo.
abstract: Parkinson's disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. L-DOPA was introduced as a viable treatment option for PD over 40 years ago and still remains the most common and effective therapy for PD. Though the effects of L-DOPA to augment striatal DA production are well known, little is actually known about how L-DOPA alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-DOPA administration (50 mg/kg carbidopa + 0, 100, and 250 mg/kg L-DOPA) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry in anesthetized rats. We demonstrate that L-DOPA enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D-STR. In both regions, L-DOPA progressively attenuated reuptake kinetics, predominantly through a decrease in Vmax. These findings have important implications on understanding the pharmacodynamics of L-DOPA, which may be informative for understanding its therapeutic effects and also common side effects like L-DOPA-induced dyskinesias (LID). L-DOPA is commonly used to treat Parkinsonian symptoms, but little is known about how it affects presynaptic DA neurotransmission. Using in vivo fast-scan cyclic voltammetry, we show L-DOPA inhibits DA reuptake in a region-specific and dose-dependent manner, and L-DOPA has paradoxical effects on release. These findings may be important when considering mechanisms for L-DOPA's therapeutic benefits and adverse side-effects.
authors.affiliation: Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.|Safar Center for Resuscitation Research, Pittsburgh, Pennsylvania, USA.
authors.forename: Rashed
authors.initials: R
authors.lastname: Harun
authors.affiliation: Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Hare
authors.affiliation: Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.|Safar Center for Resuscitation Research, Pittsburgh, Pennsylvania, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brough
authors.affiliation: Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.|Department of Biological Sciences, Carnegie Mellon University, Mellon College of Science, Pittsburgh, Pennsylvania, USA.
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Munoz
authors.affiliation: Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Grassi
authors.affiliation: Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Gonzalo E
authors.initials: GE
authors.lastname: Torres
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Departments of Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Grace
authors.affiliation: Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Physical Medicine & Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.|Safar Center for Resuscitation Research, Pittsburgh, Pennsylvania, USA.|Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wagner
keywords: Parkinson's disease; dopamine; dyskinesia; levodopa; striatum; voltammetry