Effect of levodopa on striatal monoamines in mice with levodopa-induced hyperactivity

Department of Neurology, University of Alabama at Birmingham, AL 35294, USA.
Neuroscience Letters (Impact Factor: 2.03). 10/2008; 443(3):204-8. DOI: 10.1016/j.neulet.2008.07.039
Source: PubMed


The present study examines striatal monoamine changes in a murine model of levodopa-induced dyskinesia (LID), a common side effect of Parkinson's disease (PD) therapy. Mice previously exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and later made hyperactive with high-dose (200mg/kg, i.p.) exogenous levodopa were compared to mice with normal motor behavior who received either levodopa without previous MPTP or no treatment at all. Using high-performance liquid chromatography, dopamine (DA), serotonin (5HT), noradrenaline (NA) and their metabolites were then measured in samples of striatum versus olfactory bulbs as controls. In the olfactory bulb, exogenous levodopa caused increased DA levels and increased DA-, 5HT- and NA-turnover rates, but decreased 5HT and NA levels, regardless of animal activity. These trends were also seen in the striatum, but animals with LID seemed to have unique differences. Thus, in mice sacrificed at the height of their hyperactive LID behavior, striatal DA and 5HT were significantly lower and DA- and 5HT-turnover rates were significantly higher than control animals with normal motor behavior, regardless of levodopa exposure. In addition, the expected increased NA-turnover rate seen in other specimens from animals exposed to levodopa was not seen in the striatum of LID mice. The results of the present study demonstrate that there is a distinct profile of striatal monoamines conducive to LID that must be considered when trying to explain the effects of anti-LID drugs utilizing monoamine receptors.

Download full-text


Available from: Anthony P Nicholas, May 08, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Accumulated evidence has indicated that neuroinflammation is one of the important etiologic factors of Parkinson's disease (PD). Earlier studies have employed the inflammogen lipopolysaccharide (LPS) to induce inflammation of dopaminergic neurons. Methamphetamine (MA) dopaminergic toxicity similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity is frequently cited as a model of PD. In the present study, we examined whether striatal LPS exposure potentiates MA-induced dopaminergic toxicity. Combined treatment with LPS and MA significantly potentiates behavioral impairment and dopaminergic deficit. However, this combination did not significantly alter the other monoaminergic systems (e.g., serotonin, norepinephrine, and histamine). Consistently, microglial activation, labeled by F4/80 or Iba-1 in the nigrostriatal region was more pronounced with the combined treatment of LPS and MA compared to either treatment alone, but this combination did not significantly alter the microglial activation in other brain regions (e.g., hippocampus, dorsal raphe nuclei, and locus ceruleus). Furthermore, neuroinflammation, oxidative stress, and pro-apoptotic changes in the striatum were more accentuated with combined treatment of LPS and MA compared to either treatment alone. In addition, it is important that cytoplasmic accumulation of alpha-synuclein was observed in the substantia nigra of mice treated with LPS plus MA, and that L-Dopa treatment significantly attenuated behavioral changes and dopaminergic deficits induced by LPS plus MA. These results suggest that combined treatment of LPS with MA is a potential animal model for PD.
    No preview · Article · Oct 2009 · Neurochemistry International
  • [Show abstract] [Hide abstract]
    ABSTRACT: We tested the hypothesis that long-term l-DOPA treatment in Parkinson's disease (PD) would result in increased production of the dopamine oxidation product, 6-hydroxydopamine (6-OHDA) in the striatum. We administered L-DOPA (250 mg/kg) by gavation for 3 days following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg, i.p., twice, 16 h apart) in mice or for 30 days in rats which received 1-methyl-4-phenylpyridinium ion (MPP(+); 16 nmol/1 microl) unilaterally in median forebrain bundle, and measured 6-OHDA in the striatum using a sensitive HPLC-electrochemical detection procedure. While the contralateral innervated striatum of rats showed no difference, a significant increase in 6-OHDA level in the denervated (>85% dopamine depletion) ipsilateral striatum was observed. Partial nigrostriatal denervation with a lower dose of MPP(+) (8 nmol/1 microl) in rats or following sub-acute MPTP treatment in mice failed to cause any significant change in 6-OHDA level following several doses of L-DOPA administration. Since a single dose of MPTP (30 mg/kg, i.p.) or L-deprenyl (0.25 mg/kg, i.p.) in L-DOPA primed (250 mg/kg daily for 7 days) mice caused significant increase in 6-OHDA in the striatum, augmentation of reactive oxygen species production concomitant to excessive dopamine concentration in this region is proposed to be the basis of this effect. These results suggest creation of potential pro-toxic environment in the brain due to the long-term administration of L-DOPA, which may get further sensitized by the treatment of monoamine oxidase inhibitors.
    No preview · Article · Nov 2009 · Neurochemistry International
  • [Show abstract] [Hide abstract]
    ABSTRACT: The administration of L: -DOPA is the standard treatment for Parkinson's disease (PD). However, the symptomatic relief provided by long-term administration may be compromised by L: -DOPA-induced dyskinesia (LID) that presents as adverse fluctuations in motor responsiveness and progressive loss of motor control. In the later stages of PD, raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine (DA) neurons by converting and releasing DA derived from exogenous L: -DOPA. Since the serotonin system does not have an autoregulatory mechanism for DA, raphe-mediated striatal DA release may fluctuate dramatically and precede the development of LID. The 6-hydroxydopamine lesioned rats were treated with L: -DOPA (6 mg/kg) and benserazide (15 mg/kg) daily for 3 weeks to allow for the development of abnormal involuntary movement score (AIMs). In rats with LID, chronic treatment with L: -DOPA increased striatal DA levels compared with control rats. We also observed a relative increase in the expression of striatal L: -amino-acid decarboxylase (AADC) in LID rats, even though tyrosine hydroxylase (TH) expression did not increase. The administration of L: -DOPA also increased striatal serotonin immunoreactivity in LID rats compared to control rats. Striatal DA and 5-hydroxytryptamine (5-HT) levels were negatively correlated in L: -DOPA-treated rats. These results of this study reveal that 5-HT contributes to LID. Striatal DA positively influences LID, while 5-HT is negatively associated with LID. Finally, we suggest that by strategic modification of the serotonin system it may be possible to attenuate the adverse effects of chronic L: -DOPA therapy in PD patients.
    No preview · Article · Mar 2010 · Cellular and Molecular Neurobiology
Show more