Persistent changes in striatal gene expression induced by long‐term l‐DOPA treatment in a rat model of Parkinson's disease

Abstract

Current knowledge of the molecular changes induced by dopamine denervation and subsequent treatment with L-DOPA is based on studies performed on relatively acute and young animal models of parkinsonism. It is highly warranted to ask how well these models simulate the state of chronic denervation and sustained L-DOPA pharmacotherapy which are typical of advanced Parkinson's disease. This study investigates the effects of time postdenervation and L-dopa treatment duration on the striatal expression of opioid precursor mRNAs and FosB/DeltaFosB-related proteins. Unilaterally 6-hydroxydopamine-lesioned rats were treated with therapeutical doses of L-DOPA for one year (long-term group) or a few weeks (short-term group). Age-matched lesioned rats received injections of vehicle or bromocriptine, an antiparkinsonian compound which does not produce dyskinesia when administered de novo. The lesion-induced up-regulation of preproenkephalin mRNA expression persisted at more than one year postlesion, and was unaffected by the pharmacological treatments applied. L-DOPA, but not bromocriptine, induced high striatal levels of FosB/DeltaFosB immunoreactivity and prodynorphin mRNA, and these did not differ between short-term and long-term L-DOPA-treated rats. The present data provide the first demonstration that L-DOPA maintains high striatal levels of fosB and prodynorphin gene expression during a prolonged course of treatment, which simulates the clinical practice in Parkinson's disease more closely than the short-treatment paradigms studied thus far.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…In the 6-OHDA-lesioned rat, PPE-B mRNA levels were decreased in the striatum in the untreated state, whereas chronic treatment with L-DOPA-last dose administered 2 days before deathled to an increase in PPE-B mRNA levels compared with the levels encountered in the nonparkinsonian and L-DOPA-naive parkinsonian states (Westin et al, 2001). In another study, also performed in the rat, 6-OHDA lesion did not result in a decrease in striatal PPE-B mRNA levels .…”

“…In the rat, 6-OHDA lesion increased levels of PPE-A mRNA and subsequent treatment with L-DOPA-last dose given 24 hours before death-reversed this increase (Zeng et al, 1995). In contrast, in another study in which rats were killed 2 days after last dose, chronic treatment with L-DOPA resulted in a further increase in PPE-A mRNA (Westin et al, 2001). …”

Endothelial Proliferation and Increased Blood–Brain Barrier Permeability in the Basal Ganglia in a Rat Model of 3,4-Dihydroxyphenyl-l-Alanine-Induced Dyskinesia

“…This hypothesis is supported by several observations. For example, the region showing the most pronounced microvascular alterations within the striatum is one in which striking changes in gene and protein expression (Cenci et al, 1998;Andersson et al, 1999;Westin et al, 2001;Konradi et al, 2004) and energy consumption (Konradi et al, 2004) (B. Valastro and M. A. Cenci, unpublished observations) have been documented in this rat model of L-DOPA-induced dyskinesia. Moreover, the occurrence of pronounced vascular remodeling in the EP and the SNr is compatible with the anatomical pattern of 2-deoxyglucose (2-DG) uptake in 6-OHDA-lesioned rats treated with L-DOPA, showing a marked increase in 2-DG utilization in the EP and SNr on the side ipsilateral to the lesion (Trugman and Wooten, 1986;Trugman et al, 1996).…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…This nonphysiologic, discontinuous, or pulsatile stimulation of dopamine receptors leads to a variety of molecular and physiologic changes that are associated with the development of motor complications. These include a) alterations in levels of expression in striatal neurons of a variety of genes including preprodynorphin, delta fos-b, delta c-fos, and preproenkephalin, which have been observed in striatal neurons of dyskinetic rodents, primates, and patients with PD [288][289][290] ; and b) changes in neuronal firing pattern (e.g., frequency, bursts, pauses, synchronization) in basal ganglia output neurons. 266,269,291 More recently, it has been shown that levodopa treatment and the development of dyskinesia are associated with alterations in plasticity, 292 and with translocation of NR2B subunits of the NMDA receptor from a synaptic to an extrasynaptic location.…”