L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA

Abstract

Rats sustaining unilateral near-complete 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received daily injections of 3, 4 dihydroxyphenyl-l-alanine (L-DOPA, 8 mg/kg plus 15 mg/kg benserazide) for 3 weeks. During this period, about 50% of the rats gradually developed abnormal involuntary movements, lasting for 2-3 h following each L-DOPA dose. Rats were killed 3 days after the last L-DOPA injection, and sections through the striatum were processed for in situ hybridization histochemistry. Within the L-DOPA-treated group, levels of preproenkephalin (PPE) mRNA, glutamic acid decarboxylase (GAD67) mRNA, and prodynorphin (PDyn) mRNA in the dopamine-denervated caudate-putamen, as well as GAD67 mRNA expression in the globus pallidus ipsilateral to the 6-hydroxydopamine (6-OHDA) lesion, were higher in dyskinetic than non-dyskinetic animals, and positively correlated with the rats' dyskinesia scores. By contrast, striatal preprotachykinin mRNA expression and D2 receptor-radioligand binding were not significantly associated with dyskinesia. Among all these markers, PDyn mRNA levels showed the most pronounced treatment-dependence (three times higher in the L-DOPA-treated group than in saline-injected lesion-only controls), and the strongest correlation with the rats' dyskinesia scores (r2 = 0.82). However, a multiple regression equation including the three factors, GAD67 mRNA levels in the GP, GAD67 mRNA in the lateral CPu, and striatal PDyn mRNA, gave a better fit for dyskinesia scores than PDyn mRNA alone (r2 = 0.92). The results show that L-DOPA-induced dyskinesia is associated with overexpression of PDyn and GAD67 mRNA in the striatal projection neurons, and GAD67 mRNA levels in the globus pallidus. Due to its treatment-dependent expression, and strong correlation with the associated dyskinetic symptoms, striatal PDyn mRNA, in particular, may play a role in the mechanisms of behavioural sensitization brought about by the drug.

Functional interaction between mGlu 5 and NMDA receptors in a rat model of Parkinson?s disease

“…Higher doses of L-DOPA of 25 and 50 mg/kg, however, produced stereotypic movements and enhanced locomotor activity that interfered with the execution of the RT task. These movements were the expression of enhanced manifestations of normal rodent behavior (grooming, sniffing and rearing) rather than abnormal involuntary movements as previously observed after chronic L-DOPA treatment (Cenci et al 1998;Henry et al 1998;Lundblad et al 2002;Mura et al 2002). The lack of dyskinesia in our experimental conditions after long-term L-DOPA administration is probably related to the partial DA depletion of the striatum (40-50% denervation) produced by the local infusion of 6-OHDA in the striatum.…”

Effect of the metabotropic glutamate antagonist MPEP on striatal expression of the Homer family proteins in levodopa-treated hemiparkinsonian rats

“…Unilaterally 6-OHDA lesioned rats receiving a low dose of levodopa gradually developed AIMs affecting the side of the body contralateral to the lesion as previously described (Cenci et al 1998;Marin et al 2006a). The movements were present during approximately 2 h after levodopa administration, and their evolution is similar to the time course of peak-dose dyskinesia that occurs in PD.…”

“…The AIMs observed in the present study were gradually induced by levodopa treatment, affected cranial, trunk and limb musculature, and were restricted the side of the body contralateral to the lesion. Thus, AIMs in this model may be considered as similar to levodopa-induced dyskinesia in parkinsonian patients (Cenci et al 1998;Marin et al 2006a;Winkler et al 2002). We found that systemic administration of the mGluR5 glutamate antagonist MPEP reduced the intensity of dyskinetic movements elicited by chronic administration of levodopa.…”

Disruption of programmed masticatory movements in unilateral MPTP-treated monkeys as a model of jaw movement abnormality in Parkinson’s disease

“…Many of the models employed use rodent species and have proved helpful in evaluating the antiparkinsonian activity of drugs (Cenci et al 1998;Lundblad et al 2002;Papa et al 1994). However, the use of non-human primate models of the disorder, in which pathobiological changes are more homologous and changes in motor behavior more closely resemble those that occur in humans, has already proved extremely valuable in evaluating factors responsible for the onset and maintenance of motor abnormalities in clinical Parkinson's disease.…”