Behavioral and biochemical correlates of the dyskinetic potential of dopaminergic agonists in the 6‐OHDA lesioned rat

Abstract

Prolonged treatment with L-DOPA induces highly disabling dyskinesia in Parkinson's disease (PD) patients. In contrast, dopaminergic agonists display variably dyskinetic outcome, depending on pharmacokinetic/pharmacodynamic profile. The present study was aimed at assessing behavioral and biochemical correlates of intense or mild dyskinesia displayed by the different dopamine (DA) receptors stimulation in a rat model of PD. The effect of subchronic stimulation of the D(1) receptor by SKF38393, and the D(2)/D(3) receptor by ropinirole was evaluated in unilaterally 6-hydroxyDA-lesioned rats. Sensitization of contralateral turning (SCT) behavior and abnormal involuntary movements (AIMs) were assessed as behavioral correlates of dyskinetic responses. Opioid peptides mRNA in the dorsolateral striatum (dlStr) and glutamic acid decarboxylase (GAD67) mRNA content in globus pallidus (GP), were evaluated as an index of neuroadaptive changes occurring in the direct and indirect basal ganglia pathways. Subchronic SKF38393 caused AIMs and SCT whereas ropinirole elicited SCT only, indicating that both drugs induced some dyskinetic response, albeit of different type. Peptides mRNA evaluation in dlStr, showed that SKF38393 subchronic treatment was associated to an overexpression of both dynorphin (DYN) and enkephalin (ENK) mRNAs, in the direct and indirect striatal pathway respectively. In contrast, a decrease in DYN mRNA levels only was observed after treatment with ropinirole. Analysis of GAD67 mRNA levels in the GP showed an increase after both D(1) and D(2)/D(3) agonist treatments. Results suggest that presence of SCT alone or SCT plus AIMs might represent correlates of the differential severity of dyskinetic movements induced by treatment with low (ropinirole) or high (SKF38393) dyskinetic potential. Neuroadaptive increases in opioid peptide expression in both direct and indirect striatal pathways were associated to the appearance of AIMs alone. In contrast, increase of GAD67 mRNA in the GP was associated to both behavioral responses (SCT and AIMs), suggesting that neuroadaptive changes in this area were unrelated to the difference in dyskinetic potential of drugs.

Assessment of Symptomatic and Neuroprotective Efficacy of Mucuna Pruriens Seed Extract in Rodent Model of Parkinson’s Disease

“…To this regard, the finding that subchronic administration of MP extract, in contrast to subchronic L-DOPA, induced sensitization of contralateral turning behavior but not sensitization of AIMs which were of low intensity and stable throughout the duration of treatment, is of particular interest. Previous results have shown that drugs owing low dyskinetic potential such as bromocriptine or ropinirole induce sensitization in contralateral turning behavior, not associated to sensitization in AIMs (Henry et al 1998;Ravenscroft et al 2004;Carta et al 2008). On the contrary, drugs such as L-DOPA owing high dyskinetic potential induced sensitization in AIMs after repeated treatment (Lundblad et al 2002;Pinna et al 2006).…”

Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats

“…Serotonergic activation at dorsal/medial raphé and terminal receptors is sufficient to reduce LID (Carta et al, 2008), brought about by an increase in extracellular monoamine levels, reducing the synaptic release of glutamate and 5-HT and controlling dysregulated release. Under these principles AIM reduction in response to amphetamine, as shown in this study, is likely to be a through a combined modulation of grafted 5-HT neurones, host 5-HT terminals and corticostriatal connections.…”

GαolfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

“…DA D 1 receptor (D 1 R) agonists are more efficient than D 2 R agonists to induce dyskinesia in animal models and PD patients (Calon et al, 1999;Rascol et al, 2001Rascol et al, , 2006Carta et al, 2008). D 1 Rs are necessary for LID development (Westin et al, 2007;Darmopil et al, 2009).…”