Direct and indirect striatal efferent pathways are differentially influenced by low and high dyskinetic drugs: behavioural and biochemical evidence

Abstract

Clinical evidence suggests that stimulation of the D(1) rather than D(2) dopamine receptor is related to the development of dyskinesias in Parkinson's disease (PD). We evaluated, in the 6-hydroxydopamine rat model of PD, sensitization of contralateral turning (SCT) behaviour and abnormal involuntary movements (AIMs) as behavioural parameters of dyskinetic response, and changes in zif-268 mRNA expression in striatonigral and striatopallidal neurons on subchronic administration of the D(2)/D(3) agonist ropinirole, defined as a mild dyskinetic drug in the clinic. Results were compared with previous findings on repeated L-dopa treatment. Ropinirole displayed a mild dyskinetic response characterized by SCT only, which contrasted with the presence of SCT in association with AIMs elicited by repeated L-dopa. Zif-268 mRNA levels were decreased in both striatonigral and striatopallidal neurons by ropinirole, in contrast to hyper-expression of zif-268 mRNA selectively induced by L-dopa in striatonigral neurons. Unbalanced responsiveness of striatal efferent neurons might represent a molecular correlate of high dyskinetic potential and AIMs in rats; in contrast, a balanced striatal output might underlie the low dyskinetic potential displayed by ropinirole.