Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats.

Long-term administration of l-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson's disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb, and orofacial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that the direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) (Morgese et al., 2007). In this study, we showed that the stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that the direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268, and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa anti-parkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacological target for the treatment of LID.

Neurochemical changes in the striatum of dyskinetic rats after administration of the cannabinoid agonist WIN55,212-2.

Chronic use of levodopa, the most effective treatment for Parkinson's disease, causes abnormal involuntary movements named dyskinesias, which are linked to maladaptive changes in plasticity and disturbances of dopamine and glutamate neurotransmission in the basal ganglia. Dyskinesias can be modeled in rats with unilateral 6-hydroxydopamine lesions by repeated administration of low doses of levodopa (6 mg/kg, s.c.). Previous studies from our lab showed that sub-chronic treatment with the cannabinoid agonist WIN55,212-2 attenuates levodopa-induced dyskinesias at doses that do not interfere with physiological motor function. To investigate the neurochemical changes underlying WIN55,212-2 anti-dyskinetic effects, we used in vivo microdialysis to monitor extracellular dopamine and glutamate in the dorsal striatum of both the hemispheres of freely moving 6-hydroxydopamine-treated, SHAM-operated and intact rats receiving levodopa acutely or chronically (11 days), and studied how sub-chronic WIN55,212-2 (1 injection x 3 days, 20 min before levodopa) affected these neurochemical outputs. Our data indicate that: (1) the 6-hydroxydopamine lesion decreases dopamine turnover in the denervated striatum; (2) levodopa injection reduces extracellular glutamate in the side ipsilateral to the lesion of dyskinetic rats; (3) sub-chronic WIN55,212-2 prevents levodopa-induced glutamate volume transmission unbalances across the two hemispheres; and (4) levodopa-induced dyskinesias are inversely correlated with glutamate levels in the denervated striatum. These data indicate that the anti-dyskinetic properties of WIN55,212-2 are accompanied by changes of dopamine and glutamate outputs in the two brain hemispheres of 6-hydroxydopamine-treated rats.