The CB1 cannabinoid receptor agonist reduces L-DOPA-induced motor fluctuation and ERK1/2 phosphorylation in 6-OHDA-lesioned rats.
The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) has been used as an effective drug for treating dopamine depletion-induced Parkinson's disease (PD). However, long-term administration of L-DOPA produces motor complications. L-DOPA has also been found to modify the two key signaling cascades, protein kinase A/dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), in striatal neurons, which are thought to play a pivotal role in forming motor complications. In the present study, we tested the possible effect of a CB1 cannabinoid receptor agonist on L-DOPA-stimulated abnormal behavioral and signaling responses in vivo. Intermittent L-DOPA administration for 3 weeks induced motor fluctuation in a rat model of PD induced by intrastriatal infusion of dopamine-depleting neurotoxin 6-hydroxydopamine (6-OHDA). A single injection of a CB1 cannabinoid receptor agonist WIN-55,212-2 had no effect on L-DOPA-induced motor fluctuation. However, chronic injections of WIN-55,212-2 significantly attenuated abnormal behavioral responses to L-DOPA in 6-OHDA-lesioned rats. Similarly, chronic injections of WIN-55,212-2 influence the L-DOPA-induced alteration of DARPP-32 and ERK1/2 phosphorylation status in striatal neurons. These data provide evidence for the active involvement of CB1 cannabinoid receptors in the regulation of L-DOPA action during PD therapy.
Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, People's Republic of China.
Lu
L
Song
Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, People's Republic of China.
Xinxin
X
Yang
Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, People's Republic of China.
Yaping
Y
Ma
Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, People's Republic of China.
Na
N
Wu
Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, People's Republic of China.
Zhenguo
Z
Liu
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D005260:Female; D007980:Levodopa / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism
D000978:Antiparkinson Agents; D043884:Receptor, Cannabinoid, CB1; D007980:Levodopa; D016627:Oxidopamine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
212-2; 6-hydroxydopamine; L-DOPA; Parkinson’s disease; motor fluctuation; striatum; the CB1 receptor agonist WIN-55