L-Dopa treatment, the gold standard
therapy for
Parkinson's disease, is hampered by motor complications such as
dyskinesias. Recently, impairment of striatal Akt/GSK3 signaling was proposed to play a role in the mechanisms implicated in development of
L-Dopa-induced
dyskinesias in a rodent model of
Parkinson's disease. The present experiment investigated in
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) monkeys, the effects on Akt/GSK3 of chronic
L-Dopa treatment inducing
dyskinesias compared to
L-Dopa with
CI-1041 (
NMDA receptor antagonist) or a low dose of
cabergoline (
dopamine D2 receptor agonist) preventing
dyskinesias. The extensive
dopamine denervation induced by
MPTP was associated with a decrease by about half of phosphorylated Akt(Ser473) levels in posterior caudate nucleus, anterior and posterior putamen; smaller changes were observed for phosphorylated Akt(Thr308) levels that did not reach statistical significance.
Dopamine depletion reduced phosphorylated
GSK3beta(Ser9) levels, mainly in posterior putamen whereas pGSK3beta(Tyr216) and pGSK3alpha(Ser21) were unchanged. In posterior caudate nucleus, anterior and posterior putamen of dyskinetic
L-Dopa-treated
MPTP monkeys, pAkt(Ser473) and pGSK3beta(Ser9) were elevated whereas L-Dopa+cabergoline treated
MPTP monkeys without
dyskinesias had lower values in posterior striatum as vehicle-treated
MPTP monkeys. In non-dyskinetic
MPTP monkeys treated with L-Dopa+CI-1041, putamen pAkt(Ser473) and pGSK3beta(Ser9) levels remained elevated as in dyskinetic monkeys while in posterior caudate nucleus, these levels were low as vehicle-treated and lower than
L-Dopa treated
MPTP monkeys. Extent of phosphorylation of Akt and
GSK3beta in putamen correlated positively with
dyskinesias scores of
MPTP monkeys; these correlations were higher with
dopaminergic drugs (
L-Dopa,
cabergoline) suggesting implication of additional mechanisms and/or signaling molecules in the
NMDA antagonist antidyskinetic effect. In conclusion, our results showed that in
MPTP monkeys, loss of striatal
dopamine decreased Akt/GSK3 signaling and that increased phosphorylation of Akt and
GSK3beta was associated with
L-Dopa-induced
dyskinesias.