Abstract
The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6-kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms.
Highlights
Ropinirole and pramipexole are nonergoline dopaminergic agonists indicated for the treatment of Parkinson’s disease and restless leg syndrome (RLS) [1, 2]
In support of possible neurorestorative effects, we previously showed that D3 receptor- (D3R-)preferential DA agonists increase dendrite arborization and soma size in cultured mouse mesencephalic DA neurons by activation of the mammalian target of rapamycin and extracellular signal-regulated kinase (ERK) [16, 28, 29], two molecular pathways critical for cell growth and structural remodeling [30]
CP01 human fibroblasts from a healthy donor were reprogrammed according to the protocol of Maherali et al [40] (Supplementary Figure S1A), resulting in several human-inducible pluripotent stem cells (hiPSCs) colonies, including a clone called F3
Summary
Ropinirole and pramipexole are nonergoline dopaminergic agonists indicated for the treatment of Parkinson’s disease and restless leg syndrome (RLS) [1, 2]. Improvement of depressive symptoms has been consistently seen in these patients [3, 4], while controlled clinical trials demonstrated antidepressant efficacy mainly as adjunctive treatment in insufficiently responsive patients with mood disorders [5,6,7,8]. The latter observations are consistent with experimental data. In rodents, antagonism of D2R and D3R in the frontal cortex disrupts and promotes cognitive function, respectively [19,20,21]
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