Regulation of intraocular pressure in mice: Structural analysis of dopaminergic and serotonergic systems in response to cabergoline

Abstract

Elevated intraocular pressure (IOP) is the main recognized risk factor of glaucoma. To investigate the contribution of dopaminergic and serotonergic systems in IOP regulation, we used cabergoline, a mixed dopamine and serotonin agonist, in C57BL/6J WT and dopamine D3 receptor knock-out (D3R−/−) mice with normal eye pressure or steroid-induced ocular hypertension. Furthermore, we studied the structural basis of the cabergoline-mediated activation of the dopaminergic and serotonergic systems by molecular modeling. Topical application of cabergoline, significantly decreased, in a dose-dependent manner, the intraocular pressure in WT mice, both in an ocular normotensive group (−9, −5 and −2mmHg with 5%, 1%, and 0.1%, respectively) and an ocular hypertensive group, with a prolonged effect in this latter group. No change of intraocular pressure was observed after topical application of cabergoline in D3R−/− mice. We modeled and optimized, with molecular dynamics, structures of hD3, h5HT1A and h5HT2A–C receptors; thereafter we carried out molecular docking of cabergoline. Docking revealed that binding of cabergoline into D3 and 5HT1A receptors is associated with a better desolvation energy in comparison to 5HT2A–C binding. In conclusion, the present study support the hypothesis that dopaminergic system is pivotal to regulate IOP and that D3R represents an intriguing target in the treatment of glaucoma. Furthermore, the structure-based computational approach adopted in this study is able to build and refine structure models of homologous dopaminergic and serotonergic receptors that may be of interest for structure-based drug discovery of ligands, with dopaminergic selectivity or with multi-pharmacological profile, potentially useful to treat optic neuropathies.