Dopamine D1 receptor activation improves adult hippocampal neurogenesis and exerts anxiolytic and antidepressant-like effect via activation of Wnt/β-catenin pathways in rat model of Parkinson's disease

Parkinson's disease (PD) is primarily characterized by midbrain dopamine depletion. Dopamine acts through dopamine receptors (D1 to D5) to regulate locomotion, motivation, pleasure, attention, cognitive functions and formation of newborn neurons, all of which are likely to be impaired in PD. Reduced hippocampal neurogenesis associated with dopamine depletion has been demonstrated in patients with PD. However, the precise mechanism to regulate multiple steps of adult hippocampal neurogenesis by dopamine receptor(s) is still unknown. In this study, we tested whether pharmacological agonism and antagonism of dopamine D1 and D2 receptor regulate nonmotor symptoms, neural stem cell (NSC) proliferation and fate specification and explored the cellular mechanism(s) underlying dopamine receptor (D1 and D2) mediated adult hippocampal neurogenesis in rat model of PD-like phenotypes. We found that single unilateral intra-medial forebrain bundle administration of 6-hydroxydopamine (6-OHDA) reduced D1 receptor level in the hippocampus. Pharmacological agonism of D1 receptor exerts anxiolytic and antidepressant-like effects as well as enhanced NSC proliferation, long-term survival and neuronal differentiation by positively regulating Wnt/beta-catenin signaling pathway in hippocampus in PD rats. shRNA lentivirus mediated knockdown of Axin-2, a negative regulator of Wnt/beta-catenin signaling potentially attenuated D1 receptor antagonist induced anxiety and depression-like phenotypes and impairment in adult hippocampal neurogenesis in PD rats. Our results suggest that improved nonmotor symptoms and hippocampal neurogenesis in PD rats controlled by D1-like receptors that involve the activation of Wnt/beta-catenin signaling.