Dopamine D1 receptor agonism induces dynamin related protein-1 inhibition to improve mitochondrial biogenesis and dopaminergic neurogenesis in rat model of Parkinson’s disease

Abstract

Dopamine (DA) neurotransmitter act on dopamine receptors (D1-D5) to regulate motor functions, reward, addiction and cognitive behavior. The depletion of DA in midbrain due to degeneration of nigral dopaminergic (DAergic) neurons leads to Parkinson’s disease (PD). DA agonist and levodopa (L-DOPA) are the only therapies used for symptomatic relief in PD. However, the role of DA receptors in PD pathogenesis and how they are associated with mitochondrial functions and DAergic neurogenesis is still not known. Here, we investigated the mechanistic aspect of DA D1 receptor mediated control of DAergic neurogenesis, motor behavior and mitochondrial functions in rat PD model. The pharmacological activation of D1 receptors markedly improved motor deficits, mitochondrial biogenesis, ATP levels, mitochondrial membrane potential and defended nigral DAergic neurons against 6-hydroxydopamine (6−OHDA) induced neurotoxicity in adult rats. However, the D1 agonist mediated effects were abolished following D1 receptor antagonist treatment in 6−OHDA lesioned rats. Interestingly, pharmacological inhibition of dynamin related protein-1 (Drp-1) by Mdivi-1 in D1 antagonist treated PD rats, significantly restored behavioral deficits, mitochondrial functions, mitochondrial biogenesis and increased the number of newborn DAergic neurons in substantia nigra pars compacta (SNpc). Drp-1 inhibition mediated neuroprotective effects in PD rats were associated with increased level of protein kinase-B/Akt and extracellular-signal-regulated kinase (ERK). Taken together, our data suggests that dopamine D1 receptor mediated reduction in mitochondrial fission and enhanced DAergic neurogenesis may involve Drp-1 inhibition which led to improved behavioral recovery in PD rats.