Lectures Insidious Dopamine: Provocateur or Protective Agent in Parkinson’s Disease?

As the most efficacious drug for treating Parkinson’s disease, levodopa (L-DOPA), is oft viewed as a generator of reactive oxygen species (ROS), there is a question as to whether L-DOPA might accelerate progression of Parkinson’s disease. In this context we first review the potential of both L-DOPA and dopamine (DA) to generate ROS (including catecholquinones) in the presence of iron and melanin in the substantia nigra. Next, we summarize some of the actions of DA and DA agonists in animals that we have used to model Parkinson’s disease. Finally, we present our findings in rats which demonstrate neuroprotective roles for DA and L-DOPA as suppressors or sequestrators of hydroxyl radical (HO) in DA-denervated neostriatum, the target tissue for nigroneostriatal DA neurons. Within the substantia nigra, L-DOPA undergoes autoxidation to o-quinones in the process of formation of neuromelanin, a marker for these DA neurons in primates. Neuromelanin has been proposed to be both an inactivator of o-quinones and a sink for ROS. In the presence of iron, known to occur at high concentration in the substantia nigra, a battery of ROS are spontaneously formed: hydrogen peroxide (H.O.), superoxide (O. ), and HO. These, along with iron, promote formation of catechol semiquinones (QH) and quinones (Q) from endogenous DA or administered L-DOPA. Survival of the substantia nigra DA neurons is thus determined by the effectiveness of neuronal cytoprotective enzymes (catalase, superoxide dismutase, glutathione peroxidase and DT-diaphorase), reduced glutathione (GSH) levels, and sequestration of ROS by neuromelanin. In the studies in rats in which the substantia nigra is largely destroyed and in which the neostriatum is almost totally DA-denervated by 6-hydroxydopamine (6-OHDA) treatment, we have found that some DA receptors become overtly supersensitized while other DA receptors display latent supersensitivity which is unmasked by repeated agonist treatment (priming). Overt supersensitization is notable for DA D# receptors but not for D. receptors. However, if the balance between DA and serotonin (5-HT) neurons is altered, then D. receptors also become overtly supersensitized. Despite their common origin in the brainstem, 5-HT and DA neuronal terminals substantially modulate sensitivity status of the other transmitter receptors. In fact, much of the effect of DA receptor supersensitivity is mediated by the 5-HT system. These findings indicate the intricacies of coordinate neuronal systems, particularly when one of the neuronal systems (DA neurons) is compromised, and demonstrate the inherent safeguards in the brain, allowing one neuronal system (5-HT) to replace a destroyed (DA) system in an attempt to preserve function.