Researchers Report New Insights Into the Mechanisms Responsible for Slow Movements in Parkinson’s Disease
In a newly published paper in the Cerebral Cortex journal entitled “Dopamine D1 Receptor-Mediated Transmission Maintains Information Flow Through the Cortico-Striato-Entopeduncular Direct Pathway to Release Movements,” researchers from Japan reported that lack of dopamine transmission through D1 receptors is linked to slower movements in patients with Parkinson’s disease (PD).
Parkinson’s disease is a neurodegenerative disorder characterized by damaged motor neurons which control body movements. Patients with PD may suffer mainly from motor dysfunction like tremor, rigidity, postural instability, and slowness of movement. Other symptoms related to neuropsychiatry like trouble with speech, cognition, behavior, mood, thought, depression, sleep and memory commonly associated with dementia may arise. PD is assumed to be caused by genetic predisposition and environmental risk factors such as head injuries and exposure to pesticide and heavy metal commonly found in farming areas or in water sources. It is worth noting that PD affects around 0.3% of the total population in industrialized countries. The average age of onset of PD is around 60 years, and prevalence increases from 1% in people over 60 years to 4% in those over 80 years. PD invariably progresses with time and if not treated, motor dysfunction would progress aggressively in early stages of the disease, then slow down later.
It is believed that motor-related symptoms in PD result from death of dopamine-generating cells in the midbrain region called substantia nigra. Other studies suggested that dopamine binds to receptors D1 and D2. The latter have various effects on nerve cells located in brain region called basal ganglia. However, the mechanisms related to how dopamine controls information flow through these receptors and how this affects voluntary movements are still unknown. To clarify the issue, scientists from Japan performed a series of experiments using transgenic mouse model where dopamine D1 receptors could be reduced by mean of a pharmacological agent named doxycycline in a reversible way. The results illustrated that when D1 receptors were reduced, the mice suffered from decreased movements.
To gain a better understanding of the phenomenon, researchers examined the electrical activity of mice nerve cells in the brain region equivalent to globus pallidus in humans. In healthy mice, electrical stimulation of the motor neurons that lead to normal voluntary movements is expected to induce a response consisting of early excitation, inhibition and late excitation in the nerve cells, and inhibition is mediated by direct pathway to initiate movements. In the transgenic mouse where D1 receptors were decreased, a change in response to the electrical stimulation was observed and the inhibition stage responsible in initiating movement was significantly reduced. The latter highlighted the importance of dopamine transmission through mediation by D1 receptors in information flow as well as initiation of movement. Other data suggested that when D1 receptors were reduced, no change in spontaneous activity of nerve cells was observed. This does not support the view that lack of D1 receptor would increase spontaneous nerve cell activity. This means that what matters is the information flow through direct pathway to appropriately release motor action.
In conclusion, these findings revealed that lack of dopamine transmission through D1 receptors disturbs information flow through the direct pathway in motor neuron regions of the brain. The latter yields difficulties in initiating voluntary movements as in Parkinson’s disease. These findings could lead to the development of new therapies based on activation of D1 for PD and other related neurodegenerative diseases in the future.