The research team successfully developed a novel transgenic mouse model in which dopamine D1 receptors can be reversibly reduced by a pharmacological agent "doxycycline", and found that the mice showed decreased movements when D1 receptors were reduced.
The team used electrophysiological techniques in awake mice and examined the electrical activity of the nerve cells in the entopeduncular nucleus (EPN, the homologous structure to the internal segment of the globus pallidus in humans) that is the output station of the basal ganglia. Normally, the electrical stimulation of the motor cortex, which resembles the electrical activity during voluntary movements, causes triphasic response consisting of early excitation, inhibition and late excitation in the nerve cells of the EPN, and the "inhibition" is mediated by the "direct pathway" and acts to initiate movements.
When D1 receptors were reduced in the transgenic mice by "doxycycline", the triphasic response was changed, and the "inhibition" was largely decreased. These results suggest that dopamine transmission mediated by D1 receptors is essential for information flow through the "direct pathway" to appropriately initiate movements.
The research team also revealed that spontaneous activity of nerve cells in the ENP did not change when D1 receptors were reduced, which denies the prevalent view that lack of D1 receptor-mediated dopamine transmission increases spontaneous nerve cell activity in the EPN.
The results suggest that transient activity changes through the "direct pathway", not spontaneous activity changes, in the EPN are responsible for slowness of movements in Parkinson's disease.