Serotonin Important at Advanced Disease

Parkinson’s disease is characterized by a progressive degeneration of dopamine-producing neurons, which causes tremors, rigidity and lack of movement control. These neurons project from the midbrain to an area of the brain called the corpus striatum. Although dopamine signaling is impaired in Parkinson’s patients, serotonin production remains strong. In addition, several serotonin receptors are highly expressed in the striatum and available to modify the action of L-DOPA.

Two years ago there was identified a protein, called p11, that acts as a regulator of serotonin signaling in the brain. The researchers showed that p11 increases the concentration of the serotonin 1B receptor at synapses, thereby increasing the efficiency of serotonin signaling, and linked this interaction to an individual’s susceptibility to depression and his or her response to antidepressant treatments.

Researchers used a mouse model of Parkinson’s disease in which a substance called 6-OHDA causes the destruction of dopamine neurons in one hemisphere of the brain. L-DOPA, because it is a dopamine replacement and a stimulant, causes the 6-OHDA-treated mice to rotate their bodies in the opposite direction of the dopamine-depleted brain hemisphere.

When the researchers gave these mice L-DOPA, they found increased levels of the serotonin 1B receptor and the protein p11 in the striatum. The researchers then used a molecule called CP94253, which binds to the serotonin 1B receptor and mimics the action of serotonin. CP94253 was given to two sets of 6-OHDA-treated mice: one in which p11 was “knocked out” and another with p11 intact.

The researchers believe that CP94253, and similar serotonin 1B receptor agonists, may counteract L-DOPA-induced behaviors by reducing the release of GABA, a chemical messenger that inhibits the transmission of nerve impulses. GABA is released from neurons that contain the dopamine D1 receptor.; Source: Rockefeller University