Many different areas within the brain are involved in a complex chain of decisions required for even the smallest muscular movement. For an action like walking, for example, the brain must first gather all the information it needs about your body position. For example, are you sitting, lying down, or already standing up? Where are your feet? Do you have your balance? Then, the brain must add in what it knows about where you will be going. For example, do your eyes tell your brain that you'll be crossing an open field of grass or a busy street? Do your feet detect that the ground is easy to walk on or that you could lose your balance because it is bumpy or slippery? Figure 1. Your brain and spinal cord - a message pathway that turns thought into motion. This information comes together in a central area of the brain, called the striatum, which controls many aspects of bodily motion. The striatum works with other areas of the brain, including a part called the substantia nigra, to send out the commands for balance and coordination. These commands go from the brain to the spinal cord through nerve networks to the muscles that will then help you to move (figure 1).
he entire nervous system is made up of individual units called nerve cells. Nerve cells actually serve as a "communication network" within your body. To communicate with each other, nerve cells use a variety of chemical messengers called neurotransmitters. Neurotransmitters carry messages between nerve cells by crossing the space between cells, called the synapse (figure 2
Neurotransmitters also allow the nervous system to communicate with the body's muscles and translate thought into motion. One especially important messenger is dopamine, which is manufactured in the substantia nigra. Dopamine is crucial to human movement and is the neurotransmitter that helps transmit messages to the striatum that both initiate and control your movement and balance. These dopamine messages make sure that muscles work smoothly, under precise control, and without unwanted movement. When a dopamine message is needed, a nerve cell that produces dopamine gathers packets within itself filled with dopamine particles. These packets carrying the dopamine move to the end of the nerve cell, open a "window," and release the dopamine particles into the synapse. The dopamine particles flow across the synapse and fit into special pockets on the outside of the neighboring, or receiving, nerve cell (figure 3). The receiving cell is now stimulated to send on the message, so it gathers its own packets of dopamine and passes along the message to the next nerve cell in the same way.
After the receiving cell has been stimulated to pass along the message, the pockets then release the dopamine back into the synapse. To fine-tune coordination of movement, these "used" dopamine particles, along with any excess dopamine that did not originally fit into a pocket on the receiving cell, are broken down by a chemical in the synapse called MAO-B (figure 4). This is an important step in the precise control of muscle movement. Too much or too little dopamine can disrupt the normal balance between the dopamine system and another neurotransmitter system, and interfere with smooth, continuous movement.
One way to illustrate how the muscle control process works is as follows: two buckets - one for the dopamine system and one for the acetylcholine system - balanced on either end of a seesaw (figure 5). This depicts the situation at rest when the dopamine and acetylcholine systems are balanced. When you decide to move, your brain understands the movement you want to make and it sends out a balance of dopamine and acetylcholine messages to keep that movement smooth.
N= Substantia Nigra E= Globus Pallidus externa, S= Subthalamic nucleus, I/R= Globus Pallidus interna T = Thalamus Step1: Dopamine is normally produced in the pars compacta of the substantia nigra which has projections to the striatum. Step2: In the striatum, dopamine normally has an excitatory effect on D1 receptors. Step 3: This results in an increased production of GABA in neurones that project to the Gpi. GABA is an inhibitory neurotransmitter and reduces the output of the Gpi. In Parkinson’s however, Step One is removed and therefore Steps 2 and 3 don’t follow. The result is an increased output from the Gpi. (see step 8) Step4: Dopamine also has an inhibitory effect on the neurones in the striatum that make up the indirect pathway. Step 5: Inhibition here results in decreased production of GABA in the neurones that project to the Gpe. Step 6: Reduced inhibition of the Gpe results in an increased production of GABA by the neurones of the Gpe that project to the subthalamic nucleus. This results in an increased inhibitory effect on the subthalamic nucleus. Step 7: The Subthalamic nucleus, which projects to the Gpi, therefore reduces production of the excitatory neurotransmitter glutamate. In Parkinson’s disease however, the reverse occurs. There is no inhibition at step 4, therefore there is increased inhibition of the Gpe. This results in reduced production of GABA by the Gpe and reduced inhibition of the Subthalamic nucleus. It therefore produces more Glutamate and has an increased stimulatory effect on the Gpi. Step 8: In the normal situation, inhibition by the direct pathway and reduced stimulation by the indirect pathway would result in little production of GABA by the Gpi. This would mean that there would be little inhibition of the ventrolateral thalamus to which it projects via the lenticular fasciculus and the ansa lenticularis. However, in Parkinson’s disease, there is reduced inhibition by the direct pathway and increased stimulation by the indirect pathway. The result is an increased output of GABA and increased inhibition of the ventrolateral thalamus. Step 9: The ventrolateral nucleii of the thalamus are excitatory to the cortex. In the Parkinson’s patient therefore, the excessive inhibition of the thalamus from the Gpi could result in reduced excitation of the cortex and the classic symptoms of Parkinson’s disease, i.e. Bradykinesia, rigidity and tremor.
THE GREATER DISTINCTION BWN ERGOT AND NON-ERGOT IS THEIR TOLERABILITY AND SPEED OF TITRATION
