Drugs such as methamphetamine (“speed”) interact with specific neurons in the brain to produce their stimulant effects. Methamphetamine and other derivatives of amphetamine are known to produce damage to certain neurons in the brain. This was recently shown in the brains of long-term human users of methamphetamine. To understand how this happens, we must understand how methamphetamine interacts with the brain. Methamphetamine increases the release of the neurotransmitter dopamine from specific neurons where it is stored in vesicles. The extra dopamine binds to dopamine receptors on neurons and causes activation of the central nervous system to increase alertness and cause hyperactivity. Normally dopamine action is terminated when it is transported back into neurons. There, it is oxidized by oxygen (O2) with the help of enzymes (oxidases) in the mitochondria.
1. Create a drawing of a neuron and indicate where the dopamine is stored and where the oxidases are found.
2. What kinds of components are necessary for a compound to be oxidized?
3. How does the chemical structure of dopamine enable it to become oxidized?
4. Show a simple reaction equation for the oxidation of dopamine and describe what happens. Indicate which compound becomes oxidized and which compound becomes reduced. Explain what happens to electrons in this process.
5. What kinds of products are formed once dopamine becomes oxidized?
Dopamine undergoes a different fate during methamphetamine exposure. When methamphetamine is present, dopamine accumulates in the space between the neurons and can be oxidized by O2 in the absence of help from enzymes. This is called “autooxidation”. One of the products formed is called an oxygen radical. Oxygen radicals, like free radicals, are highly reactive and unstable molecules.
6. Show a simple reaction for the autooxidation of dopamine and describe what happens.
7. What kind of oxygen radical is formed once dopamine is autooxidized?
8. Describe the structure of a radical. What makes a radical so unstable?
Normally the oxygen radical formed by autooxidation of dopamine is destroyed (scavenged) by special enzymes that change them into hydrogen peroxide (H2O2) and then into water. However, if the concentration of H2O2 becomes too high, the scavengers are overpowered. In the presence of ferrous ion (Fe2+), the H2O2 is reduced to form even more reactive oxygen radicals which then attack (oxidize) cellular components such as proteins, lipids and DNA.
9. How does Fe2+ reduce H2O2? What kind of oxygen radical is formed?
10. Where in the neurons are the proteins, lipids and DNA found primarily?
11. What is the chemical nature of proteins, lipids and DNA that enables them to be attacked (oxidized) by radicals?
When proteins, lipids and DNA are oxidized by the radicals they become damaged. This affects their ability to perform their normal functions. Ultimately, the cell membranes become leaky and the cells then degenerate.
12. What are the primary functions of proteins, lipids and DNA inside cells?
13. Once the cell membranes become leaky, what makes them die?
Once specific neurons have become damaged, the normal function of the part of the brain in which they reside is disrupted. For example, neurons containing dopamine in a part of the brain called the caudate nucleus are important in controlling movement. After repeated use of drugs such as methamphetamine, movement disorders can develop. This is very similar to what happens in Parkinson’s Disease, which involves oxidative damage to dopamine neurons in the caudate nucleus.
14. List 4 additional examples of oxidative cellular damage to specific targets within the body by drugs and disease.