Mechanism of Action

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Cocaine acts on the pleasure circuit to prevent reabsorption of the neurotransmitter dopamine after its release from nerve cells. Normally, neurons that are part of the pleasure circuit release dopamine, which then crosses the synapse to stimulate another neuron in the pleasure circuit. Once this has been accomplished, the dopamine is picked up by a transporter molecule and carried back into the original neuron. However, because cocaine binds to the dopamine transporter molecule, it prevents the reabsorption of dopamine. This causes a buildup of dopamine in the synapse, which results in strong feelings of pleasure and even euphoria. The excess dopamine that accumulates in the synapse causes the neurons that have dopamine receptors to decrease the number of receptors they make. This is called down regulation. When cocaine is no longer taken and dopamine levels return to their normal (i.e., lower) concentration, the smaller number of dopamine receptors that are available for the neurotransmitter to bind to is insufficient to fully activate nerve cells. During "craving," the addict experiences a very strong need for the drug to get the level of dopamine back up. Cocaine also binds to the transporters for other neurotransmitters, including serotonin and norepinephrine, and blocks their reuptake. Scientists are still unsure about the effects of cocaine's interaction with these other neurotransmitters.

Cocaine has also been found to specifically affect the prefrontal cortex and amygdala, which are involved in aspects of memory and learning. The amygdala has been linked to emotional aspects of memory. Researchers believe that a neural network involving these brain regions reacts to environmental cues and activates memories, and this triggers biochemical changes that result in cocaine craving.

Amphetamines, such as Methamphetamine, also act on the pleasure circuit by altering the levels of certain neurotransmitters present in the synapse, but the mechanism is different from that of cocaine. Methamphetamine is chemically similar to dopamine. This similarity allows Methamphetamine to fool the dopamine transporter into carrying Methamphetamine into the nerve terminal. Methamphetamine can also directly cross nerve cell membranes. Once inside nerve terminals, Methamphetamine enters dopamine vesicles and causes the release of these neurotransmitters. The excess dopamine is then carried by transporter molecules out of the neuron and into the synapse. Once in the synapse, the high concentration of dopamine causes feelings of pleasure and euphoria.

Methamphetamine also differs from cocaine in that it can damage neurons that contain dopamine and even kill neurons that contain other neurotransmitters. This cell damage can occur in the frontal cortex, amygdala and the striatum, a brain region that is involved in movement. This may account for the dramatic decrease in dopamine levels seen with brain imaging techniques in both humans and animals. These decreases in dopamine are seen even after short-term exposure to Methamphetamine and they persist for many years, even after Methamphetamine use has been terminated.

For more information on how Methamphetamine acts in the brain, see the last chapter which is devoted entirely to Methamphetamine.

The following activities, when used along with the magazine on stimulants, will help explain to students how these substances change the brain and the body.

This publication is available for your use and may be reproduced in its entirety without permission from NIDA. Citation of the source is appreciated, using the following language: Source: National Institute on Drug Abuse; National Institutes of Health; U.S. Department of Health and Human Services.