8: How does ecstasy work: serotonin pathways in the brain

The nerve pathway that is predominantly affected by ecstasy is called the serotonin pathway. Serotonin is a neurotransmitter that is synthesized, stored, and released by specific neurons in this pathway. It is involved in the regulation of several processes within the brain, including mood, emotions, aggression, sleep, appetite, anxiety, memory, and perceptions. Tell the students that you will show them how a chemical like serotonin can regulate these processes. First, describe how serotonin pathways innervate (connect to) different brain regions. Point to the cell bodies of the serotonin pathway that are located in the brainstem area "the Raphe nucleus" in pink). Show students how these neurons send long axons to higher centers in the brain including the neocortex (yellow) and the limbic system (e.g., the amygdala--red and hippocampus--blue). Point to a second pathway for serotonin neurons that descends down the spinal cord; these neurons control muscle activity; tell the students that you will talk about this in more detail in a few minutes. Indicate that the function of serotonin depends on the region of the brain into which it is released (it also depends on the type of serotonin receptor present in that region--see discussion in image 9). For example, the serotonin neurons in the neocortex in the front of the brain (frontal cortex) regulate cognition, memory, and perceptions. The serotonin neurons in the hippocampus regulate memory. The serotonin neurons in other limbic areas such as the amygdala also regulate mood.

9: The serotonin neuron: the major target of ecstasy

In order to help students understand how ecstasy affects the function of serotonin neurons, it will be useful to review how neurotransmission takes place in a little more detail. You can explain serotonin neurotransmission as an example (serotonin is one of many neurotransmitters). This image shows the connection between two neurons (the "synapse"). Serotonin is stored in small vesicles within the nerve terminal of a neuron. Electrical impulses (arising in the Raphe nucleus, for example) traveling down the axon toward the terminal cause the release of serotonin from small vesicles into the synaptic space. Point to the space between the terminal and the neighboring neuron. When in the synaptic space, the serotonin binds to special proteins, called receptors, on the membrane of a neighboring neuron (this is usually at a dendrite or cell body). When serotonin binds to serotonin receptors (there are actually at least 14 types of serotonin receptors), it causes a change in the electrical properties of the receiving neuron that generally results in a decrease in its firing rate. Go to the next image to explain how the action of serotonin is terminated.

10: Serotonin transporters

Serotonin (in pink) is present in the synaptic space only for a limited amount of time. If it is not bound to the serotonin receptor, serotonin is removed from the synaptic space via special proteins called transporters (in green). The serotonin transporters are proteins located on the serotonin neuron terminals and they are in a unique position to transport serotonin from the synaptic space back into the neuron where it can be metabolized by enzymes. Explain to your students that the serotonin transporters are the primary targets for ecstasy.

11: Ecstasy and serotonin transporters

When ecstasy binds to the serotonin transporters, more serotonin ends up in the synaptic space. This occurs for two reasons. First, ecstasy can prevent the transporters from carrying serotonin back into the terminal. Second, ecstasy can cause the transporters to work in reverse mode-- they actually bring serotonin from the terminal into the synaptic space. So, more serotonin is present in the synaptic space and more serotonin receptors become activated. This is the major short-term effect of ecstasy that alters brain chemistry. Although the serotonin system is the primary target for ecstasy, ecstasy has similar effects on the dopamine (another neurotranmsitter) system as well. ecstasy can inhibit dopamine transporters and cause an increase in dopamine levels in the synaptic space (not shown here). To help students understand how the alteration in brain chemistry results in psychological changes, go to the next image.

12: Short-term (acute) effects of ecstasy

Explain that when a person uses ecstasy, the increase in serotonin in different brain regions (i.e., the areas where serotonin neurons traveling from the raphe nucleus terminate) causes psychological effects. These include elevated mood and feelings of empathy. The ecstasy is also reinforcing, which means that its pleasurable properties increase the likelihood that the person will take it again. Tell the students that drugs that are reinforcing are usually addictive.

Students might ask you if ecstasy is addictive. Scientists and health professionals don't have a definitive answer yet. For now there are several pieces of evidence that suggest that ecstasy has the potential to be addictive. In one study of ecstasy users, 43% of respondents met criteria that are commonly used to determine dependence for other drugs of abuse. This included symptoms such as continuing to use the drug despite knowledge of physical or psychological harm, experiencing withdrawal effects, and tolerance (or diminished response) to repeated use of ecstasy. In a research setting, monkeys will administer ecstasy to themselves (they actually press a lever to obtain an injection), just as they do for other addictive drugs. Monkeys will not self-administer drugs that are not addictive. In addition, there is emerging research to show that ecstasy has actions in a specific pathway within the limbic system called the "reward pathway", which can explain it's reinforcing effects. In fact, all addictive drugs act in some way within the "reward pathway". For more information on this, see the NIDA Teaching Packet referenced at the end.

Many of the psychological effects of ecstasy are due to its actions within the limbic system (the amygdala, in red, and hippocampus, in blue, especially). The ability of ecstasy to produce mild stimulation is due to its actions in another part of the limbic system -- the basal ganglia (in purple). It is here where ecstasy's effects on the dopamine system may be important. The heightened perceptions involve the actions of ecstasy in the neocotex (in yellow). ecstasy can also reduce the appetite, because it acts in the hypothalamus (in green), which controls feeding behavior.

13: Short-term adverse effects

People who take ecstasy desire its pleasurable or reinforcing effects (just described in the last image). However, few drugs are able to produce desirable effects without also producing side effects. ecstasy is no exception, and there are several side effects or adverse effects that can occur, especially at high doses. However, some people who take only one ecstasy pill may have negative psychological effects such as clouded thinking, agitation, and disturbed behavior. Point to areas of the brain where ecstasy may produce these adverse effects (the neocortex, in yellow and limbic structures, in red and blue). Other adverse effects can occur as well. These include sweating, dry mouth (thirsty), increased heart rate, fatigue, muscle spasms (especially jaw-clenching) and hyperthermia. In the latter case, ecstasy can disrupt the ability of the brain to regulate body temperature. This usually results in hyperthermia, especially when the user is in a hot environment and/or engaging in intense physical activity such as fast dancing at "rave" parties. You can provide some examples to show where ecstasy produces these side effects. For example, the development of thirst and the hyperthermia are due to actions of ecstasy in the hypothalamus (green), which controls drinking behavior and body temperature. You might point out that the effect of ecstasy on the hypothalamus causes multiple effects in the body, and in some cases they are very dangerous (see the next image). The muscle spasms and jaw-clenching are due to ecstasy's action at the motor neurons in the spinal cord (in yellow) (remind the students that a major serotonin pathway descends down the spinal cord). The motor neurons send signals to the muscles to contract.

14: Life-threatening effects after multiple doses or "stacking"

Some people take multiple doses of ecstasy in one night ("stacking"). This might be due to the reinforcing effect of the drug wearing off over time. Often, if something feels good, one wants to do it again! Unfortunately, increased doses also increase the adverse effects, and some of these can become life-threatening. For example, repeated doses or a high dose of ecstasy can cause heat injury due to hyperthermia, hypertension (high blood pressure), cardiac arrhythmias (irregular heart beat), muscle breakdown and renal failure due to salt and fluid depletion. Indicate that these dangerous effects can be produced by ecstasy acting in the brain. Again, the hypothalamus is very important, because it regulates heart rate and blood pressure, fluid retention and kidney function and, of course, body temperature. If the body temperature gets too high, it can cause brain damage or even kill a person.