Students build upon their understanding of neurotransmission by learning how different drugs of abuse disrupt communication between neurons. Students then conduct an activity investigating the effect of caffeine on their heart rate. Finally, students analyze data on how the way a drug is taken into the body influences its effect.
Drugs affect the biology and chemistry of the brain.
By the end of these activities, the students will
Drugs of abuse are valuable tools for investigations of brain function because they can mimic or block actions of neurotransmitters, and thus exert effects on homeostasis and behavior.
How do drugs cause their effects on the brain and behavior? Lesson 1 introduced students to the idea that a specific brain region, the reward system (part of the limbic system), regulates feelings of pleasure and that this region is activated by drugs of abuse. But what do drugs actually do in that brain region? Drugs interfere with neurotransmission. More specifically, drugs of abuse produce feelings of pleasure by altering neurotransmission by neurons in the reward system that release the neurotransmitter dopamine.1,2 Thus, drugs of abuse alter the communication between neurons that is mediated by dopamine. Because the synapse is so complex, there is a variety of sites at which drugs may affect synaptic transmission. One way to affect synaptic transmission is to increase the amount of neurotransmitter released into the synaptic space. Drugs like alcohol, heroin, and nicotine indirectly excite the dopamine-containing neurons in the ventral tegmental area (VTA) so that they produce more action potentials.1,2 As the number of action potentials increases, so does the amount of dopamine released into the synapse. Amphetamines (e.g., methamphetamine, crystal, crank) actually cause the release of dopamine from the vesicles. This is independent of the rate of action potentials and, depending on dose, can cause a relatively quick and prolonged rise of extracellular dopamine levels.
Nicotine not only acts at the cell body in the VTA to increase the number of action potentials and number of vesicles released from a neuron, but it also acts by another mechanism to alter dopamine release. When nicotine binds to nicotine receptors on the dopamine-containing axon terminals in the nucleus accumbens, more dopamine is released with each action potential.1
Drugs may also alter synaptic transmission by directly affecting the postsynaptic receptors. Some drugs activate receptors, and others block them.
While THC (the main psychoactive chemical in marijuana) and morphine activate specific receptors, other drugs block specific receptors. Caffeine, the mild stimulant found in coffee and some soft drinks, exerts its effects by preventing a neurotransmitter/neuromodulator called adenosine from binding to its receptor. Normally, the binding of adenosine to its receptor causes sedation; it is a natural sleep-inducer. Instead of causing sedation, the blocking of the adenosine receptors with caffeine leads to an increase in activity and arousal levels.1,3
The actions of some drugs are very complex. LSD, for example, acts on serotonin receptors. Serotonin, an important neurotransmitter in many brain regions, is involved in regulating a wide variety of functions, including mood and basic survival functions such as sleeping and eating. Scientists continue to study how hallucinogens act, but apparently LSD activates some serotonin receptors (LSD acts as a receptor agonist) and blocks other serotonin receptors (LSD acts as a receptor antagonist).1
A third way to affect synaptic transmission is to alter the removal of neurotransmitters from the synapse. Cocaine and amphetamines work this way (this is the second way amphetamines can alter neurotransmission).1,3 Both drugs block the dopamine transporter (reuptake pump) that removes dopamine from the synapse. The result is a fairly rapid and persistent rise of dopamine in the synapse, leading to feelings of euphoria and well-being. Most drugs of abuse don’t block enzymatic destruction of neurotransmitters, although smoking has been shown to reduce levels of an enzyme that breaks down neurotransmitters, monoamineoxidase.
Alcohol affects the brain’s neurons in several ways. It alters their membranes and ion channels, enzymes, and receptors, and it also binds directly to the receptors for acetylcholine, serotonin, and GABA and the NMDA receptors for glutamate. GABA normally reduces the activity of neurons by allowing chloride ions to enter the postsynaptic neurons. This effect is amplified when alcohol binds to the GABA receptor and the neuron’s activity is further diminished, which explains the sedative effect of alcohol.
Alcohol also reduces glutamate’s excitatory effect by blocking the receptor activated by glutamate, the NMDA receptor. NMDA receptors are known to be involved in synaptic plasticity, a cellular mechanism for learning and memory. However, chronic consumption of alcohol gradually makes the NMDA receptors hypersensitive to glutamate while desensitizing the GABA receptors.
Alcohol also helps increase the release of dopamine, by a process that is still poorly understood but that appears to involve curtailing the activity of the enzyme that breaks dopamine down.
Drugs Mimic Natural Body Chemicals
The ability of drugs to interrupt normal synaptic transmission may seem odd. After all, if receptors have such great specificity for a single type of binding partner, how can drugs disrupt the process? The answer lies in the similarity in conformation, or structure, of the drugs to natural body chemicals. For example, the receptors in the brain that bind morphine and other opioids recognize natural opioid peptides called endorphins and enkephalins that are made by our brains and used as neurotransmitters.4 It is an evolutionary coincidence that these receptors recognize a plant-derived chemical (drug) as well. This coincidence is a double-edged sword. Opioid compounds that come from plants are both the most potent analgesics (pain relievers) available and some of the most potent addictive drugs as well. Morphine continues to be one of the most effective drugs to relieve the pain associated with many chronic diseases. When abused, opioids are often taken at higher-than-prescribed doses or in ways other than as prescribed (for example, injected vs. orally), which, by stimulating the dopamine cells in the VTA, can cause profound feelings of pleasure (euphoria). Tetrahydocannabinol (THC), the active ingredient in marijuana, binds to specific receptors in the brain called cannabinoid receptors, which were discovered because scientists were trying to understand how marijuana works. Subsequently, natural (endogenous) transmitters that bind these receptors were identified—one of which is called anandamide. The cannabinoid system is distributed widely in the brain and the body and is thought to play a role in a wide variety of physiological activities, including memory, appetite, pain perception, and immune regulation. The discovery of this system may enable scientists to develop medications (without the abuse and other health liabilities of marijuana) for a variety of diseases, including obesity, schizophrenia, multiple sclerosis, and addiction.
Drugs of abuse share a common action: they act on the brain’s reward system. Within that system, they all (except perhaps for LSD) share the ability to increase the levels of dopamine in the nucleus accumbens. This almost certainly accounts for the rewarding (pleasurable) effects of abused drugs.
The effects of drugs are not limited to the reward pathway in the brain. Drugs can act in various regions of the brain to exert their effects, but their ability to alter dopamine neurotransmission in the ventral tegmental area (VTA) and the nucleus accumbens is the initial and one of the most important factors driving continued drug use.
Many factors determine how a drug affects an individual. Some of these are biological. For example, genetics can affect a person’s sensitivity to a drug or how quickly the drug is metabolized and cleared from the body. But environmental factors can also be important—stress or trauma can alter a person’s experience with drugs. Two factors that are especially important are the dose of the drug and the route of administration, which affects how fast it reaches the brain.
For a drug to work, it must be taken into the body, absorbed in the bloodstream, and delivered to the brain. Drugs can be taken in a range of doses—from low, having no detectable effect, to moderate, producing the drug’s desired effect, to large and unpleasant, or even toxic (Figure 3.4). Not everyone will respond the same way to a given drug dose—many factors can influence this, including those mentioned above, as well as age, gender, and the person’s history of using that drug or other related drugs. However, most drugs, when taken at high doses, produce effects that are both undesirable and potentially harmful to health (overdose).
In addition to dose, the manner in which a drug is taken can profoundly alter the response to the drug. A drug that is inhaled (smoked) reaches the brain very quickly. The inhaled drugs go directly from the lungs into the left side of the heart, where they enter the arterial circulation that carries them to the brain. Marijuana and nicotine are examples of drugs that are commonly taken into the body by inhalation (smoking). The intensity of the effect of inhaled drugs may be slightly less than that for injected drugs because less of the drug gets into the brain; some of the drug will be exhaled with the rest of the components of the smoke. A drug that is injected intravenously also travels quickly to the brain, where it can exert its effects. The rapid passage of injected heroin, for example, brings a high risk of overdose. In some cases, the heroin can reach lethal levels faster than medical help can be obtained to reverse the overdose. A third route of drug administration is by snorting or snuffing. A drug that is snorted or snuffed is taken in through the nose, where it is absorbed through the mucous membranes lining the nasal passages. Television and movies often depict cocaine being snorted. The effects of drugs taken by this method will be less intense than by injection or inhalation because it takes longer for the drug to get into the brain.
|Routes of Administration|
Through the skin
Figure 3.5: Drugs enter the brain by different routes.
Another route of administration is by oral ingestion. Most people are familiar with taking a medicine, either as a solid or a liquid, by mouth. People can also take drugs of abuse this way. Drugs commonly taken orally include stimulants and depressants. Drugs taken orally enter the bloodstream more slowly than by any of the other routes. The drugs that are swallowed reach the stomach and intestine, where they are absorbed into the bloodstream. Not only do they take longer to act, but the body begins to metabolize them before they can act on the brain. Enzymes in the stomach, intestines, and liver begin breaking down the drugs so they can be cleared from the body.
As shown in Figure 3.6, the route of administration causes dramatic differences in the onset, intensity, and duration of a drug’s effect. Methamphetamine, for example, can be smoked, snorted, ingested orally, or injected. If the drug is smoked or injected, the user almost immediately experiences an intense rush or “flash” that lasts a few minutes. Snorting methamphetamine produces feelings of euphoria within three to five minutes, while oral ingestion produces effects within 15 to 20 minutes. The high resulting from snorting or ingestion is not as intense as that resulting from injecting or smoking the drug.5
|For the class||For each student|
|1 transparency of Master 3.1, Cocaine Alters Neurotransmission
1 transparency of Master 3.2, Methamphetamine and Nicotine Disrupt Neurotransmission
1 transparency of Master 3.3, How Does Alcohol Affect Neurotransmission?
1 transparency of Master 3.4, What Should the Doctor Do?
|1 copy of Master 3.4, Parent Letter
1 copy of Master 3.5, Caffeine: How Does Your Heart Respond?
1 copy of Master 3.6, How Do Drugs Get Into the Brain?
|2||soft drinks, caffeinated and caffeine-free (see Preparation, below)
1 watch or classroom clock with a second hand
Arrange for students to have access to the Internet for Activities 1 and 3, if possible.
At least one week before conducting Activity 2, send a copy of Master 3.4, Parent Letter, home with each student to inform parents of the activity and get permission for the students to consume a caffeinated or a caffeinefree soft drink during science class. You can also use the letter to ask each student to bring in his or her own can of the designated soft drink. Students who don’t drink soda can drink water as another control.
Decide on a brand of soft drink that is available with and without caffeine to use in the activity. Students should drink the same brand of soft drink because each brand contains a different amount of caffeine. If students drank different brands or flavors, the results would be difficult to interpret because each student who drank a caffeinated soft drink would ingest a different dose. You will need approximately half of the students to drink a caffeinated soft drink and half the students to drink a caffeine-free soft drink. Students who do not get parental permission can participate by drinking water, thereby providing a comparison to the control group. You may obtain the necessary soft drinks through one of the following ways:
Before the day of Activity 2, have students practice taking a resting heart rate so they are used to finding their pulse, counting the beats for 15 seconds, and multiplying that number by four to get a resting heart rate for one minute (see Activity 2).
|After going to the Web site, click on Lesson 2—Neurons, Brain Chemistry, and Neurotransmission.|
|Change in neurotransmission||Effect on neurotransmitter release or availability|
Students may suggest a variety of ways in which neurotransmission can be altered. For example, maybe less neurotransmitter gets released, which would result in reduced (fewer) firings in the responding (postsynaptic) neuron. The postsynaptic neuron might have either more or fewer receptors; changing the number of receptors would cause an increased or decreased chance of postsynaptic neuron firing. The following chart outlines potential changes and their responses. Omit the third column on the chart at this time; you will complete that part in Step 4.
|Change in neurotransmission||Effect on neurotransmitter release or availability||Drug that acts this way|
|increase the number of impulses||increased neurotransmitter release||nicotine, alcohol,* opioids,* marijuana (THC)*|
|release neurotransmitter from vesicles with or without impulses||increased neurotransmitter release||amphetamines, methamphetamine|
|release more neurotransmitter in response to an impulse||increased neurotransmitter release||nicotine|
|block reuptake||more neurotransmitter present in synaptic cleft||cocaine, amphetamine|
|produce less neurotransmitter||less neurotransmitter in synaptic cleft||no drug example|
|prevent vesicles from releasing neurotransmitter||less neurotransmitter released||no drug example|
|block receptor with another molecule, or neurotransmitter cannot bind to its receptor on postsynaptic neuron||no change in amount of neurotransmitter released||LSD, caffeine|
|* These drugs cause an increase in dopamine release. However, both alcohol and opioids act indirectly. See Steps 10 and 11 for a more complete explanation of their actions.|
Students will begin to see that drugs of abuse interfere with and disrupt the process of neurotransmission. When neurons do not communicate normally, the brain does not function normally, either.
Cocaine blocks the dopamine reuptake pumps (also called dopamine transporters). Students should recall that transporters, or reuptake pumps, carry neurotransmitter, dopamine in this case, back into the presynaptic neuron, where it is repackaged into new vesicles. If the reuptake pumps cannot function, more dopamine will be present in the synaptic space, where it can cause a greater stimulation of the postsynaptic neuron.
|To view the animation, go to the Web site. Select Lesson 3—Drugs Change the Way Neurons Communicate.|
Methamphetamine acts in two ways to change dopamine neurotransmission. Both actions lead to an increase in the amount of dopamine in the synaptic cleft. When more dopamine is present in the synaptic cleft, it is more likely to bind to the dopamine receptors on the postsynaptic neuron.
Nicotine binds to nicotine receptors on the presynaptic neuron. The binding of nicotine to its receptor stimulates the generation of action potentials in the neuron that cause dopamine to be released from the neuron. The released dopamine can then bind to its receptor on the postsynaptic neuron. Nicotine also changes the amount of dopamine that is released. When the presynaptic neuron fires an action potential, more dopamine is released than normal. The increased amount of dopamine in the synaptic cleft will bind to dopamine receptors on the postsynaptic neuron.
This exercise is similar to Activity 4 in Lesson 2. Although the activity in Lesson 2 limited the signal molecules to being neurotransmitters, drugs can also be signal molecules that affect neuron activity.
Alcohol affects the brain’s neurons in several ways, most of which are not fully understood. It alters their membranes as well as their ion channels, enzymes, and receptors.
GABA’s effect is to reduce neural activity by allowing Cl– ions to enter the postsynaptic neuron. These ions have a negative electrical charge, which helps make the neuron less excitable. This physiological effect is amplified when alcohol binds to the GABA receptor, probably because it enables the ion channel to stay open longer and thus let more Cl– ions into the cell. The neuron’s activity would be further diminished, thus explaining the sedative effect of alcohol. This effect is accentuated because alcohol also reduces glutamate’s excitatory effect on NMDA receptors.
In addition to these GABA-mediated effects, alcohol may bind to other receptors. It also helps increase the release of dopamine, by a process that is still poorly understood but that appears to involve curtailing the activity of the enzyme that breaks down dopamine.
If the activity of the presynaptic neuron is decreased, it releases less neurotransmitter.
Because GABA is an inhibitory neurotransmitter, smaller quantities of it in the synaptic space create less inhibition of the postsynaptic neuron. Therefore, the activity of the postsynaptic neuron increases and more dopamine is released when alcohol is present.
If you complete a line for alcohol on the chart like the one on Master 2.8b, it would appear as follows:
|Does the signal molecule excite or inhibit Neuron #1?||Does the activity of Neuron #1 increase or decrease?||Does the amount of neurotransmitter released from Neuron #1 increase or decrease?||What is the name of the neurotransmitter released from Neuron #1?||Is the neurotransmitter released from Neuron #1 excitatory or inhibitory?||Does the activity of Neuron #2 increase or decrease?||Does the amount of dopamine released from Neuron #2 increase or decrease?|
Unlike cocaine, alcohol does not act directly on the dopamineproducing neuron. Alcohol acts on another neuron that regulates the activity of a dopamine-producing neuron. In other words, alcohol acts indirectly on dopamine neurotransmission, whereas cocaine acts directly on the neuron that produces dopamine. (Opioids and tetrahydrocannabinol (THC), the active ingredient in marijuana, act by a mechanism similar to that of alcohol.)
Both alcohol and cocaine change dopamine neurotransmission and increase the amount of dopamine present in the synaptic cleft. The increased amount of dopamine can inhibit or excite the activity of the postsynaptic neuron depending on the type of dopamine receptor present on the postsynaptic neuron.
Next: Lesson 3 (Page 2 of 2)