Drugs that block neurotransmitters

What Are Neurotransmitters?

Many mental illnesses and neurological disorders are linked to problems with neurotransmitters.

Neurotransmitters are a special type of chemical compound that occurs naturally in your body.

Their role is to carry impulses from one part of the brain to another, and from the brain to the rest of the body.

Neurotransmitters work by sending chemical signals between nerve cells called neurons, which are found throughout the brain, spinal cord, and the rest of the nervous system.

Dozens of different neurotransmitters are at work in your nervous system.

Some important neurotransmitters include:

  • Glutamate
  • Serotonin
  • Dopamine
  • Acetylcholine
  • GABA
  • Histamine

There are two main types of neurotransmitters: excitatory neurotransmitters and inhibitory neurotransmitters. Excitatory neurotransmitters stimulate nerve activity, while inhibitory neurotransmitters decrease or dampen nerve activity.

Mental illnesses, such as depression, may occur when there are imbalances of certain neurotransmitters.

Neurological disorders including Alzheimer’s disease, Parkinson’s disease, and epilepsy are also associated with changes in the way the brain produces or uses neurotransmitters.

Neurotransmitter Receptors

Many of the medications used to treat mental illness and neurological disorders target neurotransmitters in the brain, or the neurotransmitter receptors on cells that receive the chemical signals.

Drugs that bind to neurotransmitter receptors, mimicking the activity of a neurotransmitter chemical binding to the receptor, are called agonists.

Antagonist drugs block a chemical response at a neurotransmitter receptor.

Opiate painkillers, including morphine and codeine, are examples of agonist drugs that bind to and activate neurotransmitter receptors, producing feelings of pain relief.

Medications used to treat schizophrenia and other mental disorders, including clozapine (Clozaril) and haloperidol (Haldol), are antagonists that block dopamine receptors in the brain.

Neurotransmitters and Addiction

Some street drugs, including cocaine, methamphetamine, heroin, marijuana, nicotine, alcohol, and prescription painkillers, can alter a person’s behavior by interfering with neurotransmitters and the normal communication between brain cells.

Drug dependence and addiction can be caused by a drug’s cumulative impact on neurotransmission — the brain’s chemical signaling system.

Over time, with repeated drug use, some drugs can actually change the structure of the brain and its chemical makeup.

How Drugs Affect The Brain

  • Routes of Administration
  • The Importance Of Synapses
  • The Neurotransmitters
  • How Drugs Work (In General)
  • Mechanisms Of Specific Drug Activity:

Routes of Administration

In order for a drug to have an effect on someone, it must first be taken into that person’s body and bloodstream so that it can then interact with that persons’ brain. Drugs that get into the bloodstream faster tend to have faster, more intense effects.

How you take a drug has a lot to do with how quickly it will effect you, and how long its effects will last. The more directly a person is able to get their drug of choice into their bloodstream, the faster and more intense the drug effect tends to be. Thus, all other things being equal, Intravenous (IV) injection of a drug will produce a greater rush than an oral dose of that same drug because the IV administered drug is immediately available to the brain, and does not have to be absorbed or otherwise processed.

In addition to the route of administration, the amount of drug that can enter the blood stream at a time is an important factor as well. Drinking alcohol on an empty stomach will result in the alcohol entering the bloodstream faster than if the same drinks were had with a full stomach. The contents of the stomach act as a sort of sponge or buffer, limiting the amount of alcohol that can be absorbed into the blood stream and sent to the brain at any given moment.

Direct IV injection into the blood

Fast, intense onset of drug effect

Inhalation (drug gets into the bloodstream via the lungs or nasal membranes)

Eating (drug enters the bloodstream through the normal process of digestion via the stomach and intestine)

Longer more gentle onset of drug effect

Once the drug is in the blood it has almost immediate access to the brain. There is a blood-brain barrier that keeps many substances out of the brain, but the drugs we are concerned with here are able to go through that barrier with little difficulty.

The Importance Of Synapses

In order to understand how drugs work on the brain, we must first have some understanding of how the brain is constructed. The brain is a very complicated collection of cells known as neurons or (more informally) nerves. Whenever you think about something, sense something or do something, what is happening at the level of the brain is that various neurons are sending information to one another concerning what you are thinking, sensing or doing. It is at the level of this inter-neuron communication that most drugs have their effects.

A given neuron is a long skinny cell. It has three prominent parts: the dendrites, the nucleus, and the axon. Information flows through neurons starting in the dendrites and ending at the terminal part of the axon (known as the button). Neurons receive information through branch-like structures called dendrites. As neurons grow, their dendrites reach out and make contact with the axons of adjacent neurons. The input parts of a given neuron, then, makes contact with the output parts of many other neurons. Signals coming from many axons converge on the dendrites of another neuron. Some of these incoming signals (excitatory signals) tell the neuron to activate itself, while others (inhibitory signals) tell the neuron to remain passive. When the number of excitatory signals gets larger then the number of inhibitory signals, the neuron ‘activates’, which is to say, a chemical-electric signal is generated at the top of the neuron, and makes its way all the way down the axon until it hits the terminal button. The signal at the terminal button is picked up by the dendrites of other neurons, and the process repeats.

The exact nature of how a signal passes from one neuron to another is particularly important. Although neurons do talk to each another through their interconnected axons and dendrites, there is no physical contact between the terminal button of one neuron, and the dendrites of another. Rather, between the axon and the dendrites is a space or gap, which is called the ‘synapse’. When the chemical-electric signal of an activated neuron reaches its terminal button, the electrical signal stops, and chemical messengers known as ‘neurotransmitters’ are introduced into the synapse. These neurotransmitter chemicals float across the synapse and connect in lock-and-key fashion with protein structures known as ‘receptors’ that are embedded in the walls of the dendrites of the receiving neurons. It is the presence of the neurotransmitter ‘keys’ opening the receptor ‘locks’ on the surface of the dendrites of the post-synaptic neurons (and not any electrical signal that jumps the synapse) that excites or inhibits the post-synaptic neurons into activating or not.

After a short while in the synapse, the neurotransmitters that have been released are recalled back into the terminal button in a process called ‘re-uptake’ so that they are available should the neuron need to fire again.

The Neurotransmitters

There are many different chemicals in the brain that function as neurotransmitters, but a small handful do most of the work.

Neurotransmitter

What it does

What drugs affect it

Dopamine

Involved in regulation of movement, reward and punishment, pleasure, energy

Every drug that affects feelings of pleasure, including Cocaine, Amphetamine, opiates, marijuana, heroin and PCP

Epinephrine (also called Adrenaline)

Excitatory neurotransmitter involved in arousal and alertness

Norepinephrine (also called Noradrenaline)

Involved in arousal and alertness, energy and feelings of pleasure

Stimulants

Serotonin

Involved in regulation of mood and impulsivity

Alcohol, Hallucinogens, Stimulants, Anti-depressants

Acetylcholine

Inhibitory neurotransmitter involved in movement, memory function, motivation and sleep

PCP and hallucinogens, Marijuana, Stimulants

GABA (Gamma Aminobutyric Acid)

Inhibitory neurotransmitter involved in arousal, judgment and impulsiveness

Depressant drugs, Marijuana

Glutamate

Excitatory neurotransmitter

Endorphins

Substances involved in pain relief and reward/punishment

Opioids, Depressants

How Drugs Work

Drugs make their effects known by acting to enhance or interfere with the activity of neurotransmitters and receptors within the synapses of the brain. Some neurotransmitters carry inhibitory messages across the synapses, while others carry excitatory messages. Agonistic drugs enhance the message carried by the neurotransmitters; inhibitory neurotransmitters become more inhibitory, and excitatory neurotransmitters become more excitatory. Antagonistic drugs, on the other hand, interfere with the transmission of neurotransmitter messages; the natural action of neurotransmitters is interfered with so that their effects are lessened or eliminated.

There are many ways that a drug can act to enhance (Agonize) a given neurotransmitter:

  • An agonistic drug can spur increased production of particular neurotransmitters. When those neurotransmitters are then released into the synapse, they are more numerous than they would normally be, and more of the neurotransmitter substances find their way over to the post-synaptic receptors on the dendrites of the next neuron.
  • An agonistic drug can interfere with the re-uptake of neurotransmitter substances which has the effect of forcing them to remain in the synapse and interacting with receptors longer than normal (Cocaine effects the Norepinephrine and Dopamine neurotransmitter systems in just this way).
  • An agonistic drug can bypass the neurotransmitter entirely, and simply float out into the synapse and itself bind with and activate the neurotransmitter’s receptors.

Similarly, there are many ways that a drug can act to interfere with (Antagonize) a given neurotransmitter:

  • An antagonistic drug can interfere with the release of neurotransmitters into the synapse.
  • An antagonistic drug can compete with the neurotransmitter for binding to the neurotransmitter’s receptor. The antagonistic drug binds to the receptor but does not activate it, thus blocking receptors from being activated by the neurotransmitter.
  • An antagonistic drug can causes neurotransmitters to leak out of their containers in the terminal button, into the fluid of the pre-synaptic neuron itself, making the neurotransmitter substance unavailable for release into the synapse. When the neuron is activated, there is less neurotransmitter available to be released into the synapse.

Most of the drugs that get abused are agonists of various neurotransmitters – they work to enhance the natural effect of neurotransmitters.

Mechanisms Of Specific Drug Activity:

Depressant Drugs:

Alcohol, Benzodiazepines, Barbiturates and other central nervous system depressant drugs act primarily on a neurotransmitter substance known as GABA (Gamma Aminobutyric Acid). GABA is an inhibitory neurotransmitter that makes other neurons less likely to activate. The depressant drugs are GABA agonists, acting to help GABA reduce neuronal activation more efficiently than it usually would. Alcohol also inhibits (acts as an antagonist against) another excitatory neurotransmitter (Glutamate), making it harder for Glutamate to get the nervous system excited.

Stimulant Drugs

Amphetamines have their primary effects on the neurotransmitter Dopamine. Amphetamines both induce the terminal button of Dopamine-producing neurons to let more Dopamine out than normal, and also keep that Dopamine out in the synapse longer than it normally would be allowed to stay. Amphetamine also acts agonistically on receptors for a different neurotransmitter, Norepinephrine, by competing with Norepinephrine for post-synaptic receptors and turning those post-synaptic receptors on.

Cocaine has its major effect by blocking the re-uptake of the neurotransmitters Dopamine and Serotonin.

Opioid Drugs:

Opioid drugs bind to special endorphin receptors in the brain (the ‘mu’, ‘kappa’, ‘sigma’ ‘delta’ and ‘gamma’ receptors) that have to do with pain. When these receptors are occupied and activated, the perception of pain lessens.

Drug treatments for opioid addictions sometimes include the administration of Naltrexone, which is an opioid antagonist. Naltrexone competes with the opioids for their receptor sites, but is not itself capable of activating those receptor sites. An opioid addict on Naltrexone is thus rendered more or less incapable of getting high from their opioid drug of choice; they may take an opioid, but it will be blocked from the opioid receptors by the Naltrexone, and will not have its effect.

Cannabinoids:

Marijuana has a complex set of effects. It acts on the neurotransmitters Serotonin, Dopamine and Acetylcholine. It also binds to a receptor for a recently discovered neurotransmitter known as Anadamide.

Hallucinogens:

LSD is known to antagonize Serotonin by blocking its release.

Information in this article has been drawn from multiple sources which include:

American Psychiatric Association. (1994). Diagnostic And Statistical Manual Of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association.

Jung, J. (2001) Psychology Of Alcohol And Other Drugs: A Research Perspective, California, Sage.

Long, P. W., (1995-2002) Internet Mental Health (http://www.mentalhealth.com)

Nahas, G. G., & Burks, T. F. (1997), Drug Abuse In The Decade Of The Brain. IOS Press

National Institute On Drug Abuse (NIDA) (2002) Information On Common Drugs Of Abuse (http://www.nida.nih.gov/DrugAbuse.html)

Schuckit, M. A, (1995) Drug And Alcohol Abuse: A Clinical Guide To Diagnosis And Treatment (4th edition). New York & London; Plenum Medical Book Company

Smith, D. E., & Seymour, R. B., (2001) Clinician’s Guide To Substance Abuse, McGraw-Hill Companies, Inc.

Imagine for a moment that we are nothing but the product of billions of years of molecules coming together and ratcheting up through natural selection, that we are composed only of highways of fluids and chemicals sliding along roadways within billions of dancing cells, that trillions of synaptic conversations hum in parallel, that this vast egglike fabric of micron-thin circuitry runs algorithms undreamt of in modern science, and that these neural programs give rise to our decision making, loves, desires, fears, and aspirations. To me, that understanding would be a numinous experience, better than anything ever proposed in anyone’s holy text.

—David Eagleman

There are several different types of neurotransmitters released by different neurons, and we can speak in broad terms about the kinds of functions associated with different neurotransmitters. Much of what psychologists know about the functions of neurotransmitters comes from research on the effects of drugs in psychological disorders. Psychologists who take a biological perspective and focus on the physiological causes of behaviour assert that psychological disorders like depression and schizophrenia are associated with imbalances in one or more neurotransmitter systems. In this perspective, psychotropic medications can help improve the symptoms associated with these disorders. Psychotropic medications are drugs that treat psychiatric symptoms by restoring neurotransmitter balance.

Major Neurotransmitters and How They Affect Behaviour

Neurotransmitter Involved in Potential Effect on Behaviour
Acetylcholine Muscle action, memory Increased arousal, enhanced cognition
Beta-endorphin Pain, pleasure Decreased anxiety, decreased tension
Dopamine Mood, sleep, learning Increased pleasure, suppressed appetite
Gamma-aminobutyric acid (GABA) Brain function, sleep Decreased anxiety, decreased tension
Glutamate Memory, learning Increased learning, enhanced memory
Norepinephrine Heart, intestines, alertness Increased arousal, suppressed appetite
Serotonin Mood, sleep Modulated mood, suppressed appetite

Psychoactive drugs can act as agonists or antagonists for a given neurotransmitter system. Agonists are chemicals that mimic a neurotransmitter at the receptor site and, thus, strengthen its effects. An antagonist, on the other hand, blocks or impedes the normal activity of a neurotransmitter at the receptor. Agonist and antagonist drugs are prescribed to correct the specific neurotransmitter imbalances underlying a person’s condition. For example, Parkinson’s disease, a progressive nervous system disorder, is associated with low levels of dopamine. Therefore dopamine agonists, which mimic the effects of dopamine by binding to dopamine receptors, are one treatment strategy.

Certain symptoms of schizophrenia are associated with overactive dopamine neurotransmission. The antipsychotics used to treat these symptoms are antagonists for dopamine—they block dopamine’s effects by binding its receptors without activating them. Thus, they prevent dopamine released by one neuron from signalling information to adjacent neurons.

In contrast to agonists and antagonists, which both operate by binding to receptor sites, reuptake inhibitors prevent unused neurotransmitters from being transported back to the neuron. This leaves more neurotransmitters in the synapse for a longer time, increasing its effects. Depression, which has been consistently linked with reduced serotonin levels, is commonly treated with selective serotonin reuptake inhibitors (SSRIs). By preventing reuptake, SSRIs strengthen the effect of serotonin, giving it more time to interact with serotonin receptors on dendrites. Common SSRIs on the market today include Prozac, Paxil, and Zoloft. The drug LSD is structurally very similar to serotonin, and it affects the same neurons and receptors as serotonin. Psychotropic drugs are not instant solutions for people suffering from psychological disorders. Often, an individual must take a drug for several weeks before seeing improvement, and many psychoactive drugs have significant negative side effects. Furthermore, individuals vary dramatically in how they respond to the drugs. To improve chances for success, it is not uncommon for people receiving pharmacotherapy to undergo psychological and/or behavioural therapies as well. Some research suggests that combining drug therapy with other forms of therapy tends to be more effective than any one treatment alone (for one such example, see March et al., 2007).

Reflection questions

  1. Cocaine has two effects on synaptic transmission: it impairs reuptake of dopamine and it causes more dopamine to be released into the synapse. Would cocaine be classified as an agonist or antagonist? Why?
  2. Drugs such as lidocaine and novocaine act as Na+ channel blockers. In other words, they prevent sodium from moving across the neuronal membrane. Why would this particular effect make these drugs such effective local anesthetics?
  3. Have you or someone you know ever been prescribed a psychotropic medication? If so, what side effects were associated with the treatment?

Microblog activity

Search online for commonly prescribed drugs that act as agonists or antagonists and share one of your findings by posting a WENote comment for our course feed. For example:

  • An example of an agonist is…
  • An example of an antagonist is…

You must be logged in to post to WEnotes.

Note: Your comment will be displayed in the course feed.

Source This page was proudly adapted from Psychology published by OpenStax CNX. Oct 31, 2016 under a Creative Commons Attribution 4.0 license. Download for free at http://cnx.org/contents/[email protected]

The Brain: Understanding Neurobiology

Drugs Change the Way Neurons Communicate (Page 1 of 2)

Source: Principles of Neural Science, 3rd edition, Eric R. Kandel, James H. Schwartz, Thomas M. Jessell ©The McGraw-Hill Companies. (m = mitochondria)

Overview

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.

Major Concept

Drugs affect the biology and chemistry of the brain.

Objectives

By the end of these activities, the students will

  • understand that certain drugs interfere selectively with neurotransmission and
  • realize that the effect of a drug is dependent upon dosage and route of administration.

Basic Science–Health Connection

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.

Background Information

Drugs Disrupt Neurotransmission

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.

Figure 3.1: Methamphetamine alters dopamine neurotransmission in two ways. Methamphetamine enters the neuron by passing directly through nerve cell membranes. It is carried to the nerve cell terminals by transporter molecules that normally carry dopamine or norepinephrine. In the nerve terminal, methamphetamine enters the dopamine- or norepinephrine-containing vesicles and causes the release of neurotransmitter. Methamphetamine also blocks the dopamine transporter from pumping dopamine back into the transmitting neuron. Methamphetamine acts similarly to cocaine in this way.

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

Figure 3.2: Nicotine binds to specific receptors on the presynaptic neuron. When nicotine binds to receptors at the cell body, it excites the neuron so that it fires more action potentials (electrical signals, represented by jagged shape in lower left of figure) that move toward the synapse, causing more dopamine release (not shown in figure). When nicotine binds to nicotine receptors at the nerve terminal (shown above), the amount of dopamine released in response to an action potential is increased.

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.

Figure 3.3: When cocaine enters the brain, it blocks the dopamine transporter from pumping dopamine back into the transmitting neuron, flooding the synapse with dopamine. This intensifies and prolongs the stimulation of receiving neurons in the brain’s pleasure circuits, causing a cocaine high.

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.

The Dose Changes the Drug’s Effects

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).

Figure 3.4: Effects of a drug depend on the dose.

Drugs Enter the Brain in Different Ways

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

Ingestion
Inhalation
Injection Snorting/Snuffing
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

Figure 3.6: Drugs of abuse enter the body by different routes. The intensity of a drug’s effect depends on how the drug is taken.

In Advance

Web-Based Activities

Activity Web Component?
1 Yes
2 No
3 Yes

Photocopies

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 3.7, 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?

Materials

Activity Materials
1 overhead projector
computers
2 soft drinks, caffeinated and caffeine-free (see Preparation, below)
1 watch or classroom clock with a second hand
3 computers

Preparation

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:

  • purchase all the soft drinks yourself through your school budget,
  • ask for parent or business donations to cover the cost, or
  • request that each student bring in one can of soft drink, labeled with his or her name, for his or her consumption only. (If you use this approach, you will need to specify which drink each student brings to class.)

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).

Procedure

Activity 1: Drugs Alter Neurotransmission

  1. Review neurotransmission with the students. It may be helpful to have the class watch the online animation of neurotransmission to refresh their memories. Have students refer to the summary of neurotransmission that they completed on Master 2.5.

After going to the , click on Lesson 2—Neurons, Brain Chemistry, and Neurotransmission.

  1. Create a chart with the following headings on the board:
Change in neurotransmission Effect on neurotransmitter release or availability
  1. Ask students if they think there are ways that neurotransmission could be altered. As students propose ideas, fill in the chart on the board. Probe for ideas by asking questions such as
  • What would happen if certain components in the process increased or decreased in amount?
  • How would that change affect the response in the responding neuron?

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.
  1. When you have the first two columns completed on the chart, inform students that certain drugs may cause the changes in the neurons that they have suggested. Write the name of the drug next to the change as indicated in the third column on the chart.

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.

  1. Display a transparency of Master 3.1, Cocaine Alters Neurotransmission, showing cocaine’s effect on dopamine neurotransmission. Point out that cocaine blocks the dopamine transporters. Ask the following questions:
  • How does this blocking action of cocaine affect dopamine levels?
  • What is the effect on the responding postsynaptic neuron?

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.

  1. After the students understand how blocking the dopamine transporters alters neurotransmission, show the animation on the Web of cocaine’s effect on neurotransmission to the class, if possible.

To view the animation, go to the . Select Lesson 3—Drugs Change the Way Neurons Communicate.

  1. Discuss the actions of another type of drug, methamphetamine, with the class. Display a transparency of Master 3.2, Methamphetamine and Nicotine Disrupt Neurotransmission (top half only). Explain that methamphetamine can act similarly to cocaine in blocking dopamine transporters (reuptake pumps). Methamphetamine also acts in another way to alter neurotransmission. Methamphetamine passes directly through the neuron cell membrane and is carried to the axon terminals. In the terminals, methamphetamine enters the vesicles that contain dopamine. This then triggers the vesicles to be released, even without an electrical signal (action potential) to cause vesicle release. Ask students how this affects the postsynaptic neuron.

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.

  1. Continue to assess the students’ understanding of how drugs can alter neurotransmission by asking them to consider how nicotine interferes with dopamine neurotransmission in the brain. Display a transparency of Master 3.2 (bottom half). Explain that nicotine binds to receptors on the transmitting (presynaptic) neuron and causes the neuron to release more neurotransmitter each time an electrical impulse (action potential) occurs. How does this affect the activity of the postsynaptic (receiving) 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.

  1. Display a transparency of Master 3.3, How Does Alcohol Affect Neurotransmission? Inform the students that in the presence of alcohol, GABA activity is enhanced, resulting in greater Cl– influx into the postsynaptic neuron and, consequently, greater inhibition of the neuron. Ask students what other inhibitory signal they have learned.

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.

Students may benefit from reviewing their work on Masters 2.7 and 2.8. Students have learned previously that GABA is an inhibitory neurotransmitter.

  1. Ask students to use what they have learned about neurotransmission to answer the following questions:
  • How does alcohol affect the activity of the neurons?

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 presynaptic neuron releases GABA as its neurotransmitter, does the amount of GABA released increase or decrease when alcohol is present in the body?

If the activity of the presynaptic neuron is decreased, it releases less neurotransmitter.

  • How does this affect the release of dopamine from the postsynaptic neuron?

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?
inhibit GABA inhibatory
  1. Now that students understand how alcohol affects neurotransmission in the brain, ask them to compare how alcohol and cocaine change neurotransmission. Use the following questions to guide the discussion.
  • How does the way alcohol alters dopamine neurotransmission differ from the way cocaine changes dopamine neurotransmission?

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.)

  • Are there any similarities in how alcohol and cocaine change neurotransmission?

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)

Return to Lesson Plans

Neurotransmitter

The rise of drug addiction has directed attention to the role of neurotransmitters by attempting to understand how it happens and how it can be counteracted. Cocaine and crack are psychostimulants that affect neurons containing dopamine in the limbic and frontal cortex of the brain; when they are used they generate a feelings of confidence and power. However, when large amounts are taken, people “crash” and suffer from physical and emotional exhaustion as well as depression. Opiates such as heroin and morphine appear to mimic naturally-occurring peptide substances in the brain with opiate activity called endorphins. Natural endorphins of the brain act to kill pain, cause sensations of pleasure, and cause sleepiness. Endorphins released with extensive aerobic exercise, for example, are responsible for the “rush” that long-distance runners experience.

It is believed that morphine and heroin combine with the endorphin receptors in the brain, resulting in reduced natural endorphin production. As a result, the drugs are needed to replace the naturally produced endorphins and addiction may occur. Attempts to counteract the effects involve using drugs that mimic them, such as nalorphine, naloxone, and naltrexone. One of the depressant drugs in widest use, alcohol, is believed to cause its effects by interacting with the GABA receptor. Initially anxiety is controlled, but greater amounts reduce muscle control and delay reaction time due to impaired thinking.

Explainer: how do drugs work?

But how does the ibuprofen pill turn off your headache? And what does the antidepressant do to help balance your brain chemistry?

For something that seems so incredible, drug mechanics are wonderfully simple. It’s mostly about receptors and the molecules that activate them.

Receptors are large protein molecules embedded in the cell wall, or membrane. They receive (hence “receptors”) chemical information from other molecules – such as drugs, hormones or neurotransmitters – outside the cell.

These outside molecules bind to receptors on the cell, activating the receptor and generating a biochemical or electric signal inside the cell. This signal then makes the cell do certain things such as making us feel pain.

Those molecules that bind to specific receptors and cause a process in the cell to become more active are called agonists. An agonist is something that causes a specific physiological response in the cell. They can be natural or artificial.

For instance, endorphins are natural agonists of opioid receptors. But morphine – or heroin that turns into morphine in the body – is an artificial agonist of the main opioid receptor.

An artificial agonist is so structurally similar to a receptor’s natural agonist that it can have the same effect on the receptor. Many drugs are made to mimic natural agonists so they can bind to their receptors and elicit the same – or much stronger – reaction.

Simply put, an agonist is like the key that fits in the lock (the receptor) and turns it to open the door (or send a biochemical or electrical signal to exert an effect). The natural agonist is the master key but it is possible to design other keys (agonist drugs) that do the same job.

Morphine, for instance, wasn’t designed by the body but can be found naturally in opium poppies. By luck it mimics the shape of the natural opioid agonists, the endorphins, that are natural pain relievers responsible for the “endorphin high”.

Specific effects such as pain relief or euphoria happen because opioid receptors are only present in some parts of the brain and body that affect those functions.

The main active ingredient in cannabis, THC, is an agonist of the cannabinoid receptor, and hallucinogenic drug LSD is a synthetic molecule mimicking the agonist actions of the neurotransmitter serotonin at one of its many receptors – the 5HT2A receptor.

An antagonist is a drug designed to directly oppose the actions of an agonist.

Again, using the lock and key analogy, an antagonist is like a key that fits nicely into the lock but doesn’t have the right shape to turn the lock. When this key (antagonist) is inserted in the lock, the proper key (agonist) can’t go into the same lock.

So the actions of the agonist are blocked by the presence of the antagonist in the receptor molecule.

Again, let’s think of morphine as an agonist for the opioid receptor. If someone is experiencing a potentially lethal morphine overdose, the opioid receptor antagonist naloxone can reverse the effects.

This is because naloxone (marketed as Narcan) quickly occupies all the opioid receptors in the body and prevents morphine from binding to and activating them.

Morphine bounces in and out of the receptor in seconds. When it’s not bound to the receptor, the antagonist can get in and block it. Because the receptor can’t be activated once an antagonist is occupying the receptor, there is no reaction.

The effects of Narcan can be dramatic. Even if the overdose victim is unconscious or near death, they can become fully conscious and alert within seconds of injection.

Membrane transporters are large proteins embedded in a cell’s membrane that shuttle smaller molecules – such as neurotransmitters – from outside of the cell that releases them, back to the inside. Some drugs act to inhibit their action.

Selective serotonin reuptake inhibitors (SSRIs) – such as the antidepressant fluoxetine (Prozac) – work like this.

Serotonin is a brain neurotransmitter that regulates mood, sleep and other functions such as body temperature. It’s released from nerve terminals, binding to serotonin receptors on nearby cells in the brain.

For the process to work smoothly, the brain must quickly turn off the signals coming from the serotonin soon after the chemicals are released from the terminals. Otherwise moment-to-moment control of brain and body function would be impossible.

The brain does so with the help of serotonin transporters in the nerve terminal membrane. Like a vacuum cleaner, the transporters scoop serotonin molecules that haven’t bound to receptors and transport them back to the inside of the terminal for later use.

SSRI drugs work by getting stuck inside the vacuum hose so unbound serotonin molecules can’t be transported back into the terminal.

Because more serotonin molecules are then hanging around receptors for longer, they continue to stimulate them.

We can crudely say the extra serotonin moderately turns up the volume of the signal to enhance positive mood. But the actual way this has an effect on depression and anxiety is far more complicated.

Around 40 per cent of all medicinal drugs target just one superfamily of receptors – the G-protein coupled receptors. There are variations on these drug mechanisms, including partial agonists and ones that act like antagonists but slightly differently. Overall though, a lot of drugs actions fall into the categories described above.

This article by Professor Mac Christie was originally published in The Conversation. He is a Professor of Pharmacology and Associate Dean (Research), Sydney Medical School at the University of Sydney.

About the author

Leave a Reply

Your email address will not be published. Required fields are marked *