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Neurotransmitters and Related Drugs 3 Photo of 19th-century advertisement for cocaine toothache drops that reads, "Cocaine toothache drops. Instantaneous cure! Price 15 cents. Prepared by the Lloyd Manufacturing Co. 219 Hudson Ave., Albany, N.Y. For sale by all druggists. (Registered March 1885.) See other side. Bettmann/CORBIS Learning Objectives After completing this chapter, you should be able to: Name the neurotransmitter families and the neurotransmitters associated with each family. Identify the neurotransmitters not associated with neurotransmitter families. Describe the functions of acetylcholine in the central, somatic, and parasympathetic nervous systems. Explain how nicotine, curare, muscarine, and atropine affect the nervous system and behavior. Differentiate between the function of glutamate and GABA in the nervous system. Identify several peptide neurotransmitters and their functions. Explain the differences among the monoamine neurotransmitters: serotonin, norepinephrine, and dopamine. Describe the relationship between cannabinoid neurotransmitters and marijuana. List several ways in which nitric oxide affects the nervous system and behavior. Draw a synapse between two neurons and indicate where acetylcholinesterase, MAO, COMT, and SSRIs have their effect. Matt celebrated his 21st birthday with a keg party at his apartment. The first few beers went down smoothly, and he felt no ill effects from the alcohol at first. However, when he began dancing with his girlfriend, he found that he lost his balance easily and that he could not coordinate his movements to the music. As the party continued, Matt drank several more beers. He soon began staggering around the apartment, hugging the walls as he moved from one room to the next. When people talked to him, he had a hard time following the conversation. His speech became slurred and effortful. After a few more beers, Matt nearly fell over when his girlfriend kissed him. She giggled and led him to his bedroom, where he staggered to his bed, lay down, and promptly fell asleep. This chapter will focus on the chemicals that influence the activity of neurons. Some of these chemicals are neurotransmitters manufactured by the neurons themselves, and some are substances such as alcohol that are ingested and then transported across the blood-brain barrier. Alcohol is a good example of an ingested substance that affects the functioning of neurons. The opening text describes how overconsumption of alcohol affected Matt's nervous system. Let's consider how alcohol affects neurons. Recall from Chapter 2 that in order to excite a neuron, the membrane must be depolarized. Depolarization takes place when positively charged sodium ions flow into the neuron. Alcohol blocks the flow of sodium into the neuron by binding with a protein on the surface of the cell membrane, thereby preventing the cell from getting excited. That's why alcohol is classified as a depressant: It depresses, or decreases, the activity of neurons. In the opening text, alcohol interfered with Matt's ability to walk, talk, and maintain his balance by inhibiting the neurons that control these functions. All chemicals that affect neurons cause a change in the activity of neurons. Some chemicals, like alcohol, decrease the activity of neurons, and other chemicals increase the activity of neurons. The chemicals produced by neurons, called neurotransmitters, typically affect a neuron's activity by opening particular ion channels. As you learned in Chapter 2, opening sodium channels increases a neuron's activity because sodium rushes into the neuron when the sodium channel is open, depolarizing the neuron. Chemicals that open potassium or chloride channels of a neuron inhibit a neuron by hyperpolarizing the neuron and making the neuron less likely to get excited. The control of behavior is a very complicated process, involving chemicals that play different roles depending on their location in the nervous system, as you will learn in Chapter 4. Don't forget that many chemicals that come from outside the body also bind with postsynaptic receptors. In this chapter we will consider the effects of various drugs on behavior. Psychopharmacology is the study of chemical substances that affect the activity of neurons. Therefore, much of the information that we have about drug action in the brain comes from the research of psychopharmacologists. Some drugs are classified as agonists, and others are classified as antagonists. Agonists are chemical substances that bind with a receptor and activate the receptor, much as a neurotransmitter does. In contrast, antagonists also bind with a receptor, but they block the action of the neurotransmitter by preventing the neurotransmitter from binding with its receptor (Figure 3.1). We will examine the roles of well-known neurotransmitter agonists and antagonists in this chapter. 3.1 Classifying Neurotransmitters In this section we will examine a wide variety of chemicals, called neurotransmitters, that are synthesized and used by neurons to transmit information across chemical synapses. Dozens of these transmitter substances have been identified. However, this chapter will focus only on the neurotransmitters that play an important role in the regulation of human behavior. These neurotransmitters are listed in Table 3.1. Another type of chemical, called a hormone, is synthesized by certain brain structures or by organs outside of the brain, is released into the bloodstream, and travels to target neurons. Hormones generally have longer lasting effects on the action of neurons. For example, epinephrine, which is also known as adrenaline, is a hormone that is released by the adrenal gland, a structure located above the kidney. When released into the bloodstream, epinephrine travels to neurons in the sympathetic nervous system, activating those neurons and producing the physiological effects that we associate with sympathetic arousal: increased heart rate, rapid breathing, pupil dilation, constriction of blood vessels in the gut, and increased flow of blood to skeletal muscles (Figure 3.2). Figure 3.2: Action of epinephrine Epinephrine affects many areas of the body. What causes your brain to release epinephrine in your body to cause these reactions? Image of a person showing the physiological effects of the release and action of epinephrine: dilates pupil, relaxes bronchi in the lungs, accelerates/strengthens heartbeat, inhibits activity in the stomach/intestines, and constricts blood vessels of internal organs. Neurotransmitter Families Neuroscientists have attempted to classify neurotransmitters and group them into "families" (Table 3.1). But neurotransmitters are difficult to classify due to their wide variety. However, some are easy to group together. For example, some neurotransmitters are simple amino acids, like glutamate or gamma-aminobutyric acid (GABA). Amino acids are relatively simple compounds that contain an NH2 (amino) group and COOH (acid) group. Peptides such as endorphin and cholecystokinin form another class of neurotransmitters. Peptides are nothing more than a short chain of amino acids joined end to end. Another well-known family of neurotransmitters is the monoamine family, which are derivatives of amino acids that contain one amine (NH2) group. Monoamines that have been demonstrated to act as neurotransmitters include serotonin, norepinephrine, and dopamine. Serotonin, the neurotransmitter associated with positive mood and satisfaction, is derived from the amino acid tryptophan, which is found in foods that you eat every day, such as red meat, fish, poultry, eggs, milk, cheese, chocolate, and oats. In fact, there is evidence that you can alter brain serotonin levels by changing your diet (see the "For Further Thought" box). Norepinephrine and dopamine come from another amino acid, tyrosine, which is commonly found in a variety of protein-rich foods. Table 3.1: Important neurotransmitters associated with human behavior Family name Associated neurotransmitters Amino acid Glutamate, aspartate, glycine, gamma-aminobutyricacid (GABA) Peptide Substance P, cholecystokinin, endorphins Monoamine Serotonin, norepinephrine, dopamine, histamine Cannabinoids Anandamide Unknown Acetylcholine Unknown Nitric oxide Another recently identified family of neurotransmitters is the cannabinoid family. These neurotransmitters bind with a group of receptors called cannabinoid receptors. The term cannabinoid refers to any natural or synthetic chemical substances that resemble tetrahydrocannabinol (THC), the active ingredient of marijuana, in structure and function. Several neurotransmitters have been discovered that bind with cannabinoid receptors, which will be discussed later in the chapter. Other transmitter substances synthesized by neurons, such as acetylcholine and nitric oxide, do not fit neatly into a particular family of neurotransmitters. These substances are not derived from amino acids. Nitric oxide, for example, contains no carbon and is an inorganic compound. Perhaps in the future, neuroscientists will discover related chemicals that function as neurotransmitters. For the present, acetylcholine and nitric oxide are the sole occupants of their respective family trees (Table 3.1). For Further Thought: Serotonin and Diet What you eat can affect serotonin levels in your brain. Recall that serotonin is derived from the amino acid tryptophan. When tryptophan crosses the blood-brain barrier, it is converted to serotonin. However, tryptophan has to compete with other large amino acids to get into the brain. Because tryptophan is present in very small quantities in most foods, especially compared to other large amino acids, it is usually outnumbered by molecules of other amino acids vying to cross the blood-brain barrier and cannot easily get into the brain. Potatoes, bagels, and uncooked macaroni on a white background. Thomas Northcut/Photodisc/Thinkstock Photo 3.1 Carbohydrates contain large amounts of tryptophan and, when consumed, produce serotonin in your brain. Foods high in protein contain relatively large quantities of other amino acids, compared to tryptophan. Thus, consuming foods rich in protein tends to prevent tryptophan from crossing the blood-brain barrier. In contrast, foods that are poor in protein have tiny amounts of all amino acids. This means that, when low-protein foods are consumed, tryptophan has less competition when crossing the blood-brain barrier and enters the brain more readily. Research has demonstrated that meals that contain less than 5% protein cause an increase in serotonin production in the brain (Fernstrom, 1987). In addition, meals rich in carbohydrates promote the passage of tryptophan across the blood-brain barrier. Carbohydrates stimulate the release of insulin in the body, and the more carbohydrates consumed, the more insulin is released. Tryptophan requires insulin to cross the blood-brain barrier, which means that larger quantities of insulin in the blood will transport larger amounts of tryptophan into the brain. Hence, meals rich in carbohydrates and poor in protein will facilitate the entry of tryptophan into the brain, resulting in increased synthesis of serotonin, which in turn may elevate mood (Silverstone, 1993). 3.2 The Roles of Neurotransmitters in Human Behavior Let's examine the roles that major neurotransmitters play in regulating human behavior. We'll begin our discussion with acetylcholine, the first neurotransmitter to be discovered. Next, we'll take a look at the major amino acid, peptide, and monoamine transmitter substances, and we'll conclude with a discussion of two recently discovered neurotransmitters: nitric oxide and anandamide. Acetylcholine Acetylcholine is believed to play an important role in a wide range of behaviors. For that reason, acetylcholine receptors are found throughout the central and peripheral nervous systems. Table 3.2 lists the functions of acetylcholine in the nervous system. Table 3.2: Functions of acetylcholine Nervous system Function 1. Central Learning, memory, decision making, antiexcitation, control of posture 2. Peripheral     a. Somatic Contraction of skeletal muscles     b. Autonomic       i. Parasympathetic Contraction of smooth muscles, digestion, relaxation Acetylcholine is the neurotransmitter that initiates contractions in all smooth and skeletal muscles, as you will learn in Chapter 5. Thus, acetylcholine is necessary for the functioning of the somatic and autonomic nervous systems. Chemicals such as cobra snake venom that block the action of acetylcholine can interfere with muscle contraction, causing paralysis. Curare, for example, is derived from a South American plant and is still used by native hunters there as a poison on the tip of their arrows. When a curare-tipped arrow strikes a prey animal, the curare binds with acetylcholine receptors in the animal, preventing acetylcholine from reaching its muscle receptors. Consequently, the animal becomes paralyzed and drops to the ground, which makes it easy to capture. Curare has several useful medical applications because of its ability to paralyze muscles. Two life-threatening illnesses caused by bacteria are associated with the interference of acetylcholine transmission in skeletal muscles. Tetanus, also known as "lockjaw," usually results from a deep puncture wound that is not cleaned properly, allowing the bacterium Clostridium tetani to multiply in the area surrounding the wound. The Clostridium bacterium produces a powerful toxin (poison) that is released into the bloodstream and interferes with acetylcholine function by blocking the release of neurotransmitters that inhibit acetylcholine. That is, the tetanus toxin stops the inhibition of muscle contraction. A person afflicted with tetanus experiences prolonged, unmitigated muscle contractions that can lead to death, if not treated. Image of gloved hands administering a Botox injection into a woman's lip. Digital Vision/Getty Images Photo 3.2 The drug Botox, used to remove wrinkles, is a toxin produced from the same bacteria that causes botulism. Another illness, known as botulism, results from ingestion of a bacterium called Clostridium botulinum, which is found in canned and preserved foods that have not been properly prepared. This bacterium, after it is ingested, is not destroyed by enzymes in the digestive tract and gets into the bloodstream, where it multiplies and produces a toxin that inhibits acetylcholine release at the junction between the motor neuron and the muscle fiber (Baskaran et al., 2013; Pellizzari, Rossetto, Schiavo, & Montecucco, 1999). Botulism causes weakness and eventual paralysis of all skeletal muscles, including the muscles needed for breathing. Death due to suffocation results in several hours to days if the illness goes untreated. The drug Botox is derived from the toxin produced by the Clostridium botulinum bacterium. When injected in tiny doses directly into the muscles of the face, Botox paralyzes these muscles, removing wrinkles from the face, especially the frown lines around the eyes. This treatment, favored by movie stars and other celebrities because it is noninvasive, will last up to 8 months. In addition to the important role that acetylcholine plays in muscle contraction, acetylcholine plays a number of other important roles in the central and peripheral nervous systems. In the autonomic division of the peripheral nervous system, acetylcholine activates the parasympathetic nervous system, producing a variety of responses associated with relaxation, including decreased heart rate, increased rhythmic contractions in the stomach and intestines, constriction of the pupil of the eye, and increased secretions of various glands associated with digestion, including salivary glands. Acetylcholine also plays an important role in the central nervous system, particularly in learning, memory, attention, decision making, reduction in anxiety, and the control of posture (Blokland, 1996; Decker, Brioni, Bannon, & Arneric, 1995; Edmonds, Gibb, & Colquhoun, 1995; Ehlert, Roeske, & Yamamura, 1995; Felder et al., 2001; Levin & Simon, 1998; McGehee & Role, 1995; Mesulam, 1995; Picciotto, Higley, & Mineur, 2012; Reiner & Fibiger, 1995; Schwarz et al., 1999). Drugs Associated with Acetylcholine Receptors There are two types of acetylcholine receptors in the nervous system: (1) a receptor that binds with nicotine, called a nicotinic receptor; and (2) a receptor that binds with muscarine (a deadly toxin that comes from a poisonous mushroom), called a muscarinic receptor. Nicotine and muscarine are able to bind with acetylcholine receptors because they resemble acetylcholine structurally. A chemical fits into a receptor site like a key fits into a lock, so any chemical substance that has the correct shape will fit into the receptor and bind with it. Keeping in mind that there are two major classes of acetylcholine receptors, you shouldn't be surprised to learn that totally different chemical substances bind to nicotinic and muscarinic acetylcholine receptors. Curare, which you learned about earlier in this chapter, binds with nicotinic receptors and prevents acetylcholine from activating the receptor. Because it blocks the action of acetylcholine, curare is a nicotinic antagonist. Nicotine, on the other hand, is a nicotinic agonist. Whether derived from tobacco or from nicotine gum or patches, nicotine enters the bloodstream, crosses the blood-brain barrier, and activates nicotinic receptors. This is because nicotine has a molecular shape that is very similar to the acetylcholine molecule (Domino, 1998; Grimster et al., 2012). Nicotine has been demonstrated to improve cognitive processing, increase cerebral blood flow, and decrease anxiety—functions associated with activation of nicotinic receptors (Decker, Brioni, Bannon, & Arneric, 1995; Rowland et al., 2010). If you don't remember the difference between an agonist and antagonist, this is a good time to review these terms. Figure 3.1 illustrates how the actions of agonists and antagonists differ. Drugs and other chemicals that affect neurons act as agonists or antagonists for a particular neurotransmitter. Nicotine is an acetylcholine agonist because it activates the action of acetylcholine, and curare is an acetylcholine antagonist because it blocks the action of acetylcholine. You have already learned about one agonist of the muscarinic acetylcholine receptor, muscarine. Muscarine binds with the muscarinic receptor, producing a number of parasympathetic responses, including constriction of the pupil of the eye (Scott & Fryer, 2012). A muscarinic antagonist that has a number of medical applications is atropine. Like muscarine, nicotine, and curare, atropine is a natural substance that is derived from a plant. It can fit into the muscarinic receptor and prevent acetylcholine from binding with the receptor. In ancient times atropine was used as a poison. Today it has many useful medical applications. For example, it is used to produce dilation of the pupil so that the physician may examine the interior of the eyeball. If you have had your pupils dilated by an eye doctor, you have experienced the effects of atropine. Remember, muscarine has the opposite effect: pupillary constriction. Table 3.3 summarizes the agonists and antagonists associated with acetylcholine receptors. Table 3.3: Review of acetylcholine agonists and antagonists Type of acetylcholine receptor Example of an agonist Example of an antagonist Nicotinic Nicotine Curare Muscarinic Muscarine Atropine Amino Acid Neurotransmitters: Glutamate and GABA Amino acid neurotransmitters are the most common transmitter substances found in the human nervous system. Unfortunately, because amino acids are found inside all cells in the body, scientists overlooked their role as neurotransmitters for many years. Receptors for the amino acids—glutamate, aspartate, glycine, and gamma-aminobutyric acid—have been identified in the cell membranes of neurons, and these amino acids are now regarded as true neurotransmitters. Glutamate and aspartate bind with receptors that open sodium channels and are excitatory neurotransmitters. Glycine and gamma-aminobutyric acid open chloride channels and are inhibitory neurotransmitters. We'll focus on glutamate and GABA in this chapter because the roles of glutamate and GABA in regulating human behavior are well documented, whereas the functions of glycine and aspartate are not well understood. Glutamate Research has demonstrated that there are at least 13 different receptors for glutamate, so the functions of glutamate are numerous. Most neurons in the brain use glutamate to produce rapid excitation in postsynaptic neurons. Glutamate is also believed to play an important role in the encoding of long-term memory and the storage of information in the brain. In Chapter 13 we'll examine the role of glutamate in brain damage and several degenerative brain diseases such as Alzheimer's disease. Chemicals Associated with Glutamate Receptors Although a large number of synthetic drugs have been created that bind with glutamate receptors, we will focus on two better-known chemical substances that we encounter every day. The first substance is caffeine, which is found in most coffee, tea, and carbonated beverages. Caffeine's main effect is to increase the activity of glutamate receptors that activate the heart muscle, which elevates cardiac output and increases the flow of oxygen to the brain. Caffeine does not bind with glutamate receptors directly, but instead it blocks the action of adenosine, a neurotransmitter that inhibits glutamate release. That is, caffeine binds with adenosine receptors, preventing adenosine from binding with its own receptors. When adenosine cannot bind with its own receptors, it cannot inhibit the release of glutamate. Thus, caffeine blocks the action of adenosine and indirectly increases glutamate release. A second substance that is associated with glutamate receptors is monosodium glutamate, also known as MSG, which is used in some types of cuisine to enhance the flavor of food. (Chinese restaurants, for example, typically use MSG in their dishes, although some do not use MSG and promote themselves as being MSG-free.) MSG does not cross the blood-brain barrier, so it has no effect on the brain. However, because the blood-brain barrier is not fully developed in the very young, MSG can cross the blood-brain barrier in young children. MSG does bind with glutamate receptors in the peripheral nervous system and can produce tingling, burning, loss of sensation, ringing in the ears, and other peripheral symptoms in people who are sensitive to MSG or who have ingested too much of the substance (Settipane, 1987). GABA Gamma-aminobutyric acid (GABA) is considered to be the most important inhibitory neurotransmitter in the brain (Paul, 1995). A wide variety of different GABA receptors have been discovered in the human nervous system. Therefore, like the other neurotransmitters we have considered to this point, GABA plays a number of different roles in the brain, many of them still undiscovered. One GABA receptor that has received a great deal of study is called the GABAA receptor. It is a large complex that contains receptor sites for other substances in addition to GABA. Figure 3.3 illustrates a typical GABAA receptor. The receptor itself is a protein composed of five subunits that form an ion channel. It is embedded in the cell membrane, with receptor sites for GABA located on the surface of the neuron. Some subunits also have receptor sites for other substances, including alcohol, antianxiety agents known as benzodiazepines (for example, Valium), barbiturates (sleeping pills), and general anesthetics (Mihic, Sanna, Whiting, & Harris, 1995; Tan, Rudolph, & Lüscher, 2011) that stimulate GABA activity and act as GABA agonists. Figure 3.3: The GABAA receptor complex The GABAA receptor complex is a complicated structure that contains binding sites for GABA, barbiturates, and antianxiety drugs (benzodiazepines). Figure of a GABA-A receptor complex with the barbiturate, benzodiazepine, GABA, and channel pore labeled. Although investigators are beginning to understand the structure of GABA receptors, they are still far away from linking specific receptor types to specific behaviors. Certainly, the wide variety of GABA receptors that exist point to an enormous range of behaviors and functions that are regulated by GABA (Eulenburg & Gomeza, 2010). Some investigators believe that very minor alterations in the GABA receptor structure can profoundly affect receptor function and may be implicated in a number of behavior disorders, including anxiety disorders, alcohol abuse, epilepsy, sleep disorders, and certain degenerative disorders such as Huntington's disease (Ali, Jha, Kaur, & Mallick, 1999; Luchetti et al., 2011; Malizia & Richardson, 1995; Mihic, Sanna, Whiting, & Harris, 1995). Drugs Associated with GABA Receptors Many chemical substances are associated with the GABA receptors. For example, a variety of compounds have been synthesized that bind directly with the GABA receptor site, acting as GABA agonists or antagonists. These compounds are useful for research purposes when comparing the various receptor types, but they are not important for you, the student of behavior, to study. Instead, we will focus on several well-known drugs that bind with the GABA receptor. The drugs we will examine in this context are benzodiazepines, barbiturates, alcohol, and general anesthetics. Benzodiazepines are a class of drugs that were first developed in the 1950s (Ballenger, 1995). These drugs are chiefly prescribed as antianxiety agents and have sedative and muscle relaxant effects as well. Valium is probably the best-known benzodiazepine—in fact, it was once the most widely prescribed drug in America. Benzodiazepines can also be used to control epileptic convulsions. In 1977 several investigators working in different laboratories discovered that benzodiazepines bind to receptor sites on GABAA receptor complexes. Benzodiazepines boost GABA activity by increasing GABA binding to its receptor. Like benzodiazepines, barbiturates are antiepileptic agents, but they are also used to induce sleep or unconsciousness in patients. Drugs that induce sleep are called hypnotics; drugs that induce unconsciousness are called general anesthetics. Barbiturates can be used as an antiepileptic, a hypnotic, or a brief-acting general anesthetic. They bind to the GABAA receptor complex much as benzodiazepines do (Figure 3.3; Paul, 1995; Tan, Rudolph, & Lüscher, 2011). Alcohol also binds to specific sites on the GABAA receptor complex. Similar to benzodiazepine in action, alcohol augments GABA binding to its receptor, producing increased inhibition. This inhibitory action most likely produces the anxiety-reducing and sedative effects of alcohol. General anesthetics, used during surgery to induce unconsciousness in the surgical patient, also bind with the GABAA receptor, increasing the inhibitory function of GABA (Mihic, Sanna, Whiting, & Harris, 1995). Thus, it appears that one of GABA's functions in the brain is to calm a person down and to induce sleep and unconsciousness as GABA activity increases. Peptide Neurotransmitters Neuroscientists have identified nearly 50 different peptides that are made by neurons and used as transmitter substances. These peptide neurotransmitters, or neuropeptides, as they're often called, differ from other neurotransmitters because they are synthesized in ribosomes in the soma of the neuron, whereas other neurotransmitters are manufactured in the axon near the site of release. In addition, peptide neurotransmitters are almost always released by the presynaptic neuron in conjunction with another neurotransmitter (Hökfelt, Castel, Morino, Zhang, & Dagerlind, 1995; Matthews & Fuchs, 2010). This observation (that neuropeptides do not act alone as a signaling transmitter) has raised many questions about the role of peptides as neurotransmitters. Most neuroscientists believe that neuropeptides enrich the message of the other neurotransmitter. At present, the functions of very few peptide neurotransmitters are truly understood. We will focus on only three neuropeptides in this chapter, although you will learn about more in later chapters. Substance P Substance P gets its funny name from the fact that it was first identified as an active substance in a powder made from brain extract. It is found in many parts of the brain and spinal cord, especially those parts of the nervous system associated with the sensation of pain. Currently, substance P is believed to be the primary neurotransmitter that signals pain. Several investigators have demonstrated that substance P is released in response to stress and that it may play a role in depression, as you will learn in Chapter 12 (Burnet & Harrison, 2000; Ratti et al., 2011; Kramer et al., 1998; Wahlestedt, 1998). Cholecystokinin Cholecystokinin (CCK) is a hormone synthesized by cells in the small intestine and in the nervous system. It is released into the blood and travels to the central nervous system, where it binds with CCK receptors on neurons. CCK's main function involves transmitting signals about satiation following a meal. However, CCK also appears to play a role in blocking pain and reducing anxiety (Marchand & Gaumond, 2013). Endorphins and Other Endogenous Opiate Peptides A 19th-century advertisement for Bayer Pharmaceutical products: Aspirin, Heroin, Lycetol, and Salophen. Bettmann/CORBIS Photo 3.3 Heroin was once an over-the-counter pain remedy. The term endorphin is actually a contraction of the term endogenous morphine, so called because this class of neuropeptides functions like morphine in countering pain and reducing stress. Morphine is a synthetic drug that mimics the painkilling effect of opium, a natural substance derived from the poppy plant. Endorphin is a class of morphine-like chemicals, referred to as endogenous opiate peptides, manufactured by certain neurons in the brain. At least six different peptides have been identified as endogenous opiate peptides. Endogenous opiate peptides bind with opioid receptors on the membranes of neurons. In addition to reducing pain, endogenous opiate peptides have also been implicated in the regulation of blood pressure, stress responses, food intake, sexual behavior, temperature regulation, and memory (Bodnar, 2012). Drugs Associated with Opioid Receptors Usually, neurotransmitters are first identified by neuroscientists, and then their respective receptors are located and characterized. In the case of endorphins, these two steps were reversed. The opioid receptor was isolated and identified first, and then researchers discovered the endogenous transmitter that binds to the receptor (Snyder, 1980.) Why was this discovery process reversed for opioid receptors? Opium, a derivative of the poppy plant, has been known for centuries to produce sedation and euphoria in the user. Other drugs that are derived naturally or synthetically from opium, called opiates or narcotics, were developed in the 19th and 20th centuries. These new opiates, including morphine, heroin, codeine, and Demerol, were effective in reducing pain. Researchers reasoned that opium and its derivatives must interact with neurons to produce their effects, and some began searching for receptor sites on neurons that bind with opiates. In 1973 Candice Pert and Solomon Snyder at Johns Hopkins University discovered the receptor binding site for opiate drugs. After the opioid receptor was identified, investigators embarked on a search for chemicals in the nervous system that bind to the opioid receptor. In 1974 and 1975 researchers in Europe and the United States found a brain extract (later called endorphin) that binds to the opioid receptor (Hughes, 1975; Pasternak, Goodman, & Snyder, 1975; Terenius & Wahlstrom, 1975). Hence, the discovery of the opioid receptors in the brain that prompted the search for endorphins. Monoamine Neurotransmitters Earlier in this section on neurotransmitters, you learned that serotonin, norepinephrine, and dopamine belong to the same family, called monoamine neurotransmitters. Collectively, these neurotransmitters play an important role in regulating mood, sleep, appetite, and memory (Choi & Son, 2013). Individually, these three neurotransmitters each have a particular distribution in the brain and have been implicated in special functions. Other amines such as histamine have been identified in the central nervous system, but their roles are unclear at present. Therefore, we will focus on serotonin, norepinephrine, and dopamine in this section. Serotonin Serotonin was discovered more than 100 years ago in the serum of blood; hence its prefix sero-. The suffix -tonin comes from the observation that this blood-borne substance increases muscle tone in smooth muscle in the gut (Watts, Priestley, & Thompson, 2009). Recall that serotonin is derived from the amino acid tryptophan and therefore has the chemical name hydroxytryptamine (abbreviated as 5-HT). Seven classes of serotonin receptors have been identified, each with its own distribution in the brain and its own function. For example, one type of receptor is implicated in anxiety, aggression, and depression, whereas another type seems to be involved in appetite and motor control, and a third type appears to play a role in nausea, vomiting, anxiety, and schizophrenia (Di Giovanni, Esposito, & Di Matteo, 2010). The fact that serotonin has so many different types of receptors tells us that serotonin plays many roles in the brain. In fact, no other neurotransmitter has been implicated in so many important human functions (Jacobs & Fornal, 1995). Serotonin's most important function appears to be the regulation of sleep. But, it has also been demonstrated to be involved in vigilance, mood regulation, stereotyped or repetitive movements such as response to pain, and appetite (especially appetite for carbohydrates). For example, a study on diabetic patients reveals that reduced brain serotonin levels may be recovered by increased carbohydrate consumption (Yu et al., 2013). As you will learn in later chapters, serotonin has also been implicated in a host of disorders, including mood disorders, anxiety disorders, obsessive-compulsive disorder, schizophrenia, eating disorders, migraine headaches, and sleep disorders (Elliot, Zahn, Deakin, & Anderson, 2011; Marino et al., 2010; Price & Drevets, 2012). Drugs Associated with Serotonin Receptors Given that there are at least 15 different types of serotonin receptors, there are dozens of drugs that could be discussed in this section. However, the discussion will be limited to two illicit drugs, lysergic acid diethylamide (LSD) and methylene-dioxymethamphetamine (MDMA), that appear to interact with serotonin receptors but that are not generally prescribed for medical purposes. The molecular structure of LSD is strikingly similar to that of serotonin, and, hence, LSD is able to fit into serotonin receptor sites. LSD's effect is hallucinogenic, producing hallucinations and altering cognition and sensory experiences. The active ingredient in psychedelic mushrooms, called psilocybin, also resembles serotonin in chemical structure. Like LSD, psilocybin fits into the serotonin receptor and causes hallucinations. MDMA, known as ecstasy for the short-term surge of euphoria and feeling of well-being that it produces, also binds with certain serotonin receptors. However, exposure to MDMA appears to be toxic to neurons. Damage to the axons of serotonin neurons has been observed in the brains of people who have taken MDMA more than 200 times (McCann, Szabo, Scheffel, Dannals, & Ricaurte, 1998). Using a radiolabel that binds to serotonin markers on the axons of neurons that release serotonin, McCann and colleagues (1998) were able to show in brain scans that axon terminals in serotonin neurons were destroyed in human subjects who used large doses of MDMA over the course of 4 to 5 years, compared to control subjects who had never used MDMA. This damage was dose-related because the damage observed was greater in subjects who used MDMA more times (400 versus 100 doses). Norepinephrine Norepinephrine and its catecholamine cousin, epinephrine, bind to the same receptors called adrenergic receptors. Altogether, there are four types of adrenergic receptors, each having its own agonists and antagonists and each having its own distribution in the brain. It is quite interesting that a neurotransmitter (norepinephrine) and a hormone (epinephrine) would bind to the same receptors, but it tells us that both norepinephrine and epinephrine are involved in activation of the sympathetic nervous system. Both produce an increase in heart rate, respiration rate, sweating, and pupil dilation. In addition, norepinephrine plays a role in mood, drive reduction, sleep, arousal, cognition, and emotions (Foote & Aston-Jones, 1995; Morilak, 1997). Norepinephrine also has been implicated in a number of behavioral disorders, including depression, posttraumatic stress disorder, anxiety disorder, and withdrawal symptoms associated with drug addiction (Economidou et al., 2012; Kelley & Dantzer, 2011). You will learn a great deal more about norepinephrine in Chapters 8 through 12 as we discuss sleep, eating, sexual behavior, emotions, addiction, and response to stress. Drugs Associated with Adrenergic Receptors Recall that the four types of adrenergic receptors each have their own agonists and antagonists. That means that we could discuss any of a large number of possible drugs here. This section will focus on two drugs, clonidine and yohimbine, because they have important implications for human behavior. Clonidine is an agonist of one type of adrenergic receptor, and yohimbine is an antagonist of the same receptor type. Because these two drugs have opposite effects on the same receptor, you would expect them to have opposing behavioral effects—and they do! Clonidine has a sedative or calming effect when administered, whereas yohimbine agitates the subject and can provoke anxiety (Banna, Back, Do, & See, 2010). Dopamine Dopamine is considered by some investigators to be the most important catecholamine in the brain (Hasbi, O'Dowd, & George, 2011). Dopamine has its own receptors, a total of five different types, and is distributed along four major pathways in the brain (Baldessarini & Tarazi, 1996). Each dopamine pathway in the brain is associated with a different function of dopamine: motor control, thinking, affect, and hormone secretion. In addition, dopamine has been implicated in the control of emotions and feelings of pleasure and euphoria. An impressive number of disorders are associated with dopamine, including movement disorders such as Parkinson's disease and Huntington's disease, psychotic disorders such as schizophrenia, and drug addiction (Fahn et al., 2009; Ng, George, & O'Dowd, 1997). Drugs Associated with Dopamine Receptors The best-known of the drugs associated with dopamine receptors are the dopamine receptor antagonists, which include chlorpromazine, clozapine, and haloperidol. If you ever work in the mental health field, you will quickly become familiar with these drugs because they are prescribed to treat schizophrenia and other psychotic conditions. (See Chapter 12 for a full description of schizophrenia and other psychoses.) Because dopamine antagonists are so effective in eliminating many symptoms of schizophrenia, many investigators believe that dysfunction of the dopamine system is the underlying cause of schizophrenia. Cannabinoid Neurotransmitters Anandamide was the first neurotransmitter to be identified that binds with cannabinoid receptors in the nervous system. Like the endorphins, the cannabinoid receptor was isolated and identified before anandamide was discovered. These discoveries have been relatively recent. Cannabinoid receptors were first identified in 1988, and anandamide was discovered in the same laboratory at Hebrew University in Israel in 1992 (Devane, Dysarz, Johnson, Melvin, & Howlett, 1988; Devane et al., 1992). The word anandamide is derived from the Sanskrit word for "bliss," ananda, and the suffix -amide refers to its chemical structure. Several other cannabinoid neurotransmitters that bind only with cannabinoid receptors have been discovered since 1992. Effects of Marijuana Use Although pushed as a healthier choice, marijuana has been proven to have toxic effects. Marijuana is also considered a psychoactive drug that appears to affect brain receptors. What are its effects on brain chemistry? Since the discovery of the original cannabinoid receptor, a second cannabinoid receptor has been identified. It now appears that there are two cannabinoid receptors: CB1 and CB2. The CB1 receptor is found primarily in the central nervous system, and the CB2 receptor is found primarily in the peripheral nervous system. The location of cannabinoid receptors in the brain indicates that these receptors probably play a role in emotion, cognition, and motor control (Kowal et al., 2013; Moriarty, McGuire, & Finn, 2011; Terzian, Drago, & Micale, 2011). However, the exact role that cannabinoids and their receptors play is not known. Drugs Associated with Cannabinoid Receptors The word cannabinoid comes from Cannabis sativa, a leafy hemp plant that is best-known as marijuana. For centuries, cannabis has been used for both medicinal and recreational purposes. The active ingredient in cannabis, tetrahydrocannabinol (THC), is an agonist that binds to cannabinoid receptors in the brain, producing a number of effects, including changes in mood, thinking, and sensory perception. Moderate cannabis intoxication can impair memory and motor coordination. Other adverse side effects include feelings of depersonalization, panic attacks, and disturbances in thinking that closely resemble a psychosis (Zvolensky, Cougle, & Bernstein, 2010; Zvolensky, Marshall, & Bonn-Miller, 2009). Nitric Oxide Nitric oxide was first identified as a neurotransmitter in 1987 when investigators discovered that acetylcholine produces dilation of blood vessels only when nitric oxide is present (Ignarro, Buga, Wood, Byrnes, & Chaudhuri, 1987; Palmer, Ferrige, & Moncada, 1987). Since that time, neuroscientists have been trying to understand how this gaseous compound functions in the nervous system. You see, nitric oxide presents a bit of a problem to researchers. It is produced by neurons, but it is not released into the synapse like other neurotransmitters (Cooper, Winslow, Govind, & Atwood, 1996 ). In fact, nitric oxide easily diffuses across the cell membrane, which means it can readily leave one neuron and enter another (Garthwaite & Boulton, 1995; Lane & Gross, 1999; Vincent, 2010). Psychologists conducting research in this area have found that nitric oxide plays a role in learning and memory and sexual, aggressive, and ingestive behaviors (Forstermann & Sessa, 2011; Ramírez-Bermudez et al., 2010). In addition, decreased nitric oxide levels in the brain result in decreased sexual activity, increased aggression, and decreased eating. 3.3 The End of the Story: Removing Neurotransmitters from the Synapse What happens after neurotransmitters have been released into the synapse and bind with postsynaptic receptors? Do they merely stay attached to the receptor forever? Think about what this would mean if the neurotransmitter were to remain bound to the receptor for a long time. A neurotransmitter bound indefinitely to a receptor would produce prolonged depolarization or hyperpolarization—which would have devastating effects on brain function. So, proper brain function requires that neurotransmitters bind rapidly with their respective receptor sites and then just as rapidly detach from the receptor and disappear from the synapse. How is this accomplished? There are two main mechanisms by which neurotransmitters are removed from the synapse following an action potential: (1) degradation by enzymes and (2) reuptake into the presynaptic neuron. Degradation by Enzymes Enzymes are chemical substances that stimulate chemical reactions. The removal of acetylcholine from the synapse is a good example of degradation by enzymes. After its release from the presynaptic terminal, acetylcholine binds briefly with its postsynaptic receptor and then detaches. As it detaches from its receptor and slips back into the synapse, acetylcholine is immediately attacked and deactivated by an enzyme, acetylcholinesterase, that stimulates the chemical process that breaks down acetylcholine (Figure 3.4). Acetylcholinesterase deactivates acetylcholine by breaking the neurotransmitter into two components: acetyl and choline. Thus, acetylcholine is able to stimulate the postsynaptic receptor for only a brief period of time. In later chapters we will examine how neuropharmacologists have taken advantage of the action of acetylcholinesterase to fashion drugs that prolong or reduce the effect of acetylcholine. Think about it for a moment. A drug that mimics acetylcholinesterase will quickly eliminate acetylcholine from the synapse, thereby reducing acetylcholine's effect. A drug that inhibits acetylcholinesterase (an acetylcholinesterase inhibitor) will hinder the enzyme's action and allow acetylcholine to accumulate in the synapse, prolonging the neurotransmitter's effect. Because acetylcholine plays an important role in memory, a drug that enhances the activity of acetylcholinesterase (and reduces acetylcholine at the synapse) will interfere with memory. In contrast, an acetylcholinesterase inhibitor increases acetylcholine in the synapse and enhances memory (Morley et al., 2010). Reuptake by the Presynaptic Neuron Unlike acetylcholine, the monoamines are not deactivated by a synaptic enzyme but instead rely on a reuptake mechanism to remove them from the synapse. Hence, they are removed from the synapse much more slowly than acetylcholine. After their release into the synapse following an action potential, monoamines bind briefly with their postsynaptic receptors before detaching and drifting freely in the synapse. A cellular presynaptic transport mechanism, located in the membrane of the axon, pumps the monoamine back inside the presynaptic neuron. After it is inside the neuron, the monoamine is attacked by a number of enzymes that break it down so it can be removed from the brain and excreted from the body. Two enzymes that have received much study in this regard are monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). MAO breaks down all monoamines, including dopamine, norepinephrine, and serotonin. In contrast, COMT breaks down only the catecholamines dopamine and norepinephrine. The reuptake and enzymatic mechanisms that remove and deactivate monoamines have provided neuroscientists with important clues about how monoamine levels in the brain can be controlled. Altogether, there are three ways to increase the availability of monoamines in the synapse: (1) increase the release of monoamines into the synapse, (2) block the reuptake transport system that pumps monoamines back into the presynaptic neuron, and (3) inhibit the enzymes, MAO or COMT, that break down monoamines. The arousing effects of two highly abused drugs, amphetamine and cocaine, are the result of elevated catecholamine levels in the brain. Amphetamine appears to increase catecholamine levels in the synapse by stimulating the release of catecholamines and by blocking the reuptake by the presynaptic neuron. Cocaine increases dopamine levels in the synapse by blocking the dopamine reuptake transport mechanism. In addition, cocaine also blocks the reuptake of the other monoamines, norepinephrine and serotonin. For nearly half a century, physicians have been prescribing MAO inhibitors to treat patients who are depressed (Healy, 1998). MAO inhibitors block the deactivation of the monoamines by MAO and increase the availability of serotonin, norepinephrine, and dopamine in the brain. Is it possible that low levels of monoamines cause depression? Certainly some investigators think so, and the clinical evidence supports such a suggestion. Another class of drugs that is used to treat depression is called tricyclic antidepressants. These tricyclic antidepressants are believed to block the reuptake transport systems for norepinephrine, dopamine, and serotonin, elevating monoamine levels in the brain. In addition, a class of drugs known as selective serotonin reuptake inhibitors (SSRIs) is also prescribed to treat depression in some patients. As their name implies, SSRIs function by inhibiting the serotonin reuptake transport mechanism, thereby increasing serotonin levels in the brain. In contrast, another antidepressant drug, desipramine, blocks the reuptake of norepinephrine but has no effect on the reuptake of serotonin. Table 3.4 summarizes the effects of drugs used to treat depression. There have also been recent experiments involving a drug like ketamine, ADZ6765, in speeding up response to depression through the brain's glutamate system (Sanders, 2013). Table 3.4: Effects of various antidepressants Drug Drug effect Norepinephrine Serotonin Celexa Blocks serotonin reuptake No change Increases Paxil Blocks serotonin reuptake No change Increases Prozac Blocks serotonin reuptake No change Increases Zoloft Blocks serotonin reuptake No change Increases Elavil Blocks norepinephrine reuptake Increases No change Norpramin Blocks norepinephrine reuptake Increases No change Imipramine Blocks serotonin and norepinephrine reuptake Increases Increases Effexor Blocks serotonin and norepinephrine reuptake Increases Increases Wellbutrin Weakly blocks serotonin and norepinephrine reuptake Unknown Unknown Parnate Inhibits monoamine oxidase Increases Increases Norepinephrine, serotonin, and dopamine seem to play a role in depression, but their exact roles are not clear, as you will learn in Chapter 12 when we return to a consideration of depression. In fact, selecting a drug to treat depression is not always easy (see the "Case Study" box). Case Study: Choosing the Best Drug to Treat Depression Photo of a depressed-looking young woman sitting on a step with her elbows on her knees and her chin in her hands. iStockphoto/Thinkstock Photo 3.4 With the proper guidance, medication can be an effective treatment for depression. Mika was an international student enrolled in an American university when she went to the university's counseling center, complaining of depression. The psychologist who talked to Mika ascertained that she needed medication and referred her to a physician at the university health center for a prescription for an antidepressant. The physician prescribed an SSRI for Mika. A week later Mika met with her psychologist. She was still depressed, but she now had an additional symptom. She could not stay awake. While the psychologist was talking to her, Mika nodded off and fell asleep repeatedly. The psychologist consulted with the physician who prescribed the SSRI and advised her of Mika's sleepy state. Mika was then taken off the SSRI medication and prescribed a norepinephrine reuptake inhibitor, which eliminated her sleepiness. However, Mika's depression did not lift until she'd been taking the new antidepressant for more than 5 weeks. This is typical for antidepressant medications: They sometimes require 4 to 6 weeks before their antidepressant effects become apparent. The reason for this time lag is yet unknown but is probably due to changes that take place within neurons in response to the medication. Many people who are treated pharmacologically for depression get no relief from their symptoms, even after 6 weeks of self-administration of the prescribed drug. Often a different antidepressant medication is prescribed that does improve the patient's mood, but it takes several weeks more before the new medication takes effect. You've finally come to the end of this chapter on brain chemistry. By now you should have a good idea of how neurons signal to each other with chemicals, and you should understand how the chemicals affect the functioning of neurons. Remember, however, that many neurons communicate with their neighbors using gap junctions or electrical synapses. Chemical synapses are necessary for sending information to cells in other parts of the nervous system. In the next chapter you will learn the names and functions of the various regions of the central and peripheral nervous systems. And you will learn that the neurons in each region have receptors for some types of neurotransmitters but not for others. The entire picture is quite complicated, and even leading experts in the field don't understand all the intricacies. The chapters to come will keep the material as uncomplicated as possible, giving you only information that is relevant for our study of physiological psychology. 3.4 Chapter Summary Classifying Neurotransmitters Some neurotransmitters can be classified as amino acids, peptides, monoamines, or cannabinoids, although other neurotransmitters such as acetylcholine and nitric oxide are difficult to group together. The Roles of Neurotransmitters in Human Behavior All neurotransmitters bind with several different types of receptors, which indicates that each neurotransmitter can excite or inhibit other neurons in a wide variety of ways. Acetylcholine Acetylcholine, the first neurotransmitter to be discovered, initiates contraction of muscles, stimulates parasympathetic responses, and plays a role in learning, memory, and arousal. Acetylcholine has two types of receptors, nicotinic and muscarinic. Curare and nicotine are drugs that bind with nicotinic receptors. Muscarine and atropine are drugs that bind with muscarinic receptors. Amino Acid Neurotransmitters Amino acid neurotransmitters include glutamate and GABA. Glutamate typically produces rapid excitation in postsynaptic neurons and is believed to play an important role in the formation of long-term memory. Caffeine and monosodium glutamate are two chemicals associated with glutamate action. GABA is the most important inhibitory neurotransmitter in the brain. Benzodiazepines, barbiturates, alcohol, and general anesthetics bind to receptor sites in the GABA receptor. Peptide Neurotransmitters Nearly 50 different peptide neurotransmitters have been identified, including substance P, cholecystokinin, and endorphins. Substance P is the neurotransmitter that signals pain. Cholecystokinin is a hormone that signals satiety following a meal. Endorphins and other endogenous opiates function to reduce pain and to regulate blood pressure, stress responses, and food intake. Narcotic drugs such as morphine, heroin, codeine, and Demerol bind with endorphin receptors and are effective in alleviating pain. Monoamine Neurotransmitters Serotonin, dopamine, norepinephrine, and the hormone epinephrine are the best-known monoamines. Serotonin regulates mood, sleep, and appetite. Two illicit drugs, lysergic acid diethylamide (LSD) and methylene-dioxymethamphetamine (MDMA, or ecstasy), interact with serotonin receptors. Norepinephrine is involved in the activation of the sympathetic nervous system and in the regulation of mood and responses to stress. Two drugs, clonidine (a sedative) and yohimbine (an anxiety-producer), bind with adrenergic receptors. Dopamine has been implicated in motor control, thinking, affect, and hormone secretion. The best-known of the drugs associated with dopamine receptors are dopamine receptor antagonists, which are used to treat schizophrenia and other psychotic conditions. Cannabinoid Neurotransmitters Anandamide is a cannabinoid neurotransmitter that binds with cannabinoid receptors in the nervous system and is believed to play a role in emotion, cognition, and motor control. Marijuana is a drug that also binds with cannabinoid receptors. Nitric Oxide Nitric oxide is an atypical neurotransmitter that plays a role in learning and memory, as well as sexual, aggressive, and eating behaviors. The End of the Story: Removing Neurotransmitters from the Synapse There are two main mechanisms by which neurotransmitters are removed from the synapse following an action potential: (1) degradation by enzymes and (2) reuptake into the presynaptic neuron. Acetylcholinesterase deactivates acetylcholine by breaking the neurotransmitter into two components, acetyl and choline. A drug that inhibits acetylcholinesterase (an acetylcholinesterase inhibitor) will hinder the enzyme's action and allow acetylcholine to accumulate in the synapse, prolonging the neurotransmitter's effect. The monoamines are not deactivated by a synaptic enzyme but instead rely on a reuptake mechanism to remove them from the synapse. Once inside the neuron, the monoamine is attacked by a number of enzymes that break it down so it can be removed from the brain and excreted from the body. The enzyme, monoamine oxidase (MAO), breaks down serotonin, norepinephrine, and dopamine. Catechol-O-methyltransferase (COMT) deactivates only dopamine and norepinephrine. Amphetamine and cocaine increase catecholamine levels in the synapse by stimulating the release of catecholamines and by blocking the reuptake by the presynaptic neuron. MAO inhibitors, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) have been prescribed to treat patients who are depressed. Questions for Thought How might an investigator demonstrate that a certain neurotransmitter regulates a particular behavior? For example, how might a psychologist show that cholecystokinin plays a role in eating behavior? When a person becomes addicted to nicotine, what changes take place in the nervous system of the addicted person? What might happen when that person tries to quit smoking? How does nitric oxide differ from other neurotransmitters? Name drugs that increase the activity of receptors associated with acetylcholine, serotonin, dopamine, norepinephrine, anandamide, and endorphins. Tables of Drug Classes and Effects Table 3.5: Psychotropic drug classes Drug class Behavioral effect Neurotransmitter(s) affected Antidepressants Elevate mood Serotonin, norepinephrine Antipsychotics (major tranquilizers) Reduce psychotic symptoms Dopamine (strongly) Atypical antipsychotics Reduce psychotic symptoms Dopamine (weakly) Antimanics Stabilize mood Norepinephrine, serotonin, GABA Sedatives (minor tranquilizers) Reduce anxiety GABA Hypnotics Induce sleep GABA General Anesthetics Produce unconsciousness GABA Opiates Relieve pain Endorphins Cannabinoids Stimulate appetite, alter attention Endocannabinoids Stimulants Increase vigilance, enhance attention, reduce appetite and sleep Norepinephrine Table 3.6: Effects of antipsychotic drugs Drug Drug class Effect on D2 receptor Amisulpride Atypical Binds loosely (permits normal dopamine action) Aripiprazole Atypical Binds loosely (permits normal dopamine action) Chlorpromazine Classical Binds tightly (inhibits dopamine action) Clozapine Atypical Binds loosely (permits normal dopamine action) Flupenthixol Classical Binds tightly (inhibits dopamine action) Fluphenazine Classical Binds tightly (inhibits dopamine action) Haloperidol Classical Binds tightly (inhibits dopamine action) Olanzapine Atypical Binds loosely (permits normal dopamine action) Pimozide Classical Binds tightly (inhibits dopamine action) Quetiapine Atypical Binds loosely (permits normal dopamine action) Remoxipride Atypical Binds loosely (permits normal dopamine action) Risperidone Atypical Binds loosely (permits normal dopamine action) Sertindole Atypical Binds loosely (permits normal dopamine action) Trifluperazine Classical Binds tightly (inhibits dopamine action) Ziprasidone Atypical Binds loosely (permits normal dopamine action) Table 3.7: Effects of various antidepressants (Generic names are in italics) Drug Drug effect Norepinephrine Serotonin Celexa (citalopram) Blocks serotonin reuptake (serotonin selective reuptake inhibitor) No change Increases Luvox (fluvoxamine) Blocks serotonin reuptake (serotonin selective reuptake inhibitor) No change Increases Paxil (paroxetine) Blocks serotonin reuptake (serotonin selective reuptake inhibitor) No change Increases Prozac (fluoxetine) Blocks serotonin reuptake (serotonin selective reuptake inhibitor) No change Increases Zoloft (sertraline) Blocks serotonin reuptake (serotonin selective reuptake inhibitor) No change Increases Elavil (amitriptyline) Blocks norepinephrine reuptake Increases No change Norpramin (desipramine) Blocks norepinephrine reuptake Increases No change Tofranil (imipramine) Blocks norepinephrine and serotonin reuptake Increases Increases Effexor (venlafaxine) Blocks norepinephrine and serotonin reuptake Increases Increases Wellbutrin (bupropion) Weakly blocks norepinephrine and serotonin reuptake Unknown Unknown Parnate (tranylcypromine) Inhibits monoamine oxidase Increases Increases Table 3.8: Effects of recreational drugs/drugs of abuse Drug Drug effect Behavioral effect Alcohol Augments GABA binding to its receptor Increased inhibition, anxiety reduction, and sedation Amphetamine/Meth/Speed Stimulates norepinephrine release; to a lesser extent, release of dopamine and serotonin Increased vigilance and focus, reduced fatigue and appetite Caffeine Blocks adenosine receptors Inhibits effects of adenosine, produces mild stimulation Cocaine/crack Blocking the reuptake of dopamine, norepinephrine, and serotonin Increases mental alertness and produces mild euphoria Heroin Binds with endorphin receptors; mimics effects of endorphins Relieves pain, produces euphoria and clouding of mental function Ketamine Binds with glutamate receptor, antagonizes action of glutamate Produces dissociative anesthesia LSD/Acid Binds with serotonin receptors, blocks serotonin action Produces sensory overload, hallucinations, euphoria Marijuana Binds to cannabinoid receptors Changes in mood, attention, memory, motor coordination MDMA/Ecstasy/MDA Stimulates serotonin release and, to a lesser extent, release of norepinephrine and dopamine Produces mild hallucinations, euphoria Mescaline Binds with norepinephrine receptors, interferes with action of norepinephrine Produces mild hallucinations, vivid mental images and distorted vision Morphine Binds with endorphin receptors; mimics effects of endorphins Relieves pain, produces euphoria and clouding of mental function Oxycontin/oxycodone Binds with endorphin receptors; mimics effects of endorphins Relieves pain, produces euphoria and clouding of mental function Peyote Binds with norepinephrine receptors, interferes with action of norepinephrine Produces mild hallucinations, stimulates the visual and visuo-psychic areas of the brain Psilocybin/Mushrooms Binds with serotonin receptors, stimulates serotonin activity Produces hallucinations, altered sense of time, and euphoria Phencyclidine (PCP) Binds with glutamate receptor, antagonizes action of glutamate Produces dissociative anesthesia Tobacco/nicotine Binds with nicotinic acetylcholine receptors Produces mixed feelings of relaxation, sharpness, calmness, and alertness Table 3.9: Review of acetylcholine agonists and antagonists Type of acetylcholine receptor Example of an agonist Example of an antagonist Nicotinic Nicotinic Curare Muscarinic Muscarinic Atropine Chapter 3 Flashcards Web Links For more information on Botox, search the term on the MedLinePlus website, a service of the U.S. National Library of Medicine. Here you will have access to the latest news, clinical trials, and journal articles related to studies of Botox. http://medlineplus.gov/ The National Institute of Drug Abuse's website provides numerous resources and publications for learning about the effects of drugs, including alcohol and other substances, on the brain and, in turn, on human behavior. http://www.drugabuse.gov/ Key Terms Click on each key term to see the definition. acetylcholine A neurotransmitter necessary for muscle contraction, memory, and parasympathetic activity. acetylcholinesterase An extracellular enzyme that stimulates the process that deactivates acetylcholine. agonists Chemicals that bind with and activate a receptor. amino acids Relatively simple compounds that contain one NH2 (amino) group and COOH (acid) group. anandamide A neurotransmitter that binds with cannabinoid receptors. antagonists Chemicals that bind with a receptor, blocking the action of the neurotransmitter. benzodiazepines Minor tranquilizers such as Valium that bind with GABA receptors. cannabinoid receptors Receptors that bind with anandamide and tetrahydrocannabinol, the active ingredient in marijuana. catechol-O-methyltransferase (COMT) An intracellular enzyme that deactivates catecholamines. cholecystokinin (CCK) A peptide released from the duodenum that inhibits eating. curare A nicotinic antagonist that produces paralysis. dopamine A monoamine neurotransmitter that is a precursor of norepinephrine and epinephrine. endorphin An endogenous opiate neurotransmitter that inhibits pain messages. epinephrine A neurohormone, also known as adrenaline, that is released by the adrenal gland and activates the sympathetic nervous system. gamma-aminobutyric acid (GABA) A neurotransmitter that is the most abundant inhibitory neurotransmitter in the brain. glutamate A neurotransmitter that is the most abundant excitatory neurotransmitter in the brain. hormone A chemical released by a gland into the bloodstream. marijuana Cannabis sativa, a leafy hemp plant that has been used for centuries for both medicinal and recreational purposes. The active ingredient in marijuana is tetrahydrocannabinol (THC). monoamine A chemical compound that contains one amino group. monoamine oxidase (MAO) An intracellular enzyme that deactivates monoamines. muscarine A deadly toxin that comes from a poisonous mushroom. muscarinic receptor A type of acetylcholine receptor in the nervous system that binds with muscarine. nicotine An agonist that binds with acetylcholine nicotinic receptors. nicotinic receptor An acetylcholine receptor that binds with nicotine. nitric oxide An atypical neurotransmitter that readily diffuses across the cell membrane of a neuron. norepinephrine A monoamine neurotransmitter that plays a role in mood, drive reduction, sleep, arousal, cognition, and emotions. opiates Drugs that are derived naturally or synthetically from opium, such as morphine, heroin, codeine, and Demerol. opioid receptors Receptors on the cell membranes of neurons that bind with endogenous opiates and opiate drugs. peptides Short chains of amino acids joined end to end. psychopharmacology The study of chemical substances that affect the activity of neurons. selective serotonin reuptake inhibitors (SSRIs) A class of drugs that is prescribed to treat depression in some patients; SSRIs function by inhibiting the serotonin reuptake transport mechanism, thereby increasing serotonin levels in the brain. serotonin A monoamine neurotransmitter that plays a role in sleep, vigilance, mood, appetite, and repetitive movements. substance P A neurotransmitter used by pain receptors to signal the presence of tissue damage and pain.