DOCUMENT RESUME

ED 311 374 CG 021 989

AUTHOR Briclr, John

TITLE Drugs and the Brain: An Introduction toNeuropharolacology. Pamphlet Series.

INSTITUTION Rutgers, The State Univ., Piscataway, NJ. Center ofAlcohol Studies.

PUB DATE 87

NOTE 26p.; For related documents, see CG 021 983-990.AVAILABLE FROM Rutgers Center of Alcohol Studies, P.O. Box £:.,9,

Piscataway, N6 08855-0969 ($2.50 + postage; quantitydisccunt--inquire).

PUB TYPE Reports General ''40)

EDRS PRICE M101 Plus Postage. PC Not Available from EDRS.DESCRIPTORS *Drug Use; *PharmacologyIDENTIFIERS *Neuropharmacology; *Psychoactive Drugs

ABSTRACT

The thousands of different drugs on the market can beseparated into two categories: drugs that affect behavior, calledpsychoactive drugs, and drugs that do not affect behavior. Drugs getinto the body by mouth, inhalation into the lungs, by injection intoa vein, muscle or under the skin, and by absorption through mucousmembranes. Regardless of the route most drugs must get into thecirculatory system in order to travel to the target organ and exertan effect. Once in the circulation a drug must still pass several"barriers" before reaching its site of action and producing a changein behavior. Three of these barriers are the blood capillaries, theblood-brain barrier, and the placental barrier. The brain receives,integrates, and responds to sensory information it receives fromperipheral organs and their receptors, and in addition is responsiblefor all cognitive functions. Changes in brain cells are responsiblefor all behavior, including those cnanges in behavior produced bypsychoactive drugs. All psychoactive drugs produce their effects byaltering the functional activity of neurotransmitters. Psychoactivedrugs can increase or decrease the functional activity of variousneurotransmitters. There are five major classifications ofpsychoactive drugs: stimulants, anti-psychotics, sedatives/hypnotics,opiates or narcotics, and psychedelics or hallucinogens. Thetermination of drug action is accomplished primarily by changing itto another molecular structure so that it is no longer an activeagent or so that it can be removed from the body. Many psychoactivedrugs can produce tolerance or dependence. (ABL)

****t******************************************************************* Reproductions supplied by EDRS are the best that can be made* from the original document. *

***********************************************************************

About the Author

John Brick received his masters in psychology anddoctorate in biological psychology from the StateUniversity of New York at Binghamton, for his studieson the endocrine and neurochernical responses tostress following brain damage, and genetic differ-ence; in the development of tolerance to alcohol andmorphine. In 1980 Dr. Brick joined the researchfaculty at the Center of Alcohol Studies, where themajor emphasis of his research has been on the inter-action between alcohol and stress. He presentlyserves as an editorial reviewer for numerous scien-tific journals and as a consultant to the VeteransAdministration, Department of Medicine and Surgery.In addition, he co-chaired the First InternationalSymposium on Stress and Alcohol Use and is co-author of Biological Psychology. Dr. Brick is current-ly Assistant Research Professor and laboratory direc-tor of the Alcohol Behavior Research Laboratory,Rutgers University. His major research interests areon the interaction between alcohol and stress andthe medicolegal aspects of alcohol consumption.

Drugs and the BrainAn Introduction to Neuropharmacology

byJohn Brick, Ph.D.

Illustrated byKaren S. Gutwirth

Center of Alcohol StudiosPamphlet Series

1.,

,

0 1987 by Alcohol Research Documentation, Inc.Center of Alcohol Studies, Rutgers University

New Brunswick, New:Jersey)

.4

CONTENTS

What Types of Drugs Are ere? 1

How Do Drugs Work? 1

Drug Distribution 4

The Target of Psychoactive Drugs 7

Neurons, Glia and Neurotransmission 8

Neurotransmission, Drugs and Behavior 10

Major Drug Classifications 11

Relationship of Neurotransmitters to Behavior 16

Termi ',salon of Drug Action 17

Tolerance and Dependence 17

Suggested Readings 19

Drugs and the BrainAn Introduction to Neuropharmacology

This booklet is an introduction to how drugs work. The field, pharma-cology, includes the study of how drugs get into the body, exert theireffects and are removed from the body. Neuropharmacology is abranch of pharmacology that focuses on drugs affecting the centralnervous system.

WHAT TYPES OF DRUGS ARE THERE?There are thousands of different arugs on the market. These can beseparated into two categories: those that affect behavior and thosethat do not. Drugs that affect behavior are called psychoactivedrugs. For example, alcohol, which affects behavior in many differ-ent ways, is a psychoactive drug. All psychoactive drugs alter behav-ior by changing one or another brain process.

Psychoactive drugs can be further categorized based upon the wayin which they alter behavior. For example, there are five major cate-gories of psychoactive drugs: 1. stimulants, 2. antipsychotics,3. sedative-hypnotics, 4. narcotics or opiates and 5. hallucinogensor psychedelics.

Although many commonly used non-psychoactive drugs, such asantibiotics (e.g., penicillin acts against bacterial infection) and anti-inflammatants (e.g., aspirin decreases swelling and inflammation)can alter behavior indirectly, they are not considered to be psy-choactive. A drug that :educes the discomfort of a fever or infectionenables the individual to get back on track and produces a feelingof well-being.

HOW DO DRUGS WORK?In order for any drug to have an effect, it must get from the outsideworld into the body. There are several routes through which drugscan get into thr ,,ody: by mouth, by inhalation into the lungs, byinjection into a vein, muscle or under the skin, and by absorptionthrough mucous membranes. Regardless of the rout% most drugsmust get into the blood (circulatory system) in order to travel to theirtarget organ and exert an effect.

The Oral Route. The most common method of drug delivery isthrough oral administration, i.e., drugs are swallowed and enter thestomach (Figure 1). in the stomach, however, m,)st drugs still willhave no effect; they must get from the stomach to the small intestineor ileum where they are absorbed i.to the blood supply. In order forthis to happen two conditions must be met. First, the drug must bewater soluble; that is, it must be able to dissolve in water. Second, it

meminssmonoisiorsosvonnotein....simpw

1

FIGURE 1

LIVER

LUNGS

HEART

\- - _ _ _ _ - -iiiPORTAt7V,9EIN_ _

H

.-------FIGURE 2

ARTERIAL DISTRIBUTIONTO BRAIN AND RESTOF BODY

STOMACH, SMALLAND LARGEINTESTINES

FIGURE 1.The Common Route of Drug Administration. The most com-mon route of drug administration is by mouth. Drugs are swallowed i..to thestomach and then pass into the small intestine or ileum. The rate at whichdrugs enter the circulation from the gastrointestinal tract depends largely onthe presence of food in the stomach, solubility of the drug iri water and itspermeability through the walls of intestine.

FIGURE 2.The Circulation of Drugs. Drugs pass into the circulationthrough blood vessels surrounding the ileum. Once in the circulation, thedrug travels to toe liver via the hepatic porta! vein. From the liver, the drugcon'inlies to travel, in olooa, to the right side of the heart, then, via tne pul-monary artery, to the lung. Blood returning from the lung to the left side ofthe heart, via the pulmonary vein, is pumped th.oughout the body.

must be cell permeable, Ineaning it must be fat or lipid soluble sothat it can pass through the cell membranes. If the drug is soluble inboth water and lipid then small quantities of it can pass from thesmall intestine or ileum into surrounding, very small blood vesselscalled capillaries. Once in the capillaries of the circulatory system,the drug travels through the hepatic portal (liver transport) vein tothe liver. From the liver the circulatory system returns to the heartwhere the drug, in the blood, is pumped to the lungs and then backto the heart and onward to the rest of the body. The entire bloodsupply makes its way around the body about every minute andeventually the drug is distributed to every organ and every 'jellin the body (Figure 2).

There are a number of advantages and disadvantages to the oralroute. The main advantage of oral drug delivery is that it is easy.Also, in the event of an overdose or an immediate adverse reaction,the drug not yet absorbed in the stomach can be) removed 1)y pump-

08

Ing the stomach or inducing vomiting. The disadvantages relate tothe fact that not everyone can swallow pills: older, unconscious andvomiting patients may not be good candidates. Stomach acids andenzymes that aid in digestion may alter drug potency, and food con-tents may delay the absorption of drugs so that it will take longer forthe drug to enter into circulation. Therefore, the dose that actuallyenters the circulation may be unknown.

The Pulmonary Route. Drugs that are inhaled enter the lungs andpass through the alveoli, small sacs in the lung that exchange gases.In order for a drug to pass through the alveoli into the circulation itmust be in a gaseous form. The most common drugs enteringthrough the pulmonary system are the volatile anesthetics used forsurgery: halotnane, metaphane and nitrous oxide (also called laugh-ing gas) are a few examples of lipid soluble gases. Vapors from gaso-line and certain cleaning agents and glue, smelling "salts," mouthinhalers (for asthma), marijuana and nicotine, the active ingredientin cigarettes, all enter 'he body via the lungs. The two majoradvantages of pulmonery administration are rapid onset of effectsand ease of discontinuihg administration. The drug enters thecirculation almost instantly (Figure 2). Those who have had gasadministered at the dentist's office know that within a few momentsthere is a loss of sensation and within a couple of minutes the den-tist is drilling away. The other major advantage of this route is thatonce gas inhalation is discontinued, there is no further increase inthe effect of the drug. It may, however, take some time for all of thedrug to be removed from the body's muscle and fat tissue, depend-ing on the anesthetic agent: hence, the use of a recovery room inhospita.s for post-surgery patients.

Disadvantages of pulmonary administration may arise from undesired side effects. For example, the active ingredient in tobacco isnicotine, a drug easily absorbed from the lungs into the circulation.Unfortunately, bi-products of combustion (smoking) such as "tars"do not easily pass through the lungs: their chronic presence in lungtissue causes cancer.

The Injection Route. There are three major ways in which drugs canbe injected into the body: intravenous, intramuscular and subcu-taneous. With intravenous administration the drug is injected direct-ly into the circulation, usually through a vein. It is the fastest methodof drug administration available: since there is no delay betweenadministration and entry into the circulatory system the effects arevirtually immediate. The intravenous route is also known as i.v. or,for drug abusers, "mainlining."

Intramuscuiar administration is when a drug is injected into a largemuscle, such as the upper arm or buttocks: the absorption time, usu-ally 15 to 30 minutes, is considerably slower than the i.v. route.

3

Finally, there is the subs utaneous route, in which the drug is injectedbetween the skin and underlying muscle (e.g., on the back of thehand). With drugs of abuse, it is sometimes called "skin popping."Like the intramuscular technique, absorption after subcutaneousinjection can take 15 to 30 minues.

The major advantages of drug administratior by injection are that avery accurate dose can be given and it can be delivered to its site ofaction very rapidly. The disadvantages include overdose, since alarge amount of drug is rapidly delivered and, in the event of a badreaction, the drug cannot be recalled. There is also the problem ofsterile syringes and hypodermic needles. If these are not sterile theuser may contract an infectious disease such as hepatitis, AIDS, etc.Also, some individuals have a strong aversion to receiving injections,so this may be a disadvantage of sorts.

The Absorptien Route. Drugs may also be administered by a' :9rp-tion from mucosal surfaces. For example, drugs may be absorbedthrough blood vessels in the vagina or rectIm (suppositories), nose(nasal sprays) and mouth (heart medications such as nitro-glycerine). This method provides a relatively simple way of takingdrugs, which may have advantages in certain individuals, such asolder patients who cannot swallow tablets or who have collapsedveins. The absorption of drugs through the mucous lining of thenose into blood capillaries in the nasal area is often used for illicitdrugs (i.e., "snorting" cocaine or heroin).

Other Routes. Two other methods of drug delivery are worth men-tioning because they are interesting and represent newer forms ofdrug delivery. The first is transdermal, Nterallv, thre,Igh the skin. Anti-seasickness medications can be placed on an adhesive disc, whichIs applied on the skin just behind the ear. The drug is absorbedthrough the skin to the vicinity of the inner ear (disturbances in thelatter are responsible for seasickness). Heart medications can alsobe delivered through a transdermal patch applied to the chest everyfew days or longer. The second method involves the delivery of drugthrough the cornea, a clear layer cover ng the front of the eye. Thismethod, called trans-cornea! administ ation, is useful in treatingglaucoma or other eye diseases.

DRUG DISTRIBUTIONThe drug has now moved via several possible routes from the out-side world into the body. Once in the circulation a drug must stillpass several "barriers" before reaching its site of action and produc-ing a change in behavior. These barriers take the form of differentmembranes. In a sense the membrane is like a thin shell that sur-rounds each cell of the body. Membranes give the cell its shape andkeep certain cell parts from leaving the cell while it prevents otherthings outside the cell from entering.

All organs are made of cells, and all cells have a membrane. The bar-riers we will discuss in this section include blood capillaries, theblood-brain barrier and the placental barrier. For a drug to get into acell and have an effect, it must first pass through the cell membrane.Membranes are made up of layers of proteins and lipids (fats) sand-wiched together so that the protein layers form the outside and inner-most walls of the membrane

This sandwich of protein-lipid-protein provides a barrier which ispermeable to some substances but impermeable to others. Alcoholpasses through all membranes very easily, while opiates, welt -knownpain killers, pass through lipid membranes slowly.

Blood-Brain Barrier. The blood-brain barrier (BBB) acts to keepcertain drugs and other compounds away from the brain by decreas-ing the permeability of capillaries in the region of the brain. It is thischange in permeability of capillaries that results in a selective brainbarrier. This change of permeability occurs because the BBB onlyallows drugs of a specific molecular size or those bound to specialtransport proteins to pass through into the brain. Compounds thatare too large or not lipid soluble do not pass through the BBB. Thechange in permeability occurs because in the brain there is a uniquearrangement between capillaries and special cells called astrocytes:the capillaries are surrounded by astrocyte cells so that permeabilitythrough the capillary is restricted (Figure 3).

FIGURE 3

FIGURE 3.The Ulood-Brain Barrier. The Blood-Brain Barrier is a networkof capillaries in the brain. Transport of certain drugs ar'i other substancesthroup tho capillaries to brain cells is restricted by specialized cellsastrocytesthat form a sheath around the capillary. Astrocytes restrict drugtransport by blocking small pores in the capillary wall through which thesesubstances pass. The insert shows a single blood cell in a cross section of acapillary, surrounded by astrocytes.

Blood Capillaries. A capillary is a thin, tightly packed, single layer ofcells. Between the cells that form capillaries are small pores whichallow nutrients, water, and most drugs to pass out of the blood-stream and to the site of action, such as the brain, in the case ofpsychoactive drugs. Drugs, water and nutrients pass through thecapillary wall based on a concentration gradient: the higher theconcentration (amount oer unit volume) inside the capillary,the greater the rate of diffusion from the capillary.

Which Drugs Pass Through the BBB?Most drugs get into the brain fairly easily. All psychoactive drugspass out of the circulation and reach brain cells, otherwise theywould not have any effect. Not all drugs reach the brain though. Anti-biotics such as penicillin do not. Therefore, brain infections that re-sult from venereal and other infectious diseases cannot be treatedwith these drugs. Fortunately, the BBB tends to be very resistant tomost infectious disoase, preventing most bacterial and viral infec-tions from reaching the brain. An interesting example of how to getthrough the BBB comes from treatment of Parkinson's disease, acentral nervous system disorder that results in a progressive deterio-ration of motor control. A major biochemical mechanism in this dis-ease is the deficiency of dopamine, a chemical messenger in thebrain. Parkinson's disease cannot be treated by simply administeringdopamine, because dopamine does not pass through the blood-brain barrier. Yet the disease is treatable. Scientists have learnedthat brain dopamine can be replenished by administering anotherchemical, L-dopa. L-dopa does pass through the BBB but, in thebrain, it is converted into dopamine. Thus, the administration ofL-dopa restores the chemical balance of dopamine in the brain andalleviates most of the symptoms of this disease.

Placental Barrier. This term is really a misnomer. Although theplacental barrier is unique in that it separates two humans, it is notmuch of a bar; ier to drugs. The developing fetus receives nutrientsand eliminates wastes through the placenta, and drugs also passthrough the placenta quite freely so that the developing fetus is alsoexposed to whatever drugs the mother takes. This is an importantfact to be aware of, since in the U.S. women take an average of fourprescription drugs during pregnancy not including over-the-counter medications, drugs in foods and consumables (caffeine,xanthines, nicotine) and exposure to various household and environ-mental chemicals. Scientists have not yet found all of the possibleconsequences of drugs on a developing fetus but three major typesof effects are being studied: teratogenic, delivery and delayer.

Teratogenic eflects refer to major morphological change; such aswhen a limb or organ, facial structure, etc., beremas grossly mal-formed. During the 1960's the use of the tranquilizer thalOomideduring pregnancy was associated with a variety of birth defects such

6 14,0

-a.

as incompletely developed limbs. There is now evidence that alcoholuse during pregnancy also increases the risk of teratogenic defects.Alcohol, as well as other C ugs, may produce teratogenic defects bydirectly altering the normal development of cells or by altering thetransport of essential nutrients through the placenta to the fetus.Either of these effects may be due to the presence of the drug at aparticular concentration or at a "critical" period during fetaldevelopment.

Drugs may also affect the normal deliver,/ of a baby. Since newbornsmay not be able to metabolize or break down certain drugs, expo-sure to them may induce respiratory depression, anoxia or death.Finally, during pregnancy the use of several drugs, includingalcohol, barbiturates, methadone and nicotine, is associated with adecrease in the birth weight. It is not yet known whether the changesfound at birth (e.g., low birth weight) are associated with moresubtle, delayed differences later in life.

THE TARGET OF PSYCHOACTIVE DRUGSTo understand how psychoactive drugs alter behavior it is helpful tofirst examine the basic elements of behavior. We respond to manyevents in our environment in many different ways. These -vents startout as purely sensory stimuli (visual, tactile, auditory, _!factory orgustatory), but in most cases a sensory stimulus "triggers" a cog-nitive association or mental response. A simple example of isreading. First, letters and words on this page are nothing mot. thanvisual stimuli that fall on very specialized cells in the back of eacheye, called receptors. The images activate entire fields of receptorsin each eye and the information is then transmitted along the opticnerve to various parts of the brain, where it is further processed. Inthe brain, associzstions are made with previously stored informationand some response is made. The responses can vary considerablyfrom simply moving the eye to the next word (motor response), toprompting questions or forming a conclusion based upon what hasbeen read (cognitive-behavioral response). The brain not onlyreceives, integrates and responds to sensory information it receivesfrom peripheral organs (eyes, ears, nose, tongue, skin) and theirreceptors and controls motor output, it is additionally responsiblefor all cognitive functions. Each and every fact, thought, belief, feel-ing and emotion we have ever experienced resides in the brain. Howis this marvelous feat performed? The answer seems to be related tochanges in functional activity in groups of brain cells. Thus changesin brain cells are responsible for all behavior, including thosechanges in behavior produced by psychoactive drugs.

How does the brain manage all of this? In part, the answer is in thespecialization of the brain and the complexity of its nerve connec-tions and neurocommurtications. In order to appreciate how drug-induced changes in the normal activity of the brain alter behavior weneed to first examine the "nuts and bolts" of the brain.

NEURONS, GLIA AND NEUROTRANSMISSIONThe brain consists of two major types of cells called neurons andgilt'. Neurons are a specialized type of cell found only in the nervoussystem. Neurons transmit "information" about other parts of thebody as well as the oieside world via an electrochemical process. Itis the change in this functional activity, the increase or decrease inthe electrochemical activity of neurons, that produces behavior.

Different types of neurons form more specialized groups of brainstructures called nuclei while other neurons form fiber tracts whichinterconnect various nuclei. Glial cells are primarily involved in thestructural support of neurons and are involved in nutritive functions.

Figure 4A shows the human brain, Figure 4B shows a cross-sectionof the brain, from front to back, exposing several major nuclei. In ageneral sense, different nuclei are responsible for different behav-ioral and cognitive functions. For example, various portions of thecortex are devoted to specific functions involving motor control andvision; the left hemisphere of the cortex is involved in speech where-as the right cortex is involved in non-verbal imagery such recog-nition. The hypothalamus regulates a number of pituitary hormones,eating, drinking and aggression; and the corpus callosum, a thickband of fiber tracts, transmits information from one side of the brainto the other.

FIGURE 4A FIGURE 4B

FIGURES 4A and 4B.The Brain and a Cross-Section of the Brain. Thehuman brain contains approximately 100 billion cells or neurons. Differenttypes of neurons with specialized functions form different brain regions.Figure 4A shows an intact brain including frontal, parietal, temporal and visu-al cortex, brain stem and part of the cerebellum. Figure 4B shows the braincut in half (mid-sagittal section) revealing many underlying differentiatedbrain structures. Many brain regions subserve very specific behavioral func-tions. Drugs alter behavior by affecting the normal functioning of differentbrain regions.

8

FIGURE 5FIGURE 5.An Illustration of Neurons and Neurotransmitter Activity. Threeneuronsthe basic type of brain cellare shown. Neurons communicatewith each other through neurotransmitters which are released from the endof the neuron (the axon terminal) into a small space (the synapse) betweenthe axon terminal and neurotransmitter receptors located on an adjacentneuron. Psychoactive drugs alter behavior by changing neurotransmitteractivity between and within neurons. The insert illustrates released neuro-transmitter crossing the synapse and contacting specific receptors ofanother neuron.

Each nucleus is comprised of several hundred to several million neu-rons. To understand how the brain is affected by drugs we must firstreview how the basic unit of the brain, the neuron, is constructedand functions. Figure 5 shows the various parts of a neuron and thespatial relationship of three typical neurons. The branch-like process-es that extend from each neuron almost touch adjscent neurons andtheir respective processes, but they are separated by a small space.This space is called a synapse. It is through the rJlease of chemicalsinto the synapse that neurons communicate information to eachother about the internal or external environment. In the brain a neu-ron might make contact with as many as 10,000 other neurons andthe human brain contains approximately 100 billion neurons. Thus,our illustration is a very simplified representation of the complexarrangement of cells in the brain.

In order for a neuron to transmit its chemical message to anotherneuron, A series of events must take place, a process called neuro-transmission. To begin with, neurons maintain an electrical chargecalled a resting potential. The resting potential of all neurons is neg-ative in comparison to the charge outside the cell. The basis for this

-1-5

-C

negative charge is the distribution of salts and other substances in-and outside of the neuron. Neurotransmission starts with a ch::Igein the permeability of the cell membrane, in the region near thesynapse, to certain ionized salts (salts dicsolved or dissociated intosolution form ions) such as sodium and potassium. For the mostpart, the outer membrane covering of the neuron keeps negativelycharged potassium ions inside the cell and positively chargedsodium ions outside the cell, resulting in the inside of the cell beingnegatively charged. Specialized biological "pumps" help maintainthis balance of a negative resting potential. When the permeability ofthe membrane changes, sodium rushes into the neuron and potassi-um rushes out. If enough ions are ex :hanged, the resting potentialinside the cell becomes positivev charq-sd, leading to a criticalthreshold that sets off the action peter, ia. The action potential thentravels down the length of the axon to the axon terminal. When theaction potential reaches the axon terminal it causes the release ofspecialized chemicals that ace stored there, inside vessicles. Thesechemicals are called neurotransmitters.

Where Do Neurotransmitters Go? Once released, the neurotransmit-ters enter into the synapse between neurons (Figure 5B). The neuro-transmitter then comes in contact with receptors located on variousparts of the next neuron the post synaptic neuron. Depending onthe particular type of neurotransmitter released, it will increase ordecrease the probability of an action potential in that neuron. Theprocess then continues or is temporarily stopped.

Eventually, after a fraction of a second, the neurotransmitter goesback into the synapse. Once back in the synapse the neurotransmit-ter is de ^tivated by enzymes or is often taken right back into theneuron )nom which it came through a process called "reuptake." Aswe shall see many psychoactive drugs alter the functional activityof neurotransmitters by altering the metabolizing enzymes or thereuptake process. This rema&able series ofevents which we callneurotransmission takes place in the brain many billions of timeseach second.

Chart 1 lists some of the more studied neurotransmitters along withseveral behavioral functions that scientists believe are mediatedthrough these chemical messengers.

NEUROTRANSMISSION, DRUGS AND BEHAVIORAll psychoactive drugs produce their effects by altering the func-tional activity of neurotransmitters. They may do this in severaldifferent ways. For example, increases in functional activity can beaccomplished by: increasing release of a neurotransmitter; directlystimulating the receptors that the neurotransmitter stimulates; inhib-iting the reuptako of the transmitter into the neuron (thus keeping itin the synapse where it is free to interact with receptors again); or

10 6

Chart 1. Some Neurotransmitters and Associated Behavioral Functions

7Vansmater in Brain

Acetylcholine

Dopamine

Endorphins

Epinephrine

Norepinephrine

Serotonin

Gamma-aminobutyric acid(GABA)

Learning, memory

Schizophrenia, vision, motor control, consummatorybehavior

Pain, mental illness

(Unknown)

Learning, memory, affective disorders, sleep, arousal,consummatory behavior

Sleep, mental illness, pain, consummatory behavior

Anxiety

inhibiting enzymes in or near the neuron that would inactivate theneurotransmitter.

Similarly, psychoactive drugs can decrease the functional activity ofvarious neurotransmitters by blocking receptors, decreasing neurotransmission, or decreasing manufacture or synthesis, or increasingreuptake or enzymatic breakdown.

Most psychoactive drugs have a dose-response relationship withbehavior. As the concentration of the drug in the blood supply in-creases, so does the psychoactive action of the drug. As the concen-tration of drug in blood decreases, the effect on behavior alsodecreases. A dose-response curve is often used by pharmacologiststo describe a particular drug effect. One way scientists express drugpotency is in the dose required to produce a particular effect insome portion of the population. For example, if 10 milligrams wasthe effective dose (ED) required to produce a significant tranquiliz-ing effect in 50% of the population this fact could be expressed asED50 = 10 milligrams. Similarly, if 1,500 milligrams was the lethaldose (LD) of a drug that would kill 70% of the population this couldbe expressed as LD70 = 1500 milligrams.

MAJOR DRUG CLASSIFICATIONSThere are five major classes of psychoactive drugs: stimulants, anti-psychotics, sedatives-hypnotics, opiates or narcotics, and psyche-delics or hallucinogens. Listed below are some common examples ofdrugs in each of these five major classes, as well as a description oftheir mechanism of action. Chart 2 shows representative examplesof drugs in each of the categories.

CHART 2.Examples of the Five Major Classes of Psychoactive Drugs andtheir Behavioral and Pharmacological Actions

Classification Behavioral and Pharmacological Actions

General Stimulants:

cocaine

amphetamine

methylphenidate(Rita lin)

Antidepressants:

imipramine (Tofranil)amitriptyiine (Elavil)

tranylcypromine(Parnate)

Convulsants:

strychninepicrotoxinpentylendtetrazol

(Metrozol)

General Cellular Stimulants:caffeinetheophylline

nicotine

STIMULANTS

Short-acting stimulant, increases feelings of wellbeing, confidence, decreases fatigue, increasescardiac output. High doses may produce paranoia.Crack, a concentrated, more potent form ofcocaine, may produce intense craving, addictionand unpredictable violent behavior. Blocksreuptake of norepinephrine.

Similar effects to cocaine but longer acting. Lowdoses increase alertness, euphoria, athletic per-formance, energy, decrease fatigue, but may alsoproduce irritability, insomnia, increased cardiacoutput and anAiety. High doses may produce psy-chotic-like behavior. Development of toleranceand dependence variable. increases functionalactivity of norepinephrine and dopamine.

Similar to amphetamine, more prominent effectson mental than motor activity, although high dosesmay cause convulsions. Increases transmission ofnorepinephrine.

Reverses many forms of clinical depression, im-proves mood. Blockers of norepinephrine reup-take.

Reverses clinical depression, improves mood.Generally no effect in normal patients. Inhibitsmonoamine oxidase, an enzyme that metabolizesnorepinephrine.

Produce seizures and convulsions. Block inhibito-ry synapses in brain.

Increases alertness, produces clearer flow ofthought; increases cardiac output, decreasesfatigue, decreases reaction time. Tolerance anddependence may develop with repeated use. In-creases the intracellular activity of neurons.

May have both stimulant or depressant effects onheart. High doses may cause excess stimulation ofrespiratory system, convulsion or death. Stimu-lates certain receptors for the neurotransmitteracetylcholine.

'CHART 2, cont.

Behavioral and Pharmacological Actions

ANTIPSYCHOT'OS'.Phenothiazines:

chlorpromazineImproves mood in psychotic patients, reduces

Butyrophenones: delusions and hallucinations, makes patient betterhaldol candidate for therapy. Little or no tolerance or

dependence. Dons3.roine receptor blockers.

Lithium Salts: Decrease norepinephrine release; increase norepi-nephrine uptake.

SEDATIVE- HYPNOTICS

Barbiturates:

sembutal Behavioral disinhibition, decreases anxiety, pro-.seconal duces sedation, drowsiness, depression, sleep andamytal death with higher doses. Tolerance and physicalpentothal dependence with repeated high doses. Unknown

mechanism of action.

. Antianxiety Agents:

bhlordiaZepoxide Decreases anxiety, tension, insomnia; less hypnot-(Librium) is (sleep producing) than barbiturates. Tolerance

diazepam (Valium) develops slowly. Unknown mechanism of action;may decrease serotonin activity.

meprobamate Effects similar to barbiturates including relief from(Miltown) anxiety, sedation, sleep, tolerance and physical

dependence. Mechanism of action unknown; mayact through GABA.

Miscellaneous:

ethanol (alcohol) In low doses decreases anxiety, produces disin-hibition and euphoria. High doses induce sedation,sleep and death by respiratory depression or aspi-ration of vomit. Tolerance and physicaldependence with repeated high doses. Probablyalters neuronal membranes to alter neurotrans-mission.

OPIATESopium Produce drowsiness, euphoric dreamlike state, in-morphine difference to pain. Effects vary considerablyheroin among users. Repeated use produces marked tol-meperidine erance and physical dependence. Opiate receptormethadone activation.methyl-phenyl-tetra-

hydropyridine (MPTP)

219

CHART 2, cont.

Classification Behavioral and Pharmacological Actions

Miscellaneous: PSYCHEDELICSpsyilocybin Produce wide variations in behavior including anxi-mescaline (peyote) ety, confusion and sensory hallucinations depend-lysergic arid ing upon drug. Tolerance but not physical depen-

diethylamide (LSD) dence may develop with repeated use.phencyclidine (PCP) Mechanisms of action vary considerably butdimethoxy metha- include increases in the functional activity of

rraphetamine acetylcholine (psyilocybin), nnrapinephrine (mes-(STP, DOM) caline/peyote, MDA), serotonin (LED), opiate re-

3,4 methylene dioxy- ceptors (PCP), dopamine (STP, DOM, PCP, MDA).amphetamine (MDA) MDA and MDMA may be neurotoxic (see text).

ormethamphetamine(MDMA) (Ecstasy)

Stimulants. Drugs classified as stimulants generally produce a stimu-lation of behavior, such as increased alertness, sleeplessness,increased motor activity, increased intellectual functioning and feel-ings of well being. High doses of stimulants may produce stereo-typic (repetitive) motor behavior or even psychosis (described inmore detail below). Stimulants may also be used to treat severe, long-lasting depression, a clinical disorder characterized by a profounddecrease in motivation, lack of interest or pleasure in things, distur-bances in weight regulation, feelings of hopelessness and recurrentthoughts of death by suicide. Antidepressant drugs alleviate de-pression by increasing the functional activity of the noradrenergicsystem. The most common antidepressants block the reuptake ofnorepinephrine, thus enabling it to interact more with receptors inthe synapse, or they inhibit an enzyme (MAO) that inactivatesnorepinephrine.

Antipsychotics. These drugs are used primarily to treat schizophre-nia, a psychotic disorder characterized by loosening of associationsand hallucinations. The schizophrenic may have broken from reality.The response to other people and situations is often inappropriate(e.g., laughing at the news of a family member's death), paranoid(e.g., belief that government agents or aliens are after them), cata-tonic (they may remain motionless, in awkward positions for ex-tended periods of time); they cannot understand abstract conceptsand tend to interpret things very literally (e.g., when asked to explainwhat it means when someone says "a stitch in time saves nine" aschizophrenic might give an answer having to do with sewing). Thesuccessful use of antipsychotic medications to treat these disorderssuggests very strongly that the cause of these illnesses is due to aneurochemical imbalance or some other alteration in the functionalactivity of the systems on which these drugs work.

;`-

One of the most widely used antipsychotics is a class of drugs calledphenothiazines. One of the often prescribed phenothiazines, chlor-promazine, alleviates psychotic behavior by decreasing the func-tional activity of two neurotransmitters, dopamine and norepineph-rine. As the ability of the antipsychotic to block dopamine receptorsincreases, so does the psychotherapeutic effectiveness of the drug.Besides changing psychotic behavior, the blockade of dopaminereceptors has other side effects. The long-term use of dopamine anti-psychotics can result in tardive dyskinesia, a motor-function deficitwith symptoms similar to Parkinson's disease. Dopamine isdecreased in patients with Parkinson's disease. A decrease in thefunctional activity of dopamine occurs in both Parkinson's diseaseand with the long-term use of antipsychotic medications.

Sedative-Hypnotics. This category of drugs is capable of producingmany kinds of behavioral depressions. There are a number of differ-ent types of sedative-hypnotics. The mechanisms of their action arenot completely understood, but generally they produce a dose-dependent decrease in the functional activity of most brain neurons.Examples of the four major categories of sedative-hypnotics areshown in Chart 2.

In low doses, these drugs alleviate anxiety and produce disinhibition(in the case of alcohol); in moderate doses, they result in sedationand sleep; high doses can produce general anesthesia, coma anddeath from respiratory depression.

Unlike many psychoactive drugs, alcohol does not appear to act onspecific receptors on neurons. Instead, alcohol affects the perme-ability of the entire neuron. This rather general pharmacological ac-tion may explain the very broad range of behavioral and medicalconsequences associated with alcohol use and alcoholism. In addi-tion to alcohol-induced disinhibition and depression, single doses ofalcohol decrease body temperature, visual perception, psychomotorperformance, judgement and memory. Chronic alcohol use is asso-ciated with increased incidence of heart and liver disease and possi-ble central nervous system damage.

Opiates. The term opiate refers to a class of narcotic drugs originallyderived from the poppy plant. Opium, heroin and morphine are someof the most common opiates. The major uses of opiates are in thetreatment of pain, diarrhea and cough. Morphine is the major pain-relieving agent found in opium (a resin exudate obtained from thepoppy). Heroin does not occur naturally, but is a semisyntheticcompound many times more potent than morphine. Totally syntheticopiates such as meperidine (Demerol) and methadone (Dolophine)are very potent analgesics. These drugs exert their psychoactiveeffects by interacting with specific opiate-like receptors located inthe brain and other parts of the body.

15

In the early 1980's, a new type of heroin appeared on the illicit drugmarket, MPTP (methyl-phenyl-tetra-hydropyridine). This "designer"drug was synthesized by "bathtub" chemists to have properties simi-lar to heroin, but-it is different enough structurally so that, technical-ly, it is not heroin and therefore not yet illegal. Recently a largebatch of illicit MPTP was manufactured using a shortcut. The resultswere disaiterous. Once inside the brain, this form of MPTP ismetabolized to a potent neurotoxin which destroys dopamine neu-rons crucial to motor control. Addicts who used this MPTP veryrapidly developed symptoms of advanced Parkinson's disease.

Subjectively, opiates have been reported to produce decreasedresponse to pain, drowsiness, mood changes, feelings of warmth,peacefulness, contentment, a dreamlike state, and feelings of sexualgratification.

Psychedelics. Drugs that are classified as psychedelics or "mind-expanding" agents have the ability to induce visual, auditory andother sensory hallucinations. Hallucinogenic plants such as Peyoteand psilocithe mushrooms have been used for centuries as part ofreligious ceremonies practiced by Mexican Indians and AmericanIndianein the Southwestern United States. During the 1960's, theuse of psychedelic drugs such as LSD reached its peak in the UnitedStates among the "turn-on, tune-in, drop-out" generation. Thechanges in perception of reality produced by these drugs are a re-suit of changes in the functional activity of several neurotransmittersystems (see Chart 2). These drugs are capable of producing suchvivid hallucinations that the recovery from a "bad trip" (one that pro-duced acute paranoia and/or terror) sometimes takes months. TheLSD of the 1980's, MDMA, also known as "Ecstasy," has effects simi-lar to cocaine and psychedelic drugs without the intense visual hal-lucinations of the latter. A very similar hallucinogenic amphetamineis MDA, also known as "Love Drug." MDA and MDMA have neuro-toxic effects. Recent evidence suggests that MDA selectively des-troys brain cells containing the neurotransmitter serotonin.

RELATIONSHIP OF NEUROTRANSMITTERS TO BEHAVIORWe can see from the previous section that changing the activity ofspecific neurochemical "messengers" can alter behavior. Recre-ational-type drugs alter normal behavior and therapeutic drugs re-store behavior to normal. The use of pharmacological agents hasbeen an invaluable tool in learning the way the brain works and howbiochemical changes in the brain are responsible for behavior. Forexample, we now know that dopamine is an important neurotrans-mitter for motor behavior and mental health. At its simplest, too littledopamine can result in Parkinsonism, a disorder characterized by,among other things, uncontrollable tremor and loss of fine motorcontrol. In schizophrenics, blocking of dopamine receptors signifi-cantly reduces the bizarre behavioral symptoms associated with this

16 . . 0').. . - /sr..,

disease, which along with other biochemical evidence suggests thatpart of the etiology of schizophrenia involves an abnormally activedopamine system. Chronic treatment of schizophrenia with dopam-ine blockers often results in tardive dyskinesia, a motor disorder sim-ilar to Parkinson's disease. Other neurotransmitters appear to have a:role in mental functioning including sleep, arousal (serotonin,norepinephrine), teaming and memory (norepinephrine, acetyl-choline). Drugs that after the functional activity of these neuro-transmitters can be expected to significantly alter the behavio s

r ;. mediated by these neurochemicals.

TERMINATION OF DRUG ACTIONThe termination of drug action is accomplished primarily by chang-ing it to another molecular structure so that it is no longer an activeagent and/or so that it can oe removed from the body. Two organsare primarily involved in the termination of drug action and the re-moval of drugs from the body, the liver and the kidneys.

Liver. The liver is a triangular shaped organ, located on the right sideof the abdominal cavity. The liver breaks down or metabolizes drugsthrough the use of enzymes as the drug travels through the liver viathe circulation. The metabolism of fat-soluble drugs results in theformation of water-soluble metabolites which can be excretedthrough urine. Usually, but not always, these metabolites do nothave psychoactive properties.

Kidneys. The kidneys are bean-shaped organs, about the size of afist. Each of the two kidneys is located in the rear of the abdominalcavity at the level of the lower ribs. The kidneys are the primaryexcretory organ of the body. Other organs, such as the lungs, skin,intestines and colon, also function as excretory organs, but to alesser extent than the kidneys.

The kidneys perform two major functions. They remove products ofliver metabolism and regulate the levels of most substances found inbody fluids. Put sit-41y, the kidneys get rid of unwanted substancesin blood and retain the essential ones. This is accomplished by theprimary unit of the kidney, the nephron. In each kidney, there aremillions of nephrons that act to "filter" the bloodstream. As the fil-tered fluid passes through the kidney, unwanted substances passinto the urinary bladder for excretion.

TOLERANCE AND DEPENDENCEMany of the psychoactive drugs we have discussed produce toler-ance and dependence. Tolerance can be defined as a decrease in theresponsiveness to the drug with continued exposure to the drug.With repeated use of a drug, especially when each exposure is closein time, the greater the development of tolerance. As tolerance de-velops, more and more of the drug is required to achieve the effect

2317

1?

obtained with the original dose. Several types of tolerance, de-scribed below, can develop with repeated drug use.

Acute tolerance develops with a single exposure to the drug. Acutetolerance is defined as a decrease in response to the drug during thedescending portion of the blood drug concentration curve, com-pared to the response observed at the same blood concentration onthe ascending limb of the drug concentration curve. In other words,there is a greater effect of the drug on behavior as the concentrationof the drug is increasing in the blood compared to the same concen-tration when blood levels drop as a result of discontinued absorptionand continued metabolism.

Chronic tolerance develops after repeated drug exposure. With re-peated drug use the effect of the-drug declines. This may be due tochanges in the normal functioning ofIhe cell or neuron. With time,the neuron adapts and changes characteristics of transmission to"normalize" the cell even though the drug is present. Metabolic toler-ance refers to a decrease in the availability of the drug as a result ofan increase in liver enzymes so that the drug is more rapidlymetabolized.

Dependence is often associated with tolerance, but they are entirelydifferent phenomena. A person who is physically dependent requiresa drug to function "normally." The removal of the drug (abstinence)results in a "withdrawal syndrome." Withdrawal symptoms vary be-tween drugs. For example, during alcohol withdrawal patients experi-ence mental confusion, tremor, hallucinations and convulsions. Thewithdrawal syndrome usually begins six or more hours after the lastdrink and may last for days. Withdrawal from opiates is often de-scribed as an intense flu (fever, chills, weakness, gastrointestinalpain). Conversely, the readministration of the drug will alleviatewithdrawal.

Both tolerance and physical addiction occur as a result of changesin the central nervous system. Although the precise mechanismsthrough which tolerance and dependence develop are not yetknown, it is believed that changes in the functional activity of neu-rons play an important role in all behaviors, including tolerance andaddiction. For many of the drugs we have discussed, these changesmay occur in the receptors, but for other drugs, such as alcohol,tolerance and cependence may develop as a result of an alteration inthe membranes that form neurons. Changes in membrane fluidity(and therefore, the flow of ions) may alter the functional activity ofneuronal systems mediating various behaviors. Although consider-able progress has been made in our understanding of how manydrugs enter the body, exert their psychoactive effect, and have theiractivity terminated, additional basic research is needed to under-stand the neurochemica! mechanisms involved in the developmentof tolerance and dependence.

e, .14 4.:t

Suggested ReadingsGilman, A.G., Goodman, L.S., Rail, T.W. and Murad, F. (Eds.) Goodman and

Gilman's The Pharmacological Basis of Therapeutics. 7th Edition. NewYork: Macmillan; 1985.

Leavitt, F. Drugs and Behavior. 2nd Edition, Wiley Series on PersonalityProcess, New York, 1982.

Ray, O.S. Drugs, Society and Human Behavior. 3rd Edition. St. Louis:Mosby; 1983.

19

About the Center of Alcohol Studies

The Center of Alcohol Studies was founded at YaleUniversity in 1940. The center has been a leader inthe interdisciplinary research on alcohol use and itseffects and has been in the forefront of the move-ment to recognize alcoholism as a major publichealth problem. Dr. E.M. Jellinek was the center'sfirst director, and the prestigious Journal of Studieson Alcohol, still published by the center, wasfounded by Howard W. Haggard, M.D. In 1962,the Center of Alcohol Studies moved to RutgersUniversity.

The center faculty have been trained in biochemistry,economics, physiology, psychology, psychiatry,sociology, political science, public health, education,statistics and information science. The faculty teachundergraduate, graduate and continuing educationcourses, including the world famous Summer Schoolof Alcohol Studies. The SSAS alumni have assumedleadership positions in research, prevention andtreatment of alcohol problems.

"'he center's major areas of concern are: research,education, treatment and prevention. The centermaintains the foremost research library in the field tosupport these activities. As part of the center'seducational mission, this pamphlet series presentsinformation on important topics in the alcoholstudies field.