Textbook for Lecture 13-22

Question 1

Serotonin is synthesized from the amino acid tryptophan, which comes from —-

Answer 1

protein in our diet

Question 2

The biochemical pathway for Serotonin comprises two
steps. The first step is catalyzed by the enzyme ——-, which converts tryptophan to ——–. This is then
acted upon by ——– to form 5-HT.

Answer 2

• tryptophan hydroxylase (TPH)
• 5-hydroxytryptophan (5-HTP)
• aromatic amino acid decarboxylase
  (AADC)

Question 3

In 2003, researchers discovered that there are two forms of the TPH gene, designated TPH1 and TPH2. TPH2 is expressed by ——–, whereas TPH1 is expressed by certain types of —–, including ———

Answer 3

• serotonergic neurons (neurons that use 5-HT as their neurotransmitter)
• non-neuronal cells
• 5-HT–secreting enterochromaffin cells located in the gut and melatonin secreting cells in the pineal gland

Question 4

The conversion of tryptophan to 5-HTP is —— in the 5-HT pathway. Furthermore, just as tyrosine hydroxylase is found only in neurons that synthesize catecholamines, —– in the brain is a specific marker for the serotonergic neurons.

Answer 4

• rate limiting
• TPH

Question 5

Synthesis of serotonin in the brains of animals can be stimulated by (2):

Answer 5

1. Giving them large doses of tryptophan
2. Administration of 5-HTP is even more effective because it is converted so rapidly and efficiently to 5-HT.

Question 6

There is also an interesting link between food intake and 5-HT synthesis that was first discovered many years ago by John Fernstrom and Richard Wurtman. Explain the results and experiment:

Answer 6

1. Imagine a group of rats that have been fasted overnight and then fed a protein-rich meal. The level of tryptophan in their blood goes up, and thus you probably would expect brain 5-HT to rise as well, since an injection of pure tryptophan produces such an effect.
2. Surprisingly, however, Fernstrom and Wurtman found
   that consumption of a protein-rich meal did not cause increases in either tryptophan or 5-HT in the brain, even though tryptophan levels in the bloodstream were elevated.
3. The researchers explained this result by showing that tryptophan competes with a group of other amino acids (called large neutral amino acids; LNAA) for transport from the blood to the brain across the blood–brain barrier.
4. Consequently, it’s the ratio between the amount of tryptophan in the blood and the overall amount of its competitors that counts. Most proteins contain larger amounts of these competitor amino acids than tryptophan; thus, when these proteins are consumed, the critical ratio either stays the same or even goes down.

Question 7

What is an effective way of increasing serotonin/Trp in brain without injection just diet?

Answer 7

1. When these researchers fed previously fasted rats a meal low in protein but high in carbohydrates, that experimental treatment led to increases in brain tryptophan and 5-HT levels.
2. One important function of this insulin response is to stimulate the uptake of glucose from the bloodstream into various tissues, where it can be metabolized for energy. But glucose is not the only substance acted on by insulin. This hormone also stimulates the uptake of most amino acids from the bloodstream; tryptophan, however, is relatively unaffected. Because of this difference, a low-protein, high-carbohydrate meal will increase the tryptophan-to-LNAA ratio, allowing more tryptophan to cross the blood–brain barrier and more 5-HT to be made in the brain.

Question 8

Pharmacological depletion of 5-HT has been widely used to assess the role of this neurotransmitter in various behavioral functions. One method often used in rodent studies consists of administering the drug ——– which selectively ——–

Answer 8

• para-chlorophenylalanine (PCPA)
• blocks 5-HT synthesis by irreversibly inhibiting TPH.

One or two high doses of PCPA can reduce brain 5-HT levels in rats by 80% to 90% for as long as 2 weeks, until the serotonergic neurons make new TPH molecules that haven’t been exposed to the inhibitor.

Question 9

Because PCPA can cause adverse side effects in humans, researchers have developed an alternative method for decreasing brain 5-HT in human studies (2):

Method + why it occurs

Answer 9

• This method involves the administration of an amino acid “cocktail” containing a large quantity of amino acids except for tryptophan. Ingestion of this cocktail causes large reductions in both plasma and cerebrospinal fluid levels of tryptophan over a period of roughly 6–12 hours
• Tryptophan depletion occurs for two reasons: (1) the surge of amino acids in the bloodstream stimulates protein synthesis by the liver, which reduces the level of plasma tryptophan to below its starting point; and (2) the large neutral amino acids in the cocktail inhibit entry of the remaining tryptophan into the brain

Question 10

Serotonin (5-HT) is transported into synaptic vesicles using ——– which is the same vesicular transporter found in dopaminergic and noradrenergic neurons. As with the catecholamines, storage of 5-HT in the vesicles plays a critical role in protecting the transmitter from enzymatic breakdown in the nerve terminal.

Answer 10

• ## VMAT2 (vesicular monoamine transporter 2)

Question 11

Reserpine

Answer 11

• the VMAT blocker reserpine depletes serotonergic neurons of 5-HT, just as it depletes catecholamines in dopaminergic and noradrenergic cells.

Question 12

5-HT

Terminal autoreceptors vs autoreceptors on cell body:

Answer 12

Terminal autoreceptors directly inhibit 5-HT release, whereas other autoreceptors on the cell body and dendrites of the serotonergic neurons (somatodendritic autoreceptors) indirectly inhibit release by slowing the rate of firing of the neurons.

Question 13

Release of 5-HT can be directly stimulated by a family of drugs based on the structure of amphetamine. These compounds include (3):

Answer 13

• Para-chloroamphetamine, which is mainly used experimentally
• Fenfluramine, which at one time was prescribed for appetite suppression in obese patients
• 3,4-methylenedioxymethamphetamine (MDMA), which is a recreational and abused drug.

Question 14

Inactivation of 5-HT after its release:

Answer 14

1. After 5-HT is released, it is removed from the extracellular fluid by a reuptake process. As with DA and NE, this mechanism involves a protein on the nerve terminal known as the 5-HT transporter, also known as SERT.
2. Its breakdown is catalyzed by MAO-A to yield the metabolite 5-hydroxyindoleacetic acid (5- HIAA)

Question 15

Selective serotonin reuptake inhibitors (SSRIs)

Answer 15

• New class of antidepressant drugs based on the
  idea of inhibiting 5-HT reuptake

Question 16

There was ——– in the neocortex of squirrel monkeys treated with MDMA

Answer 16

• Reduced serotonergic fiber density

Question 17

The level of —– in the brains of animals or in the cerebrospinal fluid of humans or animals is often used as a measure of the activity of serotonergic neurons.

Answer 17

• 5-HIAA

when these neurons fire more rapidly, they make more 5-HT, and a corresponding increase in the formation of 5-HIAA occurs

Question 18

It turns out that almost all of the serotonergic neurons in the
CNS are found ——— loosely associated with a network of cell clusters called the raphe nuclei.

Answer 18

along the midline of the brainstem (medulla, pons, and midbrain),

Question 19

When the cat enters slow-wave sleep, which is the stage of sleep in which large-amplitude, slow electroencephalographic (EEG) waves can be recorded in the cortex, the serotonergic neurons —— and become —–. Most intriguingly, the cells are ——- when the cat is in rapideye-movement (REM) sleep, a stage of sleep characterized by side-to-side eye movements and low-amplitude, fast EEG waves in the cortex.

Answer 19

• slow down
• more irregular in their firing
• almost completely shut down

Question 20

All of 5-HT receptors are —–, except for the ——, which is an ——- receptor.

Answer 20

• metabotropic
• 5-HT3 receptor
• excitatory ionotropic

Question 21

5-HT1A RECEPTORS (3)

found in + type of receptor (auto/hetero) + mechanism

Answer 21

• Found in many brain areas, but they are particularly concentrated in the hippocampus, the septal area, parts of the amygdala, and the dorsal raphe nucleus.
• Function as somatodendritic autoreceptors or postsynaptic
• First, the receptors reduce cAMP synthesis by inhibiting adenylyl cyclase. The second mechanism involves increased opening of K+ channels and membrane hyperpolarization, which we have seen is a property shared by D2 dopamine receptors and α2-adrenergic receptors. This hyperpolarization leads to a decrease in firing of either the postsynaptic cell (in the case of 5-HT1A receptors located postsynaptically) or the serotonergic neuron itself (in the case of the 5-HT1A autoreceptors).

Question 22

5-HT2A RECEPTORS (3)

found in + type of receptor (auto/hetero) + mechanism

Answer 22

• Large numbers of 5-HT2A receptors are present in the cerebral cortex. This receptor subtype is also found in the striatum, in the nucleus accumbens, and in a variety of other brain areas.
• Postsynaptic
• Function mainly by activating the phosphoinositide second messenger system. This system increases Ca2+ levels within the postsynaptic cell and also activates protein kinase C (PKC).

When given to rodents, 5-HT2A receptor agonists such as DOI trigger a head-twitch response. In humans, such drugs (which include LSD) produce hallucinations.

Question 22

WAY 100635

Answer 22

5-HT1A receptor antagonist

Question 23

5,7-dihydroxytryptamine (5,7-DHT

Answer 23

• widely used to produce serotonergic lesions in experimental animals, although one limitation of using 5,7-DHT is that it must be given directly into the brain because it doesn’t cross the blood–brain barrier. 5,7-DHT causes massive damage to serotonergic axons and nerve terminals in the forebrain, yet cell bodies in the raphe nuclei are usually spared

Question 24

Tph2-knockout mice (3)

mortality + behaviour + restoration?

Answer 24

• show reduced body mass and fat stores, and they also have an increased rate of mortality
• The most consistently observed effect of eliminating brain 5 HT is a large increase in aggressive behavior, which is typically studied in male mice but also occurs in females. illustrates the heightened aggressiveness of male Tph2-knockout mice compared with wildtype males. In this particular study, even female Tph2-knockout mice were more aggressive than wild-type females. (Tube defending territory)
• Brain 5-HT in Tph2-knockout mice can be restored in a dose-dependent manner by injecting the animals with 5-HTP. This method works because 5-HTP is the product of the reaction catalyzed by TPH and, therefore, bypasses the missing step in the biosynthetic pathway. However, recovery of 5-HT levels is only temporary because the newly synthesized transmitter is gradually metabolized by MAO-A and cannot be replenished in the mutant mice.

Question 25

Additional experiments demonstrated that injection of 5-HTP along with a drug called carbidopa, which is an —– that doesn’t cross the blood–brain barrier, reverses the high level of aggressive behavior in Tph2-knockout males .

Answer 25

• AADC inhibitor

Because there is substantial AADC activity in some peripheral tissues
(e.g., kidneys), carbidopa was given to block peripheral conversion of 5-HTP to 5-HT. This method permits more 5-HTP to be available to the brain and also prevents adverse consequences of elevated peripheral 5-HT levels such as gastrointestinal distress and diarrhea.

Question 26

Serotonin deficiency hypothesis of aggression

Answer 26

• proposes that low CNS serotonergic activity is associated with hyperaggressiveness

A major challenge to the serotonin deficiency hypothesis is the finding that administration of either
a 5-HT1A or a 5-HT1B receptor agonist leads to a reduction in aggressive behavior, whereas mutant male
mice lacking the 5-HT1B receptor exhibit increased
aggression

Question 27

Second, advances in chemistry during the nineteenth century made it possible to:

Answer 27

purify the primary active ingredient of opium, namely, morphine, and then later the active ingredient of coca, which of course is cocaine. This allowed the drugs to be taken in much more concentrated form, increasing their addictive potential. But since the route of administration is also important, an equally significant event was the development of the hypodermic syringe in 1858, which permitted the purified substances to be injected directly into the bloodstream.

Question 28

The medicalization of drug addiction that occurred primarily in the second half of the twentieth century:

Answer 28

The medicalization of addiction had two components: that
addiction was now thought of as a disease, and that drug addicts should be treated by the medical establishment. We can trace the origin of these views to the American Association for the Cure of Inebriates, an organization founded in 1870, which stated that inebriety (excessive drinking) was a disease and proposed that inebriates (alcoholics) be admitted to hospitals and sanitaria for help. However, this medical approach to alcoholism and drug abuse later faded and was not seriously revived until the early 1950s, when alcoholism was declared a disease first by the World Health Organization and subsequently by the American Medical Association. Alcoholics Anonymous (AA), which embraces many aspects of the disease model of alcoholism, was gaining prominence during this period. The disease model of drug addiction continues to be strongly promoted by the treatment community, by self-help groups such as AA and Narcotics Anonymous, and by much of the research establishment, including the National Institute on Drug Abuse, an agency of the National Institutes of Health. It is also the view most widely accepted by the lay public.

Question 29

Modern conceptions of addiction have focused more on:

Answer 29

First, there is an emphasis on behavior, specifically, the compulsive nature of drug seeking and drug use in the addict. The addict is often driven by a strong urge to take the drug, which is called drug craving. Second, addiction is thought of as a chronic, relapsing disorder. This means that individuals remain addicted for long periods of time and that drug-free periods (remissions) are often followed by relapses in which drug use recurs despite negative consequences.

Question 30

The DSM (2)

What + categories

Answer 30

• an attempt to classify the entire range of psychiatric disorders, with objective criteria provided for the diagnosis of each disorder.
• Instead of using the term drug addiction, the DSM-5 specifies a group of substance-related disorders that cover 10 designated classes of drugs: (1) alcohol, (2) caffeine, (3) cannabis, (4) hallucinogens, (5) inhalants, (6) opioids, (7) sedative–hypnotic and anxiolytic drugs, (8) stimulants, (9) tobacco, and (10) other substances (note that all nine named drug classes are discussed in depth in this textbook)

Question 31

Substance-related disorders are further broken down in the DSM-5 into :

Answer 31

substance use disorders and substance-induced disorders

Question 32

Substance use disorders and Substance-induced disorders difference

Answer 32

Substance use disorder is a mental disorder that affects a person’s brain and behavior, leading to an inability to control the use of substances such as legal or illegal drugs, alcohol, or medications. On the other hand, substance-induced disorders refer to symptoms brought on by using drugs or alcohol

Question 34

The DSM-5 provides a specific set of criteria to
diagnose a substance use disorder for eight of the
nine drug classes listed, explain:

Answer 34

Specifically, individuals who meet only two or three of the specified criteria are considered to have a “mild” substance use
disorder, individuals who meet four or five criteria are considered to have a “moderate” disorder, and individuals who meet six or more criteria are considered to have a “severe” disorder

Question 35

Behavioral addictions and DSM5

Answer 35

The substance-related disorders in DSM-5 fall within a larger classification called substance-related and addictive disorders. The reason for this is the continually growing discussion over whether the concept of addiction should be applied to other uncontrolled or compulsive behaviors such as binge eating, sexual preoccupation, compulsive gambling, excessive internet use, and so forth. These uncontrolled behaviors are sometimes called behavioral addictions. After considerable deliberation, the authors of the DSM-5 decided to add a category called non substance-related disorders, which includes gambling disorder as its sole current entry.

Question 36

There are two types of progression in drug use (2)

Answer 36

• In one type of progression characteristic of many young people, the individual starts out taking a legal substance such as alcohol or tobacco, later progresses to marijuana, and in a small percentage of cases moves on to cocaine, heroin, other illicit substances, or illegally obtained prescription drugs. One of the theories that attempts to account for this type of progression is the gateway theory.
• Contemporary view of pathological drug use as a cyclical pattern that comprises three components: (1) periods of preoccupation with drugs and anticipation of upcoming use; (2) periods of drug intoxication that, in some cases, are associated with “bingeing” on the drug; and (3) periods following drug use that are characterized by withdrawal symptoms and negative affect (e.g., depressed mood or irritability).

Question 37

Schedule I substances

Answer 37

Substances that have no accepted medical use in the United States and have a high abuse potential.

Question 38

Although early ideas about addiction emphasized the role of physical dependence, more recent conceptions have focused on the compulsive features of drug seeking and use (despite the potentially harmful consequences) and on the concept of ———.

Answer 38

drug addiction as a chronic, relapsing disorder characterized by repeated periods of remission followed by relapses

Question 39

Most abused drugs act as positive reinforcers. This means that:

Answer 39

consuming the drug strengthens whatever preceding behavior was performed by the organism

Question 40

Drug reward

Answer 40

refers to the positive subjective experience (i.e., pleasure) associated with the drug.

the euphoric feeling or “high” induced by a variety of drugs, and the feeling of relaxation induced by alcohol, marijuana, and sedative drugs such as barbiturates.

Question 42

The two routes of administration that produce the most rapid uptake of the drug by the brain)

Answer 42

• Inhalation
• IV

Question 43

Variety of drugs have shown that when the drug is delivered using a simple schedule of reinforcement such as a fixed-ratio (FR) schedule, the typical dose–response function is ——-. The ascending part of the curve is thought to reflect ——- of the drug over that range of doses. On the other hand, the descending limb is potentially attributable to ——–

Answer 43

• an inverted U-shaped curve
• increasing reinforcing effectiveness
• multiple factors, including satiation to the drug, aversive reactions, or behaviorally disruptive side effects (e.g., extreme hyperactivity in the case of stimulant drugs, or sedation in the case of sedative–hypnotic agents)

Question 44

simple dose–response functions are not very useful for
determining the reinforcing strength of one substance
versus another. A better measure of the relative strength
of drug reinforcement makes use of a ——-. In this procedure:

Answer 44

• progressive ratio procedure
• animals are initially trained to lever press on a continuous reinforcement (CR) schedule, which means that each press is followed by drug delivery. In the second phase, the animals are switched to a low FR schedule, such as an FR-5 (one drug delivery for every five responses). Finally, the FR schedule is progressively increased until the animals stop responding, presumably because the dose being delivered is not sufficiently reinforcing to support the amount of effort required. The response ratio at which responding ceases is called the breaking point (sometimes termed breakpoint instead).

Question 45

Relapse is typically modeled in self administration studies by:

Answer 45

Stopping drug delivery (thus producing a forced abstinence that results in extinction of the operant response) and then exposing the animals to stimuli that are known to provoke renewed responding in an attempt to obtain the drug again. Such renewed responding is termed reinstatement of drug seeking behavior. Three main types of stimuli are effective in reinstating drug-related responding: (1) the experimenter delivering a small dose of the drug to the animal, known as drug priming; (2) subjecting the animal to stress; and (3) exposing the animal to environmental cues that were previously paired with drug delivery (prior to extinction).

Question 46

PROCEDURES USED TO STUDY DRUG REWARD

Place conditioning

Answer 46

Animals (typically rats and mice) are trained in a two- or three compartment apparatus in which one of the compartments is paired with the presence of a drug over several conditioning sessions. A test session is then conducted under drug-free conditions. If the drug produced a rewarding effect during training, the animal will spend more time in the drug-paired compartment than in a compartment that had been paired with a placebo.

Question 47

PROCEDURES USED TO STUDY DRUG REWARD

Electrical self-stimulation

Question 48

Certain drugs of abuse such as alcohol and opiates (e.g., heroin or morphine) can lead to physical dependence when taken repeatedly. Some researchers have proposed that this process plays a key role in the establishment and maintenance of drug addiction:

Answer 48

According to this idea, once an individual has become physically dependent as the result of repeated drug use, attempts at abstinence lead to highly unpleasant withdrawal symptoms (also called an abstinence syndrome). This motivates the user to take the drug again (relapse) to alleviate the symptoms. In the language of learning theory, relief of withdrawal symptoms promotes drug-taking behavior through a process of negative reinforcement, thus leading ultimately to a continuous behavioral loop consisting of repeated abstinence attempts followed by relapses.

Question 49

Koob and Le Moal (2005) have proposed that in the development of addiction, drug-taking behavior progresses from an “impulsive” stage, in which ———, to a “compulsive” stage, in which ——–.

Answer 49

• the primary motivation for drug use is the substance’s positive reinforcing effects
• the primary motivation is the negative reinforcement obtained by relief from drug withdrawal

Question 50

The factors contributing to drug addiction can be combined into a biopsychosocial model:

Answer 50

• A model that includes the full range of pharmacological, biological, and psychological/sociocultural factors that influence addiction risk can be called a biopsychosocial model of addiction