Drugs Brain and Behavior 6th Edition

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Chapter 6. Tolerance, Sensitization, Dependence, and Addiction

Essay questions.

Q. A researcher is investigating some of the behavioral properties of a new drug called “GR1944” (a
hypothetical drug). She trains two groups of rats on tasks in which bar pressing is occasionally reinforced with
food. For GROUP DRLR rats the longer the interval between bar presses the greater the likelihood that a bar
press will be rewarded, so GROUP DRLR rats generally press the bar fairly infrequently. For GROUP DRHR
rats the shorter the interval between bar presses the greater the likelihood that a bar press will be rewarded, so
GROUP DRHR rats press the bar fairly rapidly. After the two groups are trained over several daily sessions to
the point that their responding is at stable levels, the researcher splits the two groups into two subgroups. For
five successive daily test sessions, she injects GROUP DRLR-1 and GROUP DRHR-1 rats with 100 mg of
GR1944 30 minutes prior to each session, and for five successive daily test sessions, she injects GROUP DRLR-
2 and GROUP DRHR-2 rats with saline 30 minutes prior to each session. The researcher measures the rate of
bar pressing for each group over the five test sessions.

The researcher notes that after the first injection of GR1944, the GROUP DRLR-1 and GROUP DRHR-1 rats
respond much more frequently than their counterpart controls (i.e., GROUPs DRLR-2 and DRHR-2). However,
by the fifth test session, the GROUP DRLR-1 rats are responding at about the same level as the GROUP DRLR-
2 rats, i.e., it appears that tolerance to GR1944 has occurred. On the other hand, by the fifth test session, the
GROUP DRHR-1 rats are still responding much faster than the GROUP DRHR-2 rats, i.e., tolerance to
GR1944 does not appear to have occurred.

1. Are these observations more compatible with a pharmacodynamic or a context-specific mechanism

for tolerance development? Explain your reasoning.

A (p. 101, 103-105). Since both groups DRLR-1 and DRHR-1 were given the same amount of GR1944
over the same time intervals and only one group exhibited tolerance, a pharmacodynamic mechanism
can be ruled out, leaving a context-specific mechanism resulting from the fact that the task
requirements for the two groups of rats were very different. Specifically, group DRLR-1 rats would
have lost reinforcers upon exposure to GR1944 because it resulted in them responding more frequently,
whereas group DRHR-1 rats would likely increase their reinforcement rate with the drug because the
responded even more rapidly than without the drug. Thus, one would predict that group DRLR-1 rats
would learn some compensatory instrumental behaviors that resulted in them decreasing their rate of
responding to reestablish their original rate of reinforcement, i.e., show tolerance. Since there would be
nothing for group DRHR-1 rats to compensate for, they would show no tolerance.

2. Do these observations tell us anything regarding the question of whether GR1944 is capable of
inducing physical dependence? Explain your reasoning.

A (p. 112-117). This doesn’t tell us much about whether GR1944 could produce physical dependence
because, although tolerance always precedes physical dependence, there are a variety of tolerance
processes that are not linked to physical dependence. However, since the drug was only given once a
day, and only for five days, and tolerance only occurred in one group, it is not likely that, at least with
this dose and dosing interval and number of doses, physical dependence would result. But we don’t
know about whether higher doses, more frequent dosing, or more doses could induce physical
dependence. Furthermore, we would have to see if any signs of abstinence, that were essentially
opposite to the direct effects of the drug, would occur upon drug cessation.

Q. John Key has been injecting the drug Sopor to get “high” four to six times daily for a month. In addition to
the euphoria experienced, the drug induces low blood pressure, low heart rate, pupillary constriction, and
constipation. If John were to immediately stop taking Sopor, what might the abstinence syndrome look like and
what would be its likely time course (described in terms of duration and intensity)?

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A (p. 114-115). The abstinence syndrome would consist of effects generally opposite to the direct effects of the
drug, e.g., dysphoria, high blood pressure, tachycardia, pupillary dilation, and diarrhea. Since it was necessary
for John to take the drug this often to get high, it indicates that the drug was relatively shortacting; thus,
withdrawal would likely to be relatively intense but short-lasting, e.g., a few days.

Q. What is a pharmacological reason for receptor “down-regulation”?

A (p. 104). Greater than normal activity at receptors, either because a drug agonist activates them or the drug
enhances the levels of the neurotransmitters for those receptors

Q. Two groups of rats have a small pellet implanted under the skin. In Group A rats the pellet contains
morphine, which is slowly absorbed over a 72 hour period. In Group B rats the pellet contains an inert
substance. The rats are kept in their home cages for the three days after the pellet implantation. Both groups are
then tested for analgesia by being injected intraperitoneally with a small dose of morphine. This test consists of
the rats being placed on a hot surface and they are timed to see how long it takes them to lick their paws. (It is
assumed that the longer it takes the rats to lick their paws, the more the analgesia.) Group A rats display much
less of an analgesic response than Group B rats. Is this tolerance phenomenon more compatible with a
pharmacodynamic or a context specific mechanism for tolerance development? Explain your reasoning.

A (p. 103-105, 108-110). The fact that the Group A rats, which had been exposed to morphine prior to their
exposure in the analgesia test, exhibited less analgesia than Group B rats indicates the development of tolerance
to morphine’s analgesic properties. Because the Group A rats given the morphine pellet (1) were tested for
morphine analgesia in a context totally different from that in which they experienced the effects of morphine
and (2) never practiced the paw-licking behavior in response to heat while under the influence of morphine, it is
unlikely that this is a context-specific form of tolerance, e.g., the development of a compensatory CR to the
contextual/conditioned stimuli (CS) or an instrumental compensatory behavior. On the other hand, three days of
chronic exposure to the morphine should be sufficient to induce some pharmacodynamic neuroadaptations in the
Group A rats.

Q. What are two actions induced by psychotropic drugs that may lead to receptor “up-regulation”?

A (p. 104). Any drug action that results in a lower than normal activity at receptors for an extended period of
time (generally on the order of several hours) may lead to receptor “up-regulation”, e.g., a drug antagonist may
bind to them and prevent neurotransmitter (NT) activation or the drug may increase the levels of the NTs for
those receptors by reducing the NT reuptake, by enhancing NT release, by reducing NT metabolic degradation,
by activating autoreceptors (which reduces NT release or synthesis), by decreasing the firing of neurons that
release the NT, etc.

Q. Distinguish between “context-specific” tolerance and “pharmacodynamic” tolerance.

A (p. 103, 104-106, 109-114). Context-specific tolerance refers to a decrease in response to a drug primarily
resulting from learning processes, in which the contextual stimuli become CSs for compensatory CRs that
reduce the apparent drug-induced reactions (UCRs), or the organism learns instrumental compensatory
responses to behaviorally disruptive effects of the drug, or simple habituation occurs to the drug stimuli. If the
contextual stimuli are changed or the task contingencies change, the tolerance may be reduced or eliminated.
Pharmacodynamic tolerance refers to changes in cellular membranes, receptors, or neurotransmitter levels
reflecting physiological homeostatic processes. These processes are activated when the concentration of the
drug is high and the actions are prolonged and are generally independent of the context in which the drug is
taken.

Q. What is the relationship between tolerance and receptor “desensitization”?

A (p. 103-105). If a drug’s pharmacodynamic properties result in considerably greater activation of a particular
type of receptors (e.g., because the drug is an agonist at the receptors, or the drug causes more than normal
amounts of the natural ligand [neurotransmitter] to be accessible to the receptors) the receptors’ functional

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characteristics may decline (desensitization). Thus, in order to achieve the original effect of the drug, more drug
must be taken to act on the remaining receptors that have not desensitized. These receptors will subsequently
desensitize, so that even more drug must be taken to produce the original effect. This decrease in the drug’s
effectiveness results in tolerance.

Q. What are the distinctions between “drug abuse” and “drug dependence”?

A (p. 112-114). Drug abuse is evidenced when there is recurrent drug use by the individual that is often
accompanied by adverse consequences, e.g., social, economic, health, for the individual or society. Drug
dependence includes this feature; in addition, in the absence of the drug, the drug dependent person experiences
unpleasant and uncontrollable mood states that is accompanied with the compulsive use of drugs. Typically
tolerance is evidenced and physiological withdrawal may be evidenced if the drug is not taken.

Q. How are the processes of “enabling” and “denial” factors in drug dependency?

A (p. 127-128). Enabling occurs when friends, family members, or acquaintances engage in behaviors that
reduce the negative consequences of the addict’s drug-associated behaviors on the addict, e.g., loaning the
addict money, covering up their mistakes, making excuses for them. This decreases the recognition that there is
a problem and the motivation to do something about it, and also facilitates the process of denial. Denial refers to
the inability of addicts to consciously acknowledge that their drug-taking behaviors are causing problems for
themselves and others or that they have lost control over their drug-taking. Without recognizing that there is a
problem, there is little likelihood that treatment will be sought out and if forced into treatment, little likelihood
that the treatment will have any lasting effects on the addict.

Multiple choice questions.

1. The sight of a syringe has been noted to produce in a heroin addict a sudden desire for a “fix” and he begins
twitching. Such reactions were not present until the syringe was seen. We can say that the syringe has
become
a. a conditioned stimulus b. an unconditioned stimulus
c. a conditioned response d. an unconditioned response

2. Drugs that commonly induce both physical and psychological dependence are
a. antipsychotics b. LSD and mescaline c. sedative-hypnotics d. narcotic antagonists

3. The terms “tachyphylaxis” or “acute tolerance” refers to

a. a very rapidly developing tolerance to a drug’s effects
b. a very slowly developing tolerance
c. tolerance which alters the person’s reactions to other drugs
d. long-term tolerance

4. Which mechanism was not cited by the textbook as a factor in tolerance?

a. depletion of neurotransmitters
b. prevention of drug getting through the blood brain barrier
c. increase in drug metabolizing enzymes
d. changes in neurotransmitter receptor sensitivity

5. The hypothesis that some drug tolerance is the result of learning to compensate for the effects of drugs
would predict that
a. the rate of tolerance development is a function of the difficulty of the task performed while under the
influence of the drug
b. drug-induced decrements in performance will not show tolerance
c. drug-induced enhancements of performance should show tolerance

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 d. none of the above

6. Most of the drugs used to treat major mental and emotional disorders, such as antipsychotics,
antidepressants and lithium, generally produce
a. strong physiological dependence
b. both psychological and physiological dependence
c. moderate psychological dependence
d. none of the above

7. Greatly increased activation of postsynaptic receptors with drugs generally results in the receptors
a. becoming more sensitive b. becoming less sensitive
c. showing little increase or decrease in sensitivity d. becoming more active

8. With the exception of nicotine, the first illegal drug for high school students presently in the U. S. is almost
always _______(1)____________. If the user moves on to other drugs, the second illegal drug(s) generally
is/are ______(2)__________.
a. (1) marijuana; (2) alcohol b. (1) alcohol; (2) stimulants, depressants, or tranquilizers
c. (1) alcohol; (2) marijuana d. (1) marijuana; (2) stimulants

9. Under which conditions should one expect to find evidence for state dependent forgetting?
a. material learned while drugged, material tested while drugged
b. material learned while drugged, material tested when no drug taken
c. material learned when no drug taken, material tested when no drug taken
d. all of the above

10. Depending upon how frequently they are activated, neurotransmitter receptors generally have a “lifetime,”
i.e., the time between their synthesis, degradation, and replacement, somewhere around
a. minutes b. hours c. weeks d. months

11. When the actions of people who care about a drug dependent person allow the person to escape the harmful
consequences of drug use, it is called
a. displacement b. denial c. enabling d. rationalization

12. After being a heavy smoker for several years, you quit and don’t have a cigarette for several months. While
you hadn’t cared for cigarettes all that much before you had started smoking, you now find yourself
wanting a cigarette in certain situations. We can say that your drug craving is
a. a primary drive b. an acquired (conditioned) drive
c. a social motive d. due to physiological withdrawal

13. When monkeys are hooked up to an apparatus so that a small injection of a drug directly into the
bloodstream occurs when the animals perform same response, which of the following drugs are they likely
to self-administer?
a. cocaine b. amphetamine c. morphine d. all of these

14. If given an opportunity to release cocaine or morphine into its bloodstream, e.g., by pressing a lever that
delivers the drug intravenously, a nonhuman animal will typically do so, and when the drug is no longer
delivered after many responses by the animal, it will stop lever pressing. However, if the animal is exposed
to a stressor or sees or hears a cue that was originally presented when the drug was delivered, it will
typically start lever pressing again. This phenomenon is referred to as
a. priming b. sensitization c. augmentation d. tolerance

15. Sally was so nervous about learning to drive that she took three Valium every time she took a driving
lesson. After she learned to drive well under these conditions, she was no longer nervous about driving, but

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 she still found that she had a great deal of trouble remembering what to do when driving without taking her
Valium. Most likely this was due to
a. traumatic retrograde amnesia b. state dependent learning
c. proactive interference d. short term storage deficits

16. When John Key first began to inject heroin, he experienced numerous physiological and emotional
reactions to the drug. After several injections, John Key noticed that he has a craving to “shoot up” every
time he sees a syringe. This craving is called a(n)
a. unconditioned stimulus b. conditioned stimulus
c. unconditioned response d. conditioned response

17. When a person first begins smoking cigarettes, he often experiences numerous physiological reactions to
the ingredients of the smoke. After numerous smoking experiences, the person notices that he has a craving
to smoke a cigarette every time he sees one. The physiological reactions to the ingredients of the cigarette
smoke may be termed a(n)
a. unconditioned stimulus b. conditioned stimulus
c. unconditioned response d. conditioned response

18. The waning (decrease in probability and magnitude) of a response to an initially novel stimulus after the
person is exposed to the same stimulus on several occasions is termed
a. extinction b. habituation c. generalization d. discrimination

19. Responses that do NOT fully transfer from one set of drug conditions to another are termed
a. conditioned responses b. state-dependent responses
c. task specific responses d. unconditioned responses

20. What technique is most commonly used with nonhumans to determine whether or not a drug has
dependence liability?
a. determine if the drug disrupts instrumental behavior
b. determine if they will self-administer the drug
c. determine if the drug has a low therapeutic index
d. determine if tolerance occurs to the drug with repeated exposures

21. The hypothesis that drug tolerance is due to the development of conditioned compensatory responses to a
drug’s effects would predict that, after complete tolerance has developed in one environmental context, the
drug’s effects would again be evidenced if the
a. drug was administered in an entirely different context
b. dose of the drug was reduced
c. the person were not exposed to the drug for several days
d. all of the above

22. Physical dependence associated with down-regulation of receptors is most likely to occur with drugs that
a. deplete neurotransmitters b. reduce receptor activation
c. increase receptor activation d. enhance hepatic enzyme production

23. Which type of context-specific process that results in drug tolerance does not depend on the development of
compensatory responses for tolerance to occur?
a. instrumental conditioning b. Pavlovian conditioning
c. habituation d. metabolic drug inactivation

24. Drug dependence is distinguishable from drug abuse because drug dependence is more likely to involve a
person’s
a. experiencing uncontrollable and unpleasant mood states that motivate compulsive drug-taking
behavior

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 b. frequent use of drugs
c. use of drugs that results in adverse consequences
d. use of illicit drugs

25. Secondary psychological dependence is most likely to occur

a. after a drug user experiences abstinence symptoms following drug use
b. after drug tolerance develops
c. after the drug user experiences the euphoric properties of a drug
d. prior to developing physical dependence to a drug

26. Which type of tolerance is most directly dependent on factors such as frequency and amount of drug
administered to the organism and is independent of the drug administration context?
a. associative tolerance b. behavioral tolerance
c. pharmacodynamic tolerance d. genetic tolerance

27. When individuals who consume alcohol regularly exhibit decreased sensitivity to other drugs with sedative-
hypnotic properties, e.g., barbiturates, it is an indication of
a. tachyphylaxis b. acute tolerance
c. sensitization d. cross-tolerance

28. Which of the following tolerance mechanisms is most influenced by the environment in which a drug is
given?
a. context-specific tolerance b. pharmacodynamic tolerance
c. genetic tolerance d. metabolic tolerance

29. If two drugs exert the same pharmacodynamic actions but differ in terms of their pharmacokinetic
properties, which of the drugs is likely to produce the most intense abstinence symptoms after chronic use?
The drug with the
a. shortest duration of action b. longest duration of action
c. slowest passage through the blood brain barrier d. longest times between drug exposures

30. Which brain system has research indicated to be most directly related to the abuse properties of virtually all
recreational and abuse-prone drugs?
a. temporal cholinergic system b. mesolimbic dopamine system
c. reticular serotonin system d. basal ganglia

31. Empirical evidence has shown that relapse is not likely to occur with which type of treatment for drug
dependence?
a. drug substitution
b. extinction of conditioned responses
c. group therapy
d. none of the above; there is no empirical evidence that any treatment prevents relapse

32. Which of the following defense mechanisms prevents drug users from consciously recognizing that they are
drug dependent?
a. enabling b. denial c. projection d. regression

33. Chronic exposure of postsynaptic receptors to agonists commonly produce _________________ of the
receptors.
a. desensitization b. down-regulation c. up-regulation d. either a or b

34. __________________ of receptors would most likely occur if the receptors were chronically exposed to
antagonists at those types of receptors.
a. Up-regulation b. Down-regulation c. Desensitization d. Ionization

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35. Which of the following statements is most valid?
a. drug tolerance always precedes physical dependence to the drug
b. the development of drug tolerance always indicates physical dependence
c. physical dependence may occur without any observable drug tolerance
d. both a and b above

36. Which neurotransmitters have been most directly linked to the primary reward and dependence inducing
properties of drugs?
a. serotonin and adrenaline b. GABA and acetylcholine
c. dopamine and glutamate d. glycine and neuropeptide Y

37. Most research indicates that the brain system that underlies the primary reward properties of drugs of abuse
and natural reinforcers like food and sex is the
a. reticular activating system b. basal ganglia
c. hippocampus d. mesolimbic dopamine system

38. Which single factor accounts for most of the variation in the liability to substance abuse?
a. environment shared with parents b. environment shared with peers
c. genetic makeup d. socioeconomic level

39. Cue exposure therapy is designed to

a. reduce the primary reinforcing effects of drugs of abuse
b. reduce the secondary reinforcing effects of drugs of abuse
c. induce state dependent dissociation
d. reduce conditioned cravings

40. Which type of tolerance is directly dependent on factors such as frequency and amount of drug
administered to the organism and is independent of the drug administration context?
a. pharmacokinetic tolerance b. pharmacodynamic tolerance
c. both of these d. neither of these

41. Two individuals administered the same dose of a psychotropic drug for the very first time may exhibit very
different reactions to the drug. This is most likely due to
a. context-specific tolerance
b. pharmacodynamic tolerance
c. dispositional or genetic tolerance
d. conventional tolerance

Chapter 6. Answers to multiple choice questions and page numbers from which questions are derived.

1. a, p 110-111, 125
2. c, p 116
3. a, p 102
4. b, p 103-109
5. a, p 111-113
6. d, p 112-113
7. b, p 105
8. c, p 124
9. b, p 130
10. b, p 105
11. c, p 127

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12. b, p 110-111, 125
13. d, p 117-118
14. a, p 118
15. b, p 130
16. d, p 110-111, 125
17. a, p 110-111
18. b, p 108
19. b, p 130
20. b, p 117-118
21. a, p 110-111
22. c, p 104
23. c, p 108
24. a, p 112
25. a, p 115-116
26. c, p 103-104
27. c, p 102-103
28. a, p 103, 108
29. a, p 113-115
30. b, p 119
31. d, p 130
32. b, p 127
33. d, p 104
34. a, p 104
35. a, p 114
36. c, p 120-121
37. d, p 119
38. c, p 122
39. d, p 128-129
40. c, p 103-104, 109
41. c, p 101