Chapter 4 - Chemical Basis of Synaptic Transmission

Question 1

Drugs Affect Each Stage of ____________ and ___________

Answer 1

Neural Conduction

Synaptic Transmission

Question 2

Cholinergic Pathways in the Brain

Two types of ACh receptors:

Answer 2

Nicotinic–most are ionotropic and excitatory

Muscarinic–metabotropic and can be excitatory or inhibitory

Question 3

Drug tolerance

Answer 3

Drug tolerance can develop–successive treatments have decreasing effects
Metabolic tolerance–organ systems become more effective at eliminating the drug
Functional tolerance–target tissue may show altered sensitivity to the drug

Question 4

A Neural Pathway Implicated in Drug Abuse

Answer 4

Another pathway may involve the insula, a brain region within the frontal cortex.
People with damage to this area have been able to stop smoking effortlessly.

Question 5

exogenous substances

Answer 5

animal, vegetable, and mineral compounds from external sources

Question 6

The brain is an ____________ system

Answer 6

electrochemical

Question 7

most drugs that affect the nervous system do so by…

Answer 7

altering brain chemistry and synaptic transmission

Question 8

neurochemistry

Answer 8

The branch of neuroscience concerned with the fundamental chemical composition and processes of the nervous system.

Question 9

neuropharmacology

Answer 9

Also called psycho-pharmacology. The scientific field concerned with the discovery and study of compounds that selectively affect the functioning of the nervous system.

Question 10

exogenous

Answer 10

Arising from outside the body.

Question 11

endogenous

Answer 11

Produced inside the body.

Question 12

most drugs that affect behavior do so by

Answer 12

altering synaptic neurotransmitter chemical communication process at millions, or even billions, of synapses.

Question 13

endogenous substances

Answer 13

neurotransmitter

Question 14

To be considered a classic neurotransmitter, a substance should meet the following criteria:

Answer 14

• The substance exists in presynaptic axon terminals.
• The presynaptic cell contains appropriate enzymes for synthesizing the substance.
• The substance is released in significant quantities when action potentials reach the terminals.
• Specific receptors that recognize the released substance exist on the postsynaptic membrane.
• Experimental application of the substance produces changes in postsynaptic cells.
• Blocking release of the substance prevents presynaptic activity from affecting the postsynaptic cell.

Question 15

amine neurotransmitter

2 sub families

Answer 15

A neurotransmitter based on modifications of a single amino acid nucleus. Examples include acetylcholine, serotonin, or dopamine.

1. Quaternary amines
2. Monoamines

Question 16

amino acid neurotransmitter

Answer 16

A neurotransmitter that is itself an amino acid. Examples include GABA, glycine, or glutamate.

Question 17

peptide neurotransmitter (neuropeptide)
2 sub families

Answer 17

A neurotransmitter consisting of a short chain of amino acids.

1. Opioid peptides
2. Other neuropeptides

Question 18

gas neurotransmitter

Answer 18

A soluble gas, such as nitric oxide or carbon monoxide, that is produced and released by a neuron to alter the functioning of another neuron.

Found widely throughout the body, NO has been implicated in processes as diverse as hair growth and penile erection, in addition to its role in the brain.

Question 19

the major categories of some of the many neurotransmitters presently known

Answer 19

amine neurotransmitter
amino acid neurotransmitter
peptide neurotransmitter (neuropeptide)
gas neurotransmitter

Question 20

Examples of AMINES

Answer 20

Quaternary amines
- Acetylcholine (ACh)

Monoamines

• Catecholamines: norepinephrine (NE), epinephrine (adrenaline), dopamine (DA)
• Indoleamines: serotonin (5-hydroxytryptamine; 5-HT), melatonin

Question 21

Examples of AMINO ACIDS

Answer 21

Gamma-aminobutyric acid (GABA), glutamate, glycine, histamine

Question 22

Examples of NEUROPEPTIDES

Answer 22

Opioid peptides

• Enkephalins: met-enkephalin, leu-enkephalin
• Endorphins: β-endorphin
• Dynorphins: dynorphin A

Other neuropeptides
- Oxytocin, substance P, cholecystokinin (CCK), vasopressin, neuropeptide Y (NPY), hypothalamic releasing hormones

Question 23

Examples of gas neurotransmitters

Answer 23

Nitric oxide, carbon monoxide

Question 24

Even if a substance is known to be a transmitter in one location, proving that it
acts as a transmitter at another location may be ___________

Answer 24

difficult.

Question 25

Considering the rate at which neurotransmitters are being discovered and characterized, it would not be surprising if there turned out to be ________ _________

Answer 25

several hundred

Question 26

receptor

Answer 26

Also called receptor molecule. A protein that binds and reacts to molecules of a neurotransmitter or hormone.

neurotransmitters affect their targets by interacting with receptors,

The transmitter molecule binds to the receptor, changing its shape to open an ion channel (as with fast, ionotropic receptors) or altering chemical reactions within the target cell (as with slow, metabotropic receptors)

Receptors add an important layer of complexity in neural signaling, because any given transmitter may affect various kinds of receptors that differ from one another in structure and therefore in how they respond to that neurotransmitter.

Question 27

receptor

Answer 27

Also called receptor molecule. A protein that binds and reacts to molecules of a neurotransmitter or hormone.

neurotransmitters affect their targets by interacting with receptors,

The transmitter molecule binds to the receptor, changing its shape to open an ion channel (as with fast, ionotropic receptors) or altering chemical reactions within the target cell (as with slow, metabotropic receptors)

Receptors add an important layer of complexity in neural signaling, because any given transmitter may affect various kinds of receptors that differ from one another in structure and therefore in how they respond to that neurotransmitter.

Question 28

ionotropic receptor

Answer 28

A receptor protein that includes an ion channel that is opened when the receptor is bound by an agonist.

Question 29

metabotropic receptor

Answer 29

A receptor protein that does not contain an ion channel but may, when activated, use a G protein system to open a nearby ion channel.

Question 30

receptor subtype

Answer 30

Any type of receptor having functional characteristics that distinguish it from other types of receptors for the same neurotransmitter.

These different receptor subtypes may trigger very different responses in target cells, and in many cases they are also distributed differently within the nervous system.

Question 31

How can drug development capitalize on the existence of receptor subtypes?

Answer 31

Although a given neurotransmitter will interact with all the subtypes of its receptors, it is possible to design drugs that selectively affect only one of the subtypes, thereby producing the specific effects associated with that receptor subtype.

Question 32

Although a given neurotransmitter will interact with all the subtypes of its receptors, it is possible to design drugs that selectively affect only one of the subtypes, thereby producing the specific effects associated with that receptor subtype.

Answer 32

A substance that binds to receptor molecules, such as those at the surface of the cell.

Question 33

Three effects of competitive ligands

Answer 33

1. A ligand that is classified as an agonist initiates the normal effects of the transmitter on that receptor.
2. A receptor antagonist is a ligand that binds to a receptor and does not activate it, thereby blocking it from being activated by other ligands (including the native neurotransmitter).
3. An inverse agonist—a less common type of ligand—binds to the receptor and initiates an effect that is the reverse of the normal function of the receptor.

Question 34

agonist

Answer 34

A molecule, usually a drug, that binds a receptor molecule and initiates a response like that of another molecule, usually a neurotransmitter.

Question 35

inverse agonist

Answer 35

A substance that binds to a receptor and causes it to do the opposite of what the naturally occurring transmitter does.

Question 36

competitive ligand

Answer 36

A substance that directly competes with the endogenous ligand for the same binding site on a receptor molecule.

they bind to the same part of the receptor complex that the endogenous transmitter normally would.

Question 37

noncompetitive ligand or neuromodulator

Answer 37

A substance that alters the response to an endogenous ligand, without interacting with the endogenous ligand’s recognition site.

drugs bind to a part of the receptor complex that does not normally bind the transmitter. Because this sort of drug does not directly compete with the transmitter for its binding site, we say that the drug is a noncompetitive ligand (or neuromodulator) binding to a modulatory site on the receptor.

Noncompetitive ligands may either activate the receptor, thereby acting as noncompetitive agonists, or prevent the receptor from being activated by the transmitter, thus acting as noncompetitive antagonists.

Question 38

modulatory site

Answer 38

A portion of a receptor that, when bound by a compound, alters the receptor’s response to its transmitter.

Question 39

co-localization

Answer 39

Also called co-release. Here, the appearance of more than one neurotransmitter in a given presynaptic terminal.

Question 40

___________ was the first neurotransmitter to be identified

Answer 40

Acetylcholine

Question 41

acetylcholine (ACh)

Answer 41

A neurotransmitter produced and released by parasympathetic postganglionic neurons, by motoneurons, and by neurons throughout the brain.
acetylcholine was long known to be a transmitting agent in the peripheral nervous system, but it was harder to prove that acetylcholine serves as a transmitter in the central nervous system as well. Now it is recognized that acetylcholine is widely distributed in the brain, and many scientists study its possible relationship to the cognitive deficits seen in Alzheimer’s disease.

Question 42

cholinergic

Answer 42

Referring to cells that use acetylcholine as their synaptic transmitter.

Widespread loss of cholinergic neurons is evident in Alzheimer’s disease, suggesting that cholinergic systems are crucial for learning and memory. Similarly, the cholinergic antagonist scopolamine interferes with learning and memory in experimental settings.

Question 43

nicotinic

Answer 43

Referring to cholinergic receptors that respond to nicotine as well as to acetylcholine.

Most nicotinic receptors are ionotropic, responding rapidly and usually having an excitatory effect. Muscles use nicotinic ACh receptors, so antagonists, such as the drug curare, cause widespread paralysis.

Question 44

muscarinic

Answer 44

Referring to cholinergic receptors that respond to the chemical muscarine as well as to acetylcholine.

Muscarinic ACh receptors are G protein–coupled (metabotropic) receptors, so they have slower responses when activated, and they can be either excitatory or inhibitory (see Figure 3.15B). Muscarinic receptors can be blocked by the drugs atropine or scopolamine, producing pronounced changes in cognition, including drowsiness, confusion, memory problems, and blurred vision.

Question 45

There are two principal classes of neurotransmitters that, because they are modified amino acids, are called ___________: ___________ and ___________

Answer 45

monoamines: catecholamines and indoleamines.

Question 46

catecholamines

Answer 46

A class of monoamines that serve as neurotransmitters, including dopamine, dpinephrine, and norepinephrine.

Question 47

indoleamines

Answer 47

A class of monoamines that serve as neurotransmitters, including dopamine, dpinephrine, and norepinephrine.

Question 48

dopamine (DA)

Answer 48

A monoamine transmitter found in the midbrain—especially the substantia nigra—and basal forebrain.

Several subtypes of DA receptors have been discovered and have been numbered D1, D2, D3, D4, and D5, in the order of their discovery.

dopaminergic neurons and their projections in the brain, focusing on the mesostriatal pathway and the mesolimbocortical pathway

neurons that release release dopamine are called dopaminergic

Question 49

mesostriatal pathway

Answer 49

A set of dopaminergic axons arising from the midbrain and innervating the basal ganglia, including those from the substantia nigra to the striatum.

Originates from the mesencephalon (midbrain)—specifically the substantia nigra and nearby areas—and ascends as part of the medial forebrain bundle to innervate the striatum: the caudate nucleus
and putamen.

The mesostriatal DA pathway plays a crucial role in motor control, and significant loss of these neurons produces the movement problems of Parkinson’s disease

Question 50

mesolimbocortical pathway

Answer 50

A set of dopaminergic axons arising in the midbrain and innervating the limbic system and cortex.

The mesolimbocortical pathway also originates in the midbrain, in the ventral tegmental area (VTA), and projects to the limbic system (amygdala, nucleus accumbens, hippocampus) and the cortex. This system is important in reward and reinforcement, especially via the dopamine D2 receptor subtype

Abnormalities in the mesolimbocortical pathway are associated with some of the symptoms of schizophrenia,

Question 51

substantia nigra

Answer 51

Literally, “black spot.” A group of pigmented neurons in the midbrain that provides dopaminergic projections to areas of the forebrain, especially the basal ganglia.

Question 52

striatum

Answer 52

The caudate nucleus and putamen together.

Question 53

ventral tegmental area (VTA)

Answer 53

A portion of the midbrain that projects dopaminergic fibers to the nucleus accumbens.

Question 54

norepinephrine (NE)

Answer 54

Also called nor-adrenaline. A neurotransmitter produced and released by sympathetic postganglionic neurons to accelerate organ activity. Also produced in the brainstem and found in projections throughout the brain.

Because norepinephrine is also known as noradrenaline, NE-producing cells are said to be noradrenergic

Question 55

he two main clusters of neurons in the brainstem releasing

norepinephrine (NE) are …

Answer 55

Locus coeruleus, in the pons,

lateral tegmental system of the midbrain

Question 56

locus coeruleus

Answer 56

Literally, “blue spot.” A small nucleus in the brainstem whose neurons produce norepinephrine and modulate large areas of the forebrain.

Question 57

noradrenergic

Answer 57

Referring to systems using norepinephrine (noradrenaline) as a transmitter.

Because norepinephrine is also known as noradrenaline, NE-producing cells are said to be noradrenergic, sympathetic fibers innervating the body are also noradrenergic.

Fibers from the noradrenergic cells of the locus coeruleus project broadly throughout the cerebrum, including the cerebral cortex, limbic system, and thalamus.

The CNS contains four subtypes of NE receptors—α1-, α2-, β1-, and β2-adrenoceptors—all of which are metabotropic receptors.

Given the brain’s wide noradrenergic projections, it’s no surprise that there are noradrenergic contributions to diverse behavioral and physiological processes, including mood, overall arousal, and sexual behavior.

Question 58

serotonin (5-HT)

Answer 58

A synaptic transmitter that is produced in the raphe nuclei and is
active in structures throughout the cerebral hemispheres.

Serotonin has been implicated in the control of sleep states, mood, sexual behavior, anxiety, and many other functions. Drugs that globally increase 5-HT activity are effective antidepressants;

Question 59

serotonergic

Answer 59

Referring to neurons that use serotonin as their synaptic transmitter.

Large areas of the brain are innervated by serotonergic fibers, although 5-HT cell bodies are relatively few and are concentrated along the midline in the raphe nuclei of the midbrain and brainstem.

Question 60

raphe nuclei

Answer 60

A string of nuclei in the midline of the midbrain and brainstem that contain most of the serotonergic neurons of the brain.

Question 61

The most common transmitters in the brain are ________ ________

Answer 61

amino acids.

Question 62

The effects of the 4 most common amino acid neurotrglutamateansmitters

Answer 62

Glutamate and aspartate are important excitatory neurotransmitters.

Gamma-aminobutyric acid (GABA) and glycine typically have an inhibitory effect.

Question 63

glutamate

Answer 63

An amino acid transmitter, the most common excitatory transmitter.

Question 64

aspartate

Answer 64

An amino acid transmitter that is excitatory at many synapses.

Question 65

gamma-aminobutyric acid (GABA)

Answer 65

A widely distributed amino acid transmitter, and the main inhibitory transmitter in the mammalian nervous system.

GABA receptors are divided into large classes: GABAA, GABAB, and GABAC receptors. Although they all normally respond to GABA, the subtypes of receptors exhibit quite different properties.

Question 66

GABA receptors are divided into large classes: …

Answer 66

GABA receptors are divided into large classes: GABAa, GABAb, and GABAc receptors. Although they all normally respond to GABA, the subtypes of receptors exhibit quite different properties.

GABAa receptors are ionotropic, and when activated they produce fast inhibitory postsynaptic potentials. Each GABAA receptor is made up of five protein subunits surrounding a Cl– ion channel that can be widened or narrowed depending on the state of the surrounding complex. By mixing and matching of the various protein subunits that make up the GABAa receptors, the brain may in fact produce dozens of different kinds.

GABAb receptors are metabotropic receptors, typically producing a slow-occur-ring inhibitory postsynaptic potential.

GABAC receptors are ionotropic with a chloride channel, but they differ from other GABA receptors in certain details of their subunit structure.

Question 67

glycine

Answer 67

An amino acid transmitter, often inhibitory.

Question 68

glutamatergic

Answer 68

Referring to cells that use glutamate as their synaptic transmitter.

Glutamatergic transmission employs what are called AMPA, kainate, and NMDA receptors, which are ionotropic. Because NMDA-type glutamate receptors are active in a fascinating model of learning and memory, they have been studied very closely.

There are also several metabotropic glutamate receptors (mGluR’s), which act more slowly because they work through second messengers. Glutamate is also associated with excitotoxicity, a phenomenon in which neural injury, such as a stroke or trauma, provokes an excessive release of glutamate that overexcites cells, eventually killing them.

Question 69

excitotoxicity

Answer 69

The property by which neurons die when overstimulated, as with large amounts of glutamate.

Question 70

opioid peptide

Answer 70

A type of endogenous peptide that mimics the effects of morphine in binding to opioid receptors and producing marked analgesia and reward.

Question 71

The actions of gas neurotransmitters like NO are different from those of the classic transmitters in several important ways.

List and explain three

Answer 71

First, nitric oxide is produced in cellular locations other than the axon terminals, especially the dendrites, and molecules of nitric oxide are not held in or released from vesicles; the substance simply diffuses out of the neuron as soon as it is produced.

Second, the released NO doesn’t interact with membrane-bound receptors on the surface of the target cell, but rather it diffuses into the target cell and stimulates the production of second messengers.

And third, NO can serve as a retrograde transmitter: diffusing from the postsynaptic neuron back to the presynaptic neuron, where it stimulates changes in synaptic efficacy that may be involved in learning and memory.

Question 72

nitric oxide (NO)

Answer 72

A soluble gas that serves as a retrograde gas neurotransmitter in the nervous system.

nitric oxide, or NO (distinct from nitrous oxide, or laughing gas, which is N2O).

Question 73

retrograde transmitter

Answer 73

A neurotransmitter that diffuses from the postsynaptic neuron back to the presynaptic neuron.

Question 74

Recall that any given neurotransmitter interacts with a variety of different subtypes of receptors. This principle is crucial to neuropharmacology because…

Answer 74

unlike the transmitter, which will act on all its receptor subtypes, a drug can be targeted to interact with just one or a few receptor subtypes.

Question 75

Why can so selectively activating or blocking specific subtypes of receptors have widely varying effects?

Answer 75

The various subtypes of receptors generally differ in their distribution within the brain, and they also serve very different cellular functions.

For example, treating someone with doses of serotonin would activate all of her serotonin receptors, regardless of subtype, and produce a variety of nonspecific effects. But drugs that are selective antagonists of 5HT3 receptors, showing little activity at other subtypes of serotonin receptors, produce a powerful and specific anti-nausea effect.

Question 76

Apparently, evolution tinkers with the structure of ________ more than ___________.

Answer 76

Receptors

transmitters

Question 77

The binding at a receptor sight is usually ________.

When the drug or transmitter breaks away from the receptor, the receptor ….

Answer 77

temporary

returns to its unbound shape and functioning.

Question 78

Drug molecules _____ seek out particular receptor molecules

Answer 78

Don’t

Question 79

A drug molecule that has more than one kind of action in the body exhibits this flexibility because …

Answer 79

Because it affects more than one kind of receptor molecule.

For example, some drugs combat anxiety at low doses without producing sedation (relaxation, drowsiness), but at higher doses they cause sedation, probably because at those doses they activate additional types of receptors.

Question 80

binding affinity

Answer 80

Also called simply affinity. The propensity of molecules of a drug (or other ligand) to bind to receptors.

The degree of chemical attraction between a ligand and a receptor

A drug with high affinity for a particular type of receptor will selectively bind to that type of receptor even at low doses, and it will stay bound for a relatively long time. Lower-affinity drugs will bind fewer receptor molecules.

Question 81

If a particular drug has a low affinity for a receptor, then it will ….

Answer 81

then it will quickly uncouple from the receptor. To bind half the receptors at any given time, a higher concentration of the drug is needed.

Question 82

If a drug has a high affinity

for a receptor then …

Answer 82

the two will stay together for a longer time, and a lower concentration of drug will be sufficient to bind half the receptors.

Question 83

If equal concentrations of the two

drugs are present then…

Answer 83

the high-affinity drug will be bound to more receptors at any given time. If the drugs have an equivalent effect on the receptors, then the higher-affinity drug will be more potent

Question 84

efficacy

Answer 84

Also called intrinsic activity. The extent to which a drug activates a response when it binds to a receptor.

After binding, the propensity of a ligand to activate the receptor to which it is bound is termed its efficacy (or intrinsic activity): agonists have high efficacy and antagonists have low efficacy. Partial agonists are drugs that produce a middling response regardless of dose.

Question 85

So, it is a combination of _______and________ that determines the overall action of a drug.

Answer 85

affinity
efficacy

where it binds and what it does

To some extent we can compare the effectiveness of different drugs by comparing their affinity for the receptor of interest.

Question 86

Within certain limits, administering larger doses of a drug increase in receptor binding also increases the response to the drug; in other words …

Answer 86

greater doses tend to produce greater effects.

Question 87

Within certain limits, administering larger doses of a drug increase in receptor binding also increases the response to the drug; in other words …

Answer 87

greater doses tend to produce greater effects.

Question 88

partial agonist or partial antagonist

Answer 88

A drug that, when bound to a receptor, has less effect than the endogenous ligand would.

Question 89

dose-response curve (DRC)

Answer 89

A formal plot of a drug’s effects (on the y-axis) versus the dose given (on the x-axis).

When plotted as a graph, the relationship between drug doses and observed effects is called a dose-response curve (DRC). Careful analysis of DRCs reveals many aspects of drugs’ activity and is one of the main tools for understanding pharmacodynamics.

DRCs reveal the effective dose range of a drug and allow comparison of the potencies and efficacies of different drugs

Sometimes a DRC gives us hints that the drug may be binding more than one type of receptor. By directly comparing the DRCs for two drugs, we can determine which drug would be safer to use.

Question 90

Types of uses of the dose-response curve (DRC)

Answer 90

a. The basic dose-response curve plots increasing drug doses against increasing strength of the response being studied. The dose at which the drug shows half of its maximal effect is termed the effective dose 50% (ED50).
b. We can assess the relative potencies of two drugs by comparing their ED50 values.
c. We can compare drug efficacies by evaluating maximal responses, rather than doses.
d. The shape of a nonmonotonic DRC is normal up to a point, but then it reverses, and the measured response begins to decrease with larger doses. At that point, the drug is starting to have effects elsewhere than at the drug’s highest-affinity receptors.
e. The therapeutic index is the separation between the effective doses of a drug and the toxic doses.

Question 91

effective dose

Answer 91

The dose at which the drug shows half of its maximal effect is termed the effective dose 50% (ED50).

Question 92

maximal responses

Answer 92

The dose of the drug where the effects start to level off.

We can compare drug efficacies by evaluating maximal responses

Question 93

nonmonotonic DRC

Answer 93

The shape of a nonmonotonic DRC is normal up to a point, but then it reverses, and the measured response begins to decrease with larger doses. At that point, the drug is starting to have effects elsewhere than at the drug’s highest-affinity receptors.

Question 94

therapeutic index

Answer 94

The therapeutic index is the separation between the effective doses of a drug and the toxic doses.

A Wide therapeutic index is when the effective doses of a drug and the toxic dose are far apart.

Question 95

pharmacodynamics

Answer 95

Collective name for the factors that affect the relationship between a drug and its target receptors, such as affinity and efficacy.

dose-response curve (DRC) is one of the main tools for understanding pharmacodynamics.

Question 96

tolerance

Answer 96

A condition in which, with repeated exposure to a drug, an individual becomes less responsive to a constant dose.

in which successive treatments with a particular drug have decreasing effects

Once established, drug tolerance is believed to be a major cause of withdrawal symptoms, the unpleasant sensations that occur when one stops using a drug.

Question 97

different ways of creating tolerance

Answer 97

metabolic tolerance
functional tolerance
down-regulation
up-regulation
cross-tolerance

Question 98

metabolic tolerance

Answer 98

The form of drug tolerance that arises when repeated exposure to the drug causes the metabolic machinery of the body to become more efficient at clearing the drug.

in which the body’s metabolic systems and organs (such as the liver) become increasingly effective at eliminating the drug before it has a chance to affect the brain or another target.

Question 99

functional tolerance

Answer 99

Decreased responding to a drug after repeated exposures, generally as a consequence of up- or down-regulation of receptors.

he target tissue itself may show altered sensitivity to the drug

Question 100

down-regulation

Answer 100

A compensatory reduction in receptor availability at the synapses of a neuron.

Over the course of repeated exposures to an agonist drug, target neurons often down-regulate (decrease the number of available receptors to which the drug can bind), thereby countering the drug effect.

The effects of an agonist drug augment the effects of the endogenous ligand, enhancing the effect on the postsynaptic cell. The postsynaptic cell may respond by down-regulating (decreasing) the number of receptors it places into the synapse, in order to become less sensitive and more like the pre-drug state.

Question 101

up-regulation

Answer 101

A compensatory increase in receptor availability at the synapses of a neuron.

a competitive antagonist instead blocks an endogenous substance from having its usual effect, to which the postsynaptic cell may respond by up-regulating (increasing) the number of its receptors in order to become more sensitive and compensate for the lessened effect of the endogenous ligand.

Question 102

cross-tolerance

Answer 102

A condition in which the development of tolerance for one drug causes an individual to develop tolerance for another drug.

Tolerance to a drug often generalizes to other drugs belonging to the same chemical class.

For example, people who have developed tolerance to heroin tend to exhibit a degree of tolerance to all the other drugs in the opiate category, including codeine, morphine, and methadone.

Question 103

withdrawal symptom

Answer 103

An uncomfortable symptom that arises when a person stops taking a drug that he or she has used frequently, especially at high doses.

Once established, drug tolerance is believed to be a major cause of withdrawal symptoms, the unpleasant sensations that occur when one stops using a drug.

Question 104

sensitization

Answer 104

A process in which the body shows an enhanced response to a given drug after repeated doses.

some drug responses can become stronger with repeated treatments, rather than weaker.

opposite of tolerance

this effect is thought to contribute to the drug craving that addicts experience.

This heightened sensitivity may last for a prolonged period and is associated with long-term brain changes, altering the function of the mesolimbocortical DA reward pathway.

Question 105

route of administration

Answer 105

The amount of drug that reaches the brain and the speed with which it starts acting are determined in part by the drug’s route of administration.

Some routes, such as smoking or intravenous injection, rapidly increase the concentration of drug in the body that is bioavailable. With other routes, such as oral ingestion, drug concentration builds up more slowly over longer periods of time. The duration of a drug effect is largely determined by the manner in which the drug is metabolized and excreted from the body.

INGESTION
INHALATION
PERIPHERAL INJECTION
CENTRAL INJECTION

Question 106

INGESTION as a route of drug administration

Answer 106

Tablets and capsules
Syrups
Infusions and teas
Suppositories

EXAMPLES AND MECHANISMS
Many sorts of drugs and remedies; depends on absorption by the gut, which is somewhat slower than most other routes

TYPICAL SPEED OF EFFECTS
Slow to moderate

Question 107

INHALATION as a route of drug administration

Answer 107

Smoking
Nasal absorption
Inhaled powders and sprays

EXAMPLES AND MECHANISMS
Nicotine, cocaine, organic solvents such as airplane glue and gasoline, also used for a variety of prescription drugs and hormone treatments. Inhalation methods take advantage of the rich vascularization of the nose and lungs to convey drugs directly into the bloodstream.

TYPICAL SPEED OF EFFECTS
Moderate to fast

Question 108

PERIPHERAL INJECTION as a drug route of administration

Answer 108

Subcutaneous
Intramuscular
Intraperitoneal (abdominal)
Intravenous

EXAMPLES AND MECHANISMS
Nicotine, cocaine, organic solvents such as airplane glue and gasoline, also used for a variety of prescription drugs and hormone treatments. Inhalation methods take advantage of the rich vascularization of the nose and lungs to convey drugs directly into the bloodstream.

TYPICAL SPEED OF EFFECTS
Moderate to fast

Question 109

CENTRAL INJECTION as a route drug of administration

Answer 109

Intracerebroventricular (into ventricular system)
Intrathecal (into spinwal CSF)
Intrathecal (into spinwal CSF)
Intracerebral (directly into a brain region)

EXAMPLES AND MECHANISMS
Central methods involve injection directly into the CNS; used in order to circumvent the blood-brain barrier, to rule out peripheral effects, or to directly affect a discrete brain location.

TYPICAL SPEED OF EFFECTS
Fast to very fast

Question 110

route of elimination

Answer 110

The duration of a drug effect is largely determined by the manner in which the drug is metabolized and excreted from the body—via the kidneys, liver, lungs, and other routes.

Question 111

Internal Drug depots

Answer 111

Some drugs may be stored in depots (collecting in fat or bone, for example), only to reemerge and have physiological effects after long periods of time.

Question 112

bioavailable

Answer 112

Referring to a substance, usually a drug, that is present in the body in a form that is able to interact with physiological mechanisms.

Question 113

biotransformation

Answer 113

The process in which enzymes convert a drug into a metabolite that is itself active, possibly in ways that are substantially different from the actions of the original substance.

Question 114

pharmacokinetics

Answer 114

Collective name for all the factors that affect the movement of a drug into, through, and out of the body.

Question 115

blood-brain barrier

Answer 115

The mechanisms that make the movement of substances from blood vessels into brain cells more difficult than exchanges in other body organs, thus affording the brain greater protection from exposure to some substances found in the blood.

Question 116

Drugs and the blood-brain barrier

Answer 116

This barrier poses a major challenge for neuropharmacology because many drugs that might be clinically or experimentally useful are too large to pass the blood-brain barrier to enter the brain. To a limited extent this problem can be circumvented by delivering drugs directly into the brain, but that is a drastic step. Alternatively, some drugs can take advantage of active transport systems that normally move nutrients out of the bloodstream and into the brain.

Question 117

local anesthetic

Answer 117

A drug, such as procaine or lidocaine, that blocks sodium channels to stop neural transmission in pain fibers.

Question 118

How do drugs that act on the nervous system to produce changes in behavior alter synaptic function?
(2 ways)

Answer 118

Drugs may affect presynaptic events - Some drugs act on the presynaptic terminal, affecting how much neurotransmitter is released into the synaptic cleft.

Other drugs act on the postsynaptic membrane, altering how the target neuron responds to neurotransmitter.

Question 119

How drugs may affect presynaptic events

three categories and 8 sub categories

Answer 119

Illustrates presynaptic processes that are targeted by CNS drugs, with examples of each kind of drug. The most common presynaptic drug effects can be grouped into three main categories:

effects on transmitter production,

(1) Inhibition of transmitter synthesis
(2) Blockade of axonal transport
(3) Interference with the storage of transmitters

effects on transmitter release

(4) Prevention of synaptic transmission
(5) Alteration of synaptic transmitter release
(6) Alteration of transmitter release through modulation of presynaptic activity

effects on transmitter clearance.

(7) Inactivation of transmitter reuptake
(8) Blockade of transmitter degradation

Question 120

How drugs may affect presynaptic events:

TRANSMITTER PRODUCTION

Inhibition of transmitter synthesis

Answer 120

A drug may block synthesis enzymes, causing a depletion of transmitter.

affected presynaptic neurons are prevented from having their usual effects on postsynaptic neurons, with sometimes profound effects on behavior.

Question 121

How drugs may affect presynaptic events:

TRANSMITTER PRODUCTION

Blockade of axonal transport

Answer 121

Drugs that block axonal transport prevent materials from reaching the axon terminals in the first place, likewise causing the terminal to run out of neurotransmitter.

affected presynaptic neurons are prevented from having their usual effects on postsynaptic neurons, with sometimes profound effects on behavior.

Question 122

How drugs may affect presynaptic events:

TRANSMITTER PRODUCTION

Interference with the storage of transmitters

Answer 122

A third class of drug doesn’t prevent the production of transmitter molecules, but instead interferes with the ability of neurons to store catecholamine transmitters in synaptic vesicles, for later release. This has the effect of depleting transmitter at catecholaminergic synapses and may have a complicated effect on behavior, depending on whether and how much of the leaking transmitter reaches the postsynaptic cell.

Question 123

How drugs may affect presynaptic events:
TRANSMITTER RELEASE

Prevention of synaptic transmission

Answer 123

Even if a presynaptic terminal has an adequate supply of transmitter stored in vesicles, various agents or conditions can prevent the release of transmitter when an action potential reaches the terminal.

For example, compounds that block sodium channels (like the toxin that makes puffer fish a dangerous delicacy, called tetrodotoxin) prevent axons from firing action potentials, shutting down synaptic transmission with deadly results.

And drugs called calcium channel blockers do exactly as their name suggests, blocking the calcium influx that normally drives the release of transmitter into the synapse.

Question 124

How drugs may affect presynaptic events:

TRANSMITTER RELEASE

Alteration of synaptic transmitter release

Answer 124

Some toxins prevent the release of specific kinds of transmitters. For instance, the active ingredient in Botox—botulinum toxin.

Tetanus (lock-jaw) bacteria produce a toxin, called tetanospasmin, that interferes with the molecular machinery that causes synaptic vesicles to bind to the presynaptic membrane.

Question 125

How drugs may affect presynaptic events:

TRANSMITTER RELEASE

Alteration of transmitter release through modulation of presynaptic activity

Answer 125

A different approach involves modifying the systems that the neuron normally uses to monitor and regulate its own transmitter release. For example, presynaptic neurons often use autoreceptors to monitor how much transmitter they have released; it’s a kind of feedback system.

The caffeine that we obtain from coffee and other beverages acts by blocking the autoreceptor effect of an endogenous ligand called adenosine

Question 126

How drugs may affect presynaptic events:

TRANSMITTER CLEARANCE

Blockade of transmitter degradation

Answer 126

Some drugs interfere with transmitter reuptake by blocking specialized proteins, called transporters, that normally remove neurotransmitter from the cleft for reuse For example, we’ll see that some very common antidepressants inhibit the reuptake of serotonin, allowing the transmitter to accumulate and have a bigger effect on postsynaptic receptors. Such drugs are said to work presynaptically, because the transporters are on the presynaptic terminal.

Question 127

How drugs may affect presynaptic events:

TRANSMITTER CLEARANCE

Blockade of transmitter degradation

Answer 127

Other drugs may have a similar effect by inhibiting degradation, the chemical process of breaking down neurotransmitter into inactive metabolites, again allowing the transmitter to accumulate and have a greater effect on the postsynaptic cell. Agents that inhibit the enzyme acetylcholinesterase (AChE), called cholinesterase inhibitors, allow ACh to remain active at the synapse and alter the timing of synaptic transmission. They include certain pesticides and chemical weapons, and they produce prolonged contraction of muscles and resultant paralysis, as well as overactivity of the parasympathetic nervous system.

Question 128

How drugs may affect presynaptic events:
Effects on Transmitter Production
(3 ways)

Answer 128

In order for the presynaptic neuron to produce neurotransmitter, the axon terminals must receive a steady supply of metabolic raw materials and the enzymes that use these metabolic precursors to synthesize transmitter molecules, vesicles, and other important components.

1. Inhibition of transmitter synthesis
   Para-chlorophenylalanine inhibits tryptophan hydroxylase, preventing synthesis of serotonin from its metabolic precursor.
2. Blockade of axonal transport
   Colchicine impairs maintenance of microtubules and blocks axonal transport.
3. Interference with the storage of transmitters
   Reserpine blocks the packaging of transmitter molecules within vesicles, thereby allowing the transmitter to be broken down by enzymes.

Question 129

How drugs may affect presynaptic events:
Effects on Transmitter Release
(3 ways)

Answer 129

1. Prevention of synaptic transmission
   Tetrodotoxin, found in puffer fish, blocks voltage-gated Na+ channels and prevents nerve conduction.
2. Alteration of synaptic transmitter release
   Calcium channel blockers (e.g., verapamil) inhibit release of transmitters. Amphetamine stimulates release of catecholamine transmitters. Black widow spider venom causes overrelease, and thus depletion, of ACh.
3. Alteration of transmitter release through modulation of presynaptic activity
   Caffeine competes with adenosine for presynaptic receptors, thus preventing its inhibitory effects.

Question 130

How drugs may affect presynaptic events:
Effects on Transmitter Clearance
(2 ways)

Answer 130

Immediately after being released, transmitter is rapidly cleared from the synapse. Obviously, getting rid of the used transmitter is normally an important step because until it is gone, new releases of transmitter from the presynaptic side won’t be able to have much extra effect. But under certain circumstances, a significant reduction of synaptic transmitter availability may contribute to disorders such as depression.

1. Inactivation of transmitter reuptake
   Cocaine and amphetamine inhibit reuptake mechanisms, thus prolonging synaptic activity. Certain antidepressants inhibit serotonin reuptake.
2. Blockade of transmitter degradation
   Some drugs (e.g., monoamine oxidaseinhibitors) inhibit enzymes that normally break down neurotransmitter molecules in the axon terminal or in the synaptic cleft. As a result,transmitter remains active longer and to greater effect.

Question 131

autoreceptor

Answer 131

A receptor for a synaptic transmitter that is located in the presynaptic membrane, telling the axon terminal how much transmitter has been released.

to monitor how much transmitter they have released; it’s a kind of feedback system. Drugs that alter autoreceptor signals provide a false feedback signal, prompting the presynaptic cell to release more or less transmitter.

Question 132

Botox—botulinum toxin

Answer 132

Some toxins prevent the release of specific kinds of transmitters. For instance, the active ingredient in Botox—botulinum toxin, which is formed by a bacterium that multiplies in improperly canned food—binds to specialized receptors in nicotinic cholinergic membranes and is transported into the cell, where it blocks the Ca2+-dependent release of acetylcholine, resulting in muscle paralysis. The widespread paralysis that occurs after eating contaminated food can be lethal, but when the dilute toxin is selectively injected into facial muscles, the resulting local paralysis reduces wrinkling of the overlying skin.

Question 133

Tetanus - tetanospasmin

Answer 133

Tetanus (lock-jaw) bacteria produce a toxin, called tetanospasmin, that interferes with the molecular machinery that causes synaptic vesicles to bind to the presynaptic membrane. By blocking exocytosis, particularly at inhibitory synapses in the CNS, tetanospasmin causes the loss of normal inhibitory influences on motoneurons, resulting in strong involuntary contractions of the muscles.

Question 134

caffeine

Answer 134

A stimulant compound found in coffee, cacao, and other plants.
acts by blocking the autoreceptor effect of an endogenous ligand called adenosine.
So, by blocking adenosine, caffeine increases catecholamine release, resulting in arousal.

Question 135

adenosine

Answer 135

In the context of neural transmission, a neuromodulator that alters synaptic activity.
Adenosine acts as a neuromodulator: it is normally co-released with primary transmitters to control synaptic activity by inhibiting transmitter release.
(Interestingly, by a different route, the stimulant drug amphetamine also facilitates catecholamine release.)

Question 136

transmitter reuptake

Answer 136

The reabsorption of synaptic transmitter by the axon terminal from which it was released.

Question 137

transporters

Answer 137

Specialized receptors in the presynaptic membrane that recognize neurotransmitter molecules and return to the presynaptic neuron for reuse.

Question 138

degradation

Answer 138

The chemical breakdown of a neurotransmitter into inactive metabolites.

The chemical process of breaking down neurotransmitter into inactive metabolites, again allowing the transmitter to accumulate and have a greater effect on the postsynaptic cell

Question 139

Drugs may affect postsynaptic events

2 categories and 4 sub categories

Answer 139

Another powerful way for drugs to affect synaptic transmission is to modify the ability of postsynaptic neurons to respond to neurotransmitters.

Effects on Transmitter Receptors

(1) Blockade of receptors
(2) Activation of receptors

Effects on Cellular Processes

(3) Regulation of the number of postsynaptic receptors
(4) Modulation of intracellular signals

Question 140

Drugs may affect postsynaptic events
Effects on Transmitter Receptors
(2 sub categories)

Answer 140

(1) Blockade of receptors
Antipsychotic drugs block dopamine D2 receptors; curare blocks nicotinic Ach receptors.

(1) Activation of receptors
Nicotine activates ACh receptors. LSD is an agonist at some types of serotonin receptors (such as 5-HT2A receptors).

Question 141

Drugs may affect postsynaptic events

Effects on Transmitter Receptors

Blockade of receptors

Answer 141

Selective receptor antagonists bind directly to postsynaptic receptors and block them from being activated by their neurotransmitter. This can have immediate and dramatic effects.

Curare, for example, blocks the nicotinic ACh receptors found on muscles, resulting in immediate paralysis of all skeletal muscles, including those used for breathing (which is why curare is an effective arrow poison).

Question 142

Drugs may affect postsynaptic events

Effects on Transmitter Receptors

Activation of receptors

Answer 142

Selective receptor agonists bind to specific receptors and activate them, mimicking the natural neurotransmitter at those receptors. These drugs are often very potent, with effects that vary depending on the particular type of receptors activated.

LSD is an example, producing bizarre visual experiences through strong stimulation of a subtype of serotonin receptor (5HT2A receptors) found in visual cortex.

Question 143

Drugs may affect postsynaptic events

Effects on Cellular Processes
2 sub categories

Answer 143

(1) Regulation of the number of postsynaptic receptors
Alcohol up-regulates (increases) the number of receptors for GABA.
(2) Modulation of intracellular signals
Mood-stabilizer lithium has many effects, including changes in second messengers, probably leading to changes in gene expression and receptor density.

Question 144

Drugs may affect postsynaptic events

Effects on Cellular Processes

Regulation of the number of postsynaptic receptors

Answer 144

When they bind to their matching receptors on postsynaptic membranes, neurotransmitters can stimulate a variety of changes within the postsynaptic cell, such as activation of second messengers, activation of genes, and the production of various proteins. For example, some drugs induce the postsynaptic cell to up-regulate (increase) its receptors, thus changing the sensitivity of the synapse.

Question 145

Drugs may affect postsynaptic events

Effects on Cellular Processes

Modulation of intracellular signals

Answer 145

Other drugs cause a down-regulation of receptor density. Some drugs directly alter second messenger systems, with wide-spread effects in the brain; this is one of the ways in which the mood-stabilizing drug lithium chloride is believed to act. Future research will probably focus on drugs to selectively activate, alter, insert, or block targeted genes within the DNA of neurons. These genomic effects could produce profound long-term changes in the structure and function of the targeted neurons.

Question 146

Drugs That Affect the Brain Can Be Divided into Functional Classes

Answer 146

In addition to categorizing drugs on the basis of their cellular effects, we can classify them by their specific effects on behavior and therapeutic applications.

Antipsychotic
Antidepressants
Anxiolytics (Depressant)
Alcohol (Depressant)
Opiates
Δ9-tetrahydrocannabinol (THC)
Stimulants
hallucinogens

Question 147

antipsychotics

Answer 147

A class of drugs that alleviate schizophrenia.

• neuroleptics
• typical neuroleptics
• atypical neuroleptics

Question 148

neuroleptics

Answer 148

A class of antipsychotic drugs, traditionally dopamine receptor blockers.
they act as selective antagonists of dopamine D2 recep-tors in the brain.

Question 149

typical neuroleptics

Answer 149

A major class of antischizophrenic drugs that share antagonist activity at dopamine D2 receptors.
are so good at relieving the symptoms of schizophrenia that a dopaminergic explanation of the disease became dominant.

Question 150

atypical neuroleptics

Answer 150

A class of anti-schizophrenic drugs that have actions other than the dopamine D2 receptor antagonism that characterizes the typical neuroleptics.
The 1990s saw the advent of second-generation antipsychotics, known as atypical neuroleptics, which feature nondopaminergic actions, especially the blockade of certain serotonin receptors. 

These atypical neuroleptics, are claimed to reduce additional symptoms that typical neuroleptics generally do not relieve, although this claim has been disputed

Question 151

antidepressants

Answer 151

A class of drugs that relieve the symptoms of depression.
Increasing synaptic monoamine availability appears to be a key activity of all antidepressants.
- monoamine oxidase (MAO)
- tricyclic antidepressants
- selective serotonin reuptake inhibitor (SSRI)

Question 152

monoamine oxidase (MAO)

Answer 152

An enzyme that breaks down and thereby inactivates monoamine transmitters.
MAOs break down monoamine neurotransmitters at axon terminals, thereby reducing transmitter activity. By blocking this process, MAO inhibitors allow monoamine neurotransmitters to accumulate at synapses, with an associated improvement in mood.

Question 153

tricyclic antidepressants

Answer 153

A class of drugs that act by increasing the synaptic accumulation of serotonin and norepinephrine.
The second generation of antidepressants—the tricyclics—combat depression by increasing the synaptic content of the monoamines norepinephrine and serotonin. tricyclics block the reuptake of neurotransmitters into presynaptic axon terminals.

Question 154

selective serotonin reuptake inhibitor (SSRI)

Answer 154

A drug that blocks the reuptake of transmitter at serotonergic synapses.
More recently developed antidepressants
these drugs alleviate depression by selectively allowing serotonin to accumulate in synapses. These newer antidepressants lack some of the undesirable side effects of older drugs, although they have side effects of their own (such as disturbances of sexual function) and can take as long as 6–8 weeks to have full effect.

Question 155

anxiolytics

Answer 155

A class of substances that are used to combat anxiety.
Sometimes also called tranquilizers, anxiolytics belong to the general category of depressants: drugs that depress or reduce nervous system activity. Alcohol and opiates are perhaps the original anxiolytics, but their anxiety-fighting properties come at the cost of intoxication, addiction potential, and neuropsychological impairment with long-term abuse, so they are not suitable for therapeutic use.
- barbiturate
- benzodiazepine agonists
- Allopregnanolone
- The serotonergic agonist buspirone (Buspar)

Question 156

depressants

Answer 156

A class of drugs that act to reduce neural activity.

Question 157

barbiturate

Answer 157

A powerful sedative anxiolytic derived from barbituric acid, with dangerous addiction and overdose potential.
Barbiturate drugs (“downers”) were originally developed to reduce anxiety, promote sleep, and prevent epileptic seizures. They are still used for those purposes but are also addictive and easily overdosed, often fatally.

Question 158

benzodiazepine agonists

Answer 158

A class of antianxiety drugs that bind to sites on GABAA receptors

Nowadays, the safest and most specific anxiolytics are the benzodiazepine agonists, and they are among the most heavily prescribed drugs.

bind to specific sites on GABAA receptors and enhance the activity of GABA. Because GABAA receptors are inhibitory, benzodiazepines help GABA to produce larger inhibitory postsynaptic potentials than would be caused by GABA alone. This has the end result of reducing the excitability of neurons.

Question 159

Why can many different drugs can interact with GABAA receptor complex?

Answer 159

GABAA receptors have several different binding sites—some that
facilitate and some that inhibit the effect of GABA

Question 160

orphan receptor

Answer 160

Any receptor for which no endogenous ligand has yet been discovered.

For example, benzodiazepines bind to a unique modulatory site on the receptor complex that is distant from where GABA itself binds. The benzodiazepine-binding site is thus an orphan receptor— a receptor for which an endogenous ligand has not been conclusively identified—and the hunt for its endogenous ligand has been intense.

Question 161

allopregnanolone

Answer 161

A naturally occurring steroid that modulates GABA receptor activity in much the same way that benzodiazepine anxiolytics do.

Allopregnanolone, a steroid derived from the hormone progesterone, acts on yet another site on the GABAA receptor. Allopregnanolone is elevated during stress and has a calming effect. Alcohol ingestion also increases brain concentrations of allopregnanolone

Question 162

neurosteroids

Answer 162

Steroids produced in the brain.

Several other progesterone-like neurosteroids (steroids produced in the brain) may act on GABAA receptors to produce anxiolytic, analgesic, and anticonvulsant effects.

Question 163

Alcohol

Answer 163

The psychoactive effect of alcohol in the nervous system is biphasic: an initial stimulant phase is followed by a more prolonged depressant phase.

Alcohol activates the GABAA receptor–coupled chloride channel, thereby increasing postsynaptic inhibition. This action contributes to social disinhibition, as well as the impairment of motor coordination that occurs after a few drinks.

Alcohol also affects other transmitters. For example, low doses of alcohol stimulate dopamine pathways, and the resulting increase in dopamine may be related to the slightly euphoric feelings that many people experience when having a drink.

Chronic abuse of alcohol damages neurons. Cells of the superior frontal cortex, Purkinje cells of the cerebellum, and hippocampal pyramidal cells show particularly prominent pathological changes. Some of these degenerative effects of chronic alcohol use may be due to a secondary consequence of alcoholism: poor diet. For example, chronic alcoholism is accompanied by severe thiamine deficiency, which can lead to neural degeneration and Korsakoff’s syndrome.

The frontal lobes—especially the superior frontal association cortex—are the brain areas that are most affected by chronic alcohol use. How-ever, some of the anatomical changes associated with chronic alcoholism may be reversible with abstinence.

Question 164

fetal alcohol syndrome (FAS)

Answer 164

A disorder, including intellectual disability and characteristic facial anomalies, that affects children exposed to too much alcohol (through maternal ingestion) during fetal development.

Question 165

bingeing

Answer 165

Even in the absence of clear-cut alcoholism, periodic overconsumption of alcohol—known as bingeing—may cause brain damage. After only 4 days of bingeing on alcohol, rats exhibit neural degeneration in several areas of the brain. Damage is especially evident in the olfactory bulbs and in limbic structures connected with the hippocampus, and it is associated with impairments of cognitive ability.
Alcohol bingeing also significantly reduces the rate of neurogenesis—the formation of new neurons—in the adult hippocampus. Alcohol bingeing can depress breathing enough to kill, as happens every year to a few college students.

Question 166

opium

Answer 166

A heterogeneous extract of the seedpod juice of the opium poppy, Papaver somniferum.

Question 167

Opiates

Answer 167

The opiates morphine, heroin, and codeine bind to specific receptors—opioid receptors—that are concentrated in certain regions of the brain.

• Morphine
• Heroin
• Codeine
• endogenous opioids
  - enkephalins
  - endorphins
  - dynorphins

Question 168

morphine

Answer 168

An opiate compound derived from the poppy flower.
the major active substance in opium, is a very effective analgesic (painkiller) that has brought relief from severe pain to many millions of people. Unfortunately, morphine also has a strong potential for addiction

Question 169

analgesic

Answer 169

Referring to painkilling properties

Question 170

heroin

Answer 170

Diacetylmorphine; an artificially modified, very potent form of morphine.
has a strong potential for addiction,

Question 171

opioid receptor

Answer 171

A receptor that responds to endogenous and/or exogenous opiates.
Opioid receptors are found in the limbic and hypothalamic areas of the brain, and they are particularly rich in the locus coeruleus and in the periaqueductal gray—the gray matter that surrounds the aqueduct in the brainstem

Question 172

periaqueductal gray

Answer 172

The neuronal body-rich region of the midbrain surrounding the cerebral aqueduct that connects the third and fourth ventricles; involved in pain perception.

Injection of morphine directly into the periaqueductal gray produces strong analgesia, indicating that this is a region where morphine acts to reduce pain perception

Question 173

endogenous opioids

Answer 173

A family of peptide transmitters that have been called the body’s own narcotics. The three kinds are enkephalins, endorphins, and dynorphins.
The discovery of orphan receptors for opiates came as a surprise, and because the presence of these receptors implied that there must be an endogenous ligand produced within the body, it prompted an intense scientific effort to identify endogenous opioids.

Question 174

enkephalins

Answer 174

One of three kinds of endogenous opioids.

Question 175

endorphins

Answer 175

One of three kinds of endog-enous opioids.

Question 176

dynorphins

Answer 176

One of three kinds of endogenous opioids.

Question 177

marijuana

Answer 177

dried preparation of the Cannabis sativa plant, usually smoked to obtain THC.

Typically inhaled via smoking, marijuana contains dozens of active ingredients, chief among which is the compound Δ9-tetrahydrocannabinol (THC)

The subjective experience of marijuana use is quite variable among individuals: relaxation and mood alteration are the most frequent effects, but stimulation, hallucination, and paranoia also occur in some cases.

Sustained use of marijuana can cause addiction and accelerated cognitive decline, and frequent smoking of marijuana, as with tobacco, can contribute to respiratory diseases.

Adolescents who use marijuana are more likely to develop psychosis in adulthood
that some people are genetically vulnerable to this devastating effect of the drug

As was the case with opiates and benzodiazepines, researchers found that the brain contains cannabinoid receptors that mediate the effects of compounds like THC.

Question 178

cannabinoid receptors

Answer 178

As was the case with opiates and benzodiazepines, researchers found that the brain contains cannabinoid receptors that mediate the effects of compounds like THC. Cannabinoid receptors are concentrated in the substantia nigra, the hippocampus, the cerebellar cortex, and the cerebral cortex; other regions, such as the brainstem, show few of these receptors.

Question 179

endocannabinoid

Answer 179

An endogenous ligand of cannabinoid receptors; thus, an analog of marijuana that is produced by the brain.

The discovery of cannabinoid receptors touched off an intensive search for an endogenous ligand, and several such compounds—termed endocannabinoids—were identified. Interestingly, endocannabinoids can function as retrograde messengers, conveying messages from the postsynaptic cell to the presynaptic cell. This retrograde signal is thought to modulate the release of neurotransmitter by the presynaptic nerve terminal. The most studied endocannabinoid is anandamide.

The study of endocannabinoids will aid the search for drugs that share the beneficial effects of marijuana: relieving pain, lowering blood pressure, combating nausea, lowering eye pressure in glaucoma, and so on.

Question 180

anandamide

Answer 180

An endogenous substance that binds the cannabinoid receptor molecule.
The most studied endocannabinoid is anandamide, which has diverse
functional effects, including alterations of memory formation, appetite stimulation, reduced sensitivity to pain, and protection from excitotoxic brain damage

Question 181

Stimulants

Answer 181

Stimulants are excitatory.
They therefore have an alerting, activating effect. Many naturally occurring and artificial stimulants are widely used.
Some stimulants act directly by increasing excitatory synaptic potentials. Others act by blocking normal inhibitory processes.
-	Khat
-	Caffeine
-	amphetamine
-	nicotine
-	cocaine
-	methylphenidate (Ritalin)
-	amphetamine

Question 182

khat

Answer 182

Also spelled qat. An African shrub that, when chewed, acts as a stimulant.

Question 183

nicotine

Answer 183

A compound found in plants, including tobacco, that acts as an agonist on a large class of cholinergic receptors.

Exposed to the large surface of the lungs, the nicotine from cigarettes enters the blood and brain much more rapidly than does nicotine from other tobacco products. Nicotine in-creases heart rate, blood pressure, secretion of hydrochloric acid in the stomach, and intestinal activity. In the short run, these effects make tobacco use pleasurable. But these neural effects on body function, quite apart from the effects of tobacco tar on the lungs, make prolonged tobacco use very unhealthful. Smoking and nicotine ex-posure in adolescence has a lasting impact on attention and cognitive development, likely as a consequence of impairments of glutamatergic synapses in the prefrontal cortex

Question 184

Nicotinic receptors

Answer 184

Nicotinic receptors drive the contraction of skeletal muscles and the activation of various visceral organs, but they are also found in high concentrations in the brain, including the cortex. This is one way in which nicotine enhances some aspects of cognitive performance.

Question 185

cocaine

Answer 185

A drug of abuse, derived from the coca plant, that acts by potentiating catecholamine stimulation.

either chewed or brewed as a tea—to increase endurance, alleviate hunger, and promote a sense of well-being. This use of coca leaves does not seem to cause problems. The artificially purified coca extract cocaine, however, is a powerfully addictive alkaloid stimulant that has harmed millions of lives.

Heavy cocaine use raises the risk of serious side effects like stroke, psychosis, loss of gray matter, and severe mood disturbances. Like other psychostimulants, cocaine acts by blocking monoamine transporters, especially those for dopamine, slowing reuptake of the transmitters and therefore boosting their effects.

chronic cocaine use can provoke symptoms similar to psychosis. Cessation of cocaine use often produces very uncomfortable withdrawal symptoms: initial agitation and powerful drug cravings, followed by depression and an inability to enjoy anything else in life. Cerebral glucose metabolism is decreased for months after cocaine use is discontinued and may contribute to that depression.

Question 186

dual dependence

Answer 186

Dependence for emergent drug effects that occur only when two drugs are taken simultaneously.

in which the interaction of two (or more) drugs produces another addictive state. For example, cocaine metabolized in the presence of ethanol (alcohol) yields an active metabolite called cocaethylene, to which the user may develop an additional addiction

Question 187

amphetamine

Answer 187

A molecule that resembles the structure of the catecholamine transmitters and enhances their activity.
losely resembles that of the catecholamine transmitters (norepinephrine, epinephrine, and dopamine). Amphetamine and the even more potent methamphetamine (“meth” or “speed”) cause the release of these transmitters from presynaptic terminals even in the absence of action potentials, and when action potentials do reach the axon terminals, amphetamine also potentiates the subsequent release of transmitter.

Once transmitter has been released, amphetamine further enhances activity in two ways:

(1) by blocking the reuptake of catecholamines into the presynaptic terminal and
(2) by providing an alternative target for the enzyme (monoamine oxidase) that normally inactivates them.

Over the short term, amphetamine causes increased vigor and stamina, wakefulness, decreased appetite, and feelings of euphoria.

Addiction and tolerance to amphetamine and methamphetamine develops rapidly, requiring ever larger doses leading to sleeplessness, severe weight loss, and general deterioration of mental and physical condition.

Prolonged use of amphetamine may lead to symptoms that closely resemble those of paranoid schizophrenia: compulsive, agitated behavior and irrational suspicious-ness. In fact, some amphetamine users have been misdiagnosed as having schizophrenia. Amphetamine acts on the autonomic nervous system to produce high blood pressure, tremor, dizziness, sweating, rapid breathing, and nausea. Worst of all, people who chronically abuse speed display symptoms of brain damage long after they quit using the drug.

Question 188

hallucinogens

Answer 188

A class of drugs that alter sensory perception and produce peculiar experiences.
The effects of lysergic acid diethylamide (LSD, or acid) and related substances like mescaline (peyote) and psilocybin (“magic mushrooms”) are predominantly visual. Users often see fantastic images with intense colors, and they are often aware that these strangely altered perceptions are not real events.
Hallucinogenic agents are diverse in their neural actions. But many act as serotonin receptor agonists or partial agonists.

• (LSD) lysergic acid diethylamide
• Mescaline
• Psilocybin
• Salvia
• (PCP) phencyclidine
• Ketamine
• MDMA
• (3,4-methylenedioxymethamphetamine)

Question 189

Why is the the term hallucinogen is a misnomer?

Answer 189

Because, whereas a hallucination is a novel perception that takes place in the absence of sensory stimulation (hearing voices, or seeing something that isn’t there), the drugs in this category tend to alter or distort existing perceptions.

Question 190

LSD
lysergic acid diethylamide
(acid)

Answer 190

Also called acid. Lysergic acid diethylamide, a hallucinogenic drug.

Question 191

LSD Flashbacks

Answer 191

Former users of LSD sometimes report experiencing flashbacks—that is, having experiences as if they had taken a dose of the drug, even though they are drug-free.

Question 192

Salvia

Answer 192

Salvia is unusual among hallucinogens because it acts on the opioid kappa receptor.

Question 193

phencyclidine (PCP)

Answer 193

Also called angel dust. An anesthetic agent that is also a psychedelic drug.
(commonly known as PCP or angel dust) was developed in 1956 as a potent analgesic and anesthetic agent. Classified as a dissociative drug because it produces feelings of depersonalization and detachment from reality, it was soon dropped from use in anesthesia because it also causes agitation, excitement, delirium, hostility, and disorganization of perceptions. PCP continues to be used as a street drug, principally because of its hallucinogenic actions. But even at relatively low doses, PCP also produces numerous undesirable side effects, including combativeness and catatonia (stupor and immobility). Higher doses or repeated use can lead to long-lasting profound confusion, or convulsions and coma. The similarity
between PCP’s effects and psychosis has led some researchers to propose PCP as a chemical model of schizophrenia.

PCP antagonizes the NMDA receptor, perhaps at a special binding site, and it stimulates release of the transmitter dopamine

Question 194

dissociative drug

Answer 194

A type of drug that produces a dreamlike state in which consciousness is partly separated from sensory inputs.

Question 195

ketamine

Answer 195

A dissociative anesthetic drug, similar to PCP, that acts as an NMDA receptor antagonist.
(nicknamed Special K), is a less potent NMDA antagonist that is used as a dissociative anesthetic agent. PET studies indicate that ketamine increases metabolic activity in the prefrontal cortex
ketamine in high doses produces transient psychotic symptoms in volunteers.

Question 196

MDMA

Answer 196

Also called Ecstasy. A drug of abuse, 3,4-methylenedioxymethamphetamine.
Ecstasy is the street name for the hallucinogenic amphetamine derivative MDMA.
Major actions of MDMA in the brain include an increase in the release of serotonin, stimulation of 5HT2A receptors, and changes in the levels of dopamine and certain hormones, such as prolactin. Exactly how these activities account for the subjective effects of MDMA—positive emotions, empathy, euphoria, a sense of wellbeing, and colorful visual phenomena—remains to be established.
Several possible psychiatric and cognitive consequences of chronic MDMA use have been described, including memory disturbances
(Wareing et al., 2000) and depression (Sumnall and Cole, 2005). However, shorter-term MDMA treatment is also being studied in clinical settings, as a possible therapy for treatment-resistant posttraumatic stress disorder.

Question 197

Researchers have proposed numerous models of substance abuse and addiction
that vary in their emphasis on ____________, ____________, and ___________ factors

Answer 197

Researchers have proposed numerous models of substance abuse and addiction
that vary in their emphasis on physiological, behavioral, and environmental factors

Question 198

dependence

Answer 198

DSM Diagnosis
Also called addiction. The strong desire to self-administer a drug of abuse.
dependence is a more severe disorder than substance abuse
The essential feature of dependence on psychoactive substances (e.g.,
alcohol, tobacco, cocaine, marijuana) is a cluster of cognitive, behavioral, and physiological symptoms indicating that the person continues use of the substance despite significant substance-related problems.
To be diagnosed as dependent, a person must meet a certain number of criteria relating to patterns of consumption, craving, expenditure of time and energy in serving the addiction, and impact on the other aspects of the person’s life.

Question 199

substance abuse

Answer 199

A maladaptive pattern of substance use that has lasted more than a month but does not fully meet the criteria for dependence.
maladaptive patterns of substance use have persisted at least a month or have occurred repeatedly

Question 200

dysphoria

Answer 200

Unpleasant feelings; the opposite of euphoria.

Question 201

nucleus accumbens

Answer 201

A region of the fore-brain that receives dopaminergic innervation from the ventral tegmental area.

Question 202

insula

Answer 202

A region of cortex lying below the surface, within the lateral sulcus, of the frontal, temporal, and parietal lobes.
People suffering damage to the insula were able to effortlessly quit smoking, indicating that this brain region is also involved in addiction.

Question 203

cue-induced drug use

Answer 203

An increased likelihood to use a drug (especially an addictive drug) because of the presence of environmental stimuli that were present during previous use of the same drug.

Environmental stimuli can then become risk factors for deepening addiction or relapse: simply being in a setting where a person previously used drugs can trigger drug craving in that person.

It is not limited to longer-term users; in rats, exposure to environmental stimuli that were present during their very first cocaine treatment.

Question 204

THE MORAL MODEL

perspective on drug abuse

Answer 204

The earliest approach to explaining drug abuse was to simply blame the substance abuser for a failure of moral character or a lack of self-control.
Explanations of this sort often have a religious aspect and hold that only divine help will free a person from addiction.
Applications based on the moral model can occasionally be effective.

Question 205

Any comprehensive model of drug abuse has to answer several difficult questions:
(4)

Answer 205

(1) What social and environmental factors in a person’s life cause her to start abusing a substance?
(2) What factors cause her to continue?
(3) What physiological mechanisms make a substance rewarding?
(4) What is addiction, physiologically and behaviorally, and why is it so hard to quit?

Question 206

THE DISEASE MODEL

perspective on drug abuse

Answer 206

According to the disease model, the person who abuses drugs requires medical treatment rather than moral exhortation or punishment. This view also justifies spending money to research drug abuse in the same way that money is spent to research other diseases. However, the term disease is usually reserved for a state in which we can identify an abnormal physical or biochemical condition that initiates the problem. No abnormal physical or biochemical condition has been found in the case of drug addiction, and the disease model is mute with respect to initial development of addiction, although mounting evidence suggests that some people are genetically more susceptible to addiction than others. Nevertheless, this model continues to appeal to many, and an intensive effort is under way to identify the physiological “switch” that establishes addiction after exposure to a drug.

A related formulation of the disease model views drug abuse as a type of self-medication, in which the addict is drawn to specific drugs in an effort to compensate for a deficiency of a corresponding endogenous substance: taking opiates to compensate for a lack of endorphins, for example.

Question 207

he Terminology of Substance-Related Disorders

Answer 207

For definitions of mental disorders, psychiatrists, psychologists, and neuroscientists rely on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).
Dependence (commonly called addiction) is a more severe disorder than substance abuse.
Males are three times more likely than females to be diagnosed, at some point in life, with substance abuse or dependence

Question 208

THE PHYSICAL DEPENDENCE MODEL

perspective on drug abuse

Answer 208

The physical dependence model, sometimes called the withdrawal avoidance model, argues that people keep taking drugs in order to avoid unpleasant withdrawal symptoms.
The specific withdrawal symptoms depend on the drug, but they are often the opposite of the effects produced by the drug itself.
Whereas most drugs of abuse produce pleasurable feelings, withdrawal usually induces the opposite: dysphoria.
The model does a good job of explaining why addicts will go to great lengths to obtain their addicted drug, but it has an important shortcoming: it can’t explain how the addiction gets established in the first place. Why do some people, but not all, start to abuse a drug before physical dependence (tolerance) has ever developed? And how is it that some people can become addicted to some drugs even in the absence of clear physical withdrawal symptoms?

Question 209

THE POSITIVE REWARD MODEL

perspective on drug abuse

Answer 209

The positive reward model of addictive behavior proposes that people get started with drug abuse, and become addicted, because the abused drug provides powerful reinforcement. Using a self-administration apparatus that allows animals to administer drugs to themselves, it is possible to quantify the motivation of animals to consume drugs.

Furthermore, even animals that are not already morphine-dependent learn to press a lever for morphine, and they will happily self-administer doses of morphine that are so low that no physical dependence ever develops. Animals will also furiously press a lever to self-administer cocaine and other stimulants that do not produce withdrawal symptoms as marked as those that opiates produce.
Experiments using drug self-administration thus suggest that by itself, the physical dependence model is inadequate to explain drug addiction, although physical dependence and tolerance may contribute to drug hunger.

Many addictive drugs cause the release of dopamine in the nucleus accumbens, just like more-conventional rewards such as food, sex, or winning money. interestingly, dopamine release is also linked to
pathological gambling. As we mentioned previously, dopamine released from axons originating from the ventral tegmental area
(VTA), part of the mesolimbocortical dopaminergic pathway, has been widely implicated in the perception of reward. Then the addictive power of drugs may come from their artificial stimulation of this pathway. When the drug hijacks this system, providing unnaturally powerful reinforcement, the user learns to associate the drug-taking behavior with that pleasure and begins seeking out drugs more and more until life’s other pleasures fade into the background.

These higher-order cognitive aspects of addiction depend on glutamatergic inputs from the prefrontal cortex, integrating aspects of memory, attention, and self-control to regulate the functioning of the dopamine reward system.

Cocaine produces long-lasting changes in dopaminergic circuitry, as well as other neurotransmitter systems in the nucleus accumbens, which seems to further augment the pleasure associated with drugs while decreasing the pleasure experienced from other behaviors. The drug’s “pathological” reinforcement of associated behaviors leads to exclusive, compulsive drug seeking. If natural activities like conversation, eating, and even sex no longer provide appreciable pleasure, addicts may seek drugs as the only source of pleasure available to them.

Question 210

4 models of substance abuse and addiction

Answer 210

THE POSITIVE REWARD MODEL
THE PHYSICAL DEPENDENCE MODEL
THE DISEASE MODEL
THE MORAL MODEL

Question 211

Why people differ in their vulnerability to drug abuse?

4 general categories

Answer 211

The individual and environmental factors that account for this differential susceptibility are the subject of active investigation; they fall into several general categories:

• Biological factors - Sex is a significant variable; males are more likely to abuse drugs than are females. There is also evidence for genetic predisposition.
• Family situation - Family breakup, a poor relationship with parents, or the presence of an antisocial sibling are associated with drug abuse.
• Personal characteristics - Certain traits, such as aggressiveness and poor emotional control, are especially associated with drug abuse. Strong educational goals and maturity are associated with lower likelihood of drug abuse.
• Environmental factors - A high prevalence of drug use in the community, and especially in the peer group, predisposes an individual toward drug abuse.

Question 212

What are the ways that drug abuse and dependence can be prevented or treated?
(5 medication strategies)

Answer 212

Many of those who become dependent are able to overcome their addiction without outside help: more than 90% of ex-smokers and about half of those who recover from alcoholism appear to have quit on their own. Others gain great benefit from counseling or social interventions such as 12-step programs. For those who require medical intervention, several categories of medication are available, including the following:

• Drugs for detoxification - For example, benzodiazepines and drugs that suppress central adrenergic activity help reduce withdrawal symptoms during the early drug-free period.
• Agonist or partial agonist - analogs of the addictive drug Analogs partially activate the same mechanisms that the addictive drug activates, to help wean the individual. For example, the opioid receptor agonist methadone reduces heroin appetite and lessens withdrawal symptoms; similarly, nicotine patches.
• Antagonists to the addictive drug - Specific antagonists block the effects of an abused drug, but they also may produce harsh withdrawal symptoms.
• Reward-blocking medications - block the positive reward associated with drugs of abuse, primarily by using dopamine receptor blockers. One problem with this approach is the tendency of treatments to produce a generalized loss of pleasurable feelings.
• Anticraving medications - These medications reduce the appetite for the abused substance.

Question 213

Behavioral method of drug treatment

Answer 213

Behavioral methods often center on educational programs, peer-support systems, and therapy techniques that aim to break the learned associations between drug use, contexts, and reward.

Question 214

Problem with non-medical drug treatment

Answer 214

These approaches require a significant investment on the part of the substance abuser: he must be motivated, willing to tolerate considerable discomfort, and able to commit the time required to complete the therapy. A rapid, long-lasting, easy-to-administer pharmacological treatment would be more likely to succeed for higher-risk, low-compliance individuals.

Question 215

Drug vaccination

Answer 215

Scientists have long had tools for bending the immune system to their will so that it produces highly selective antibodies that seek out and destroy targeted substances—in it’s simplest form, that’s what we call vaccination. It turns out that it may be possible to develop vaccines against drugs like cocaine, heroin, and nicotine too.
Here the strategy is to prompt the individual’s immune system to produce antibodies that remove the targeted drugs from circulation before they ever reach the brain. The problem is that the immune system evolved to recognize large foreign proteins, not small molecules such as cocaine. The solution is to conjugate (join) molecules of the drug with a larger protein and get the immune system to react to the new combination. Just as with other forms of vaccination, the immune system has a “memory” for cocaine vaccine and continues to make the anti-cocaine antibodies. Now, when cocaine enters the bloodstream, the antibodies immediately bind to the drug molecules, forming large conglomerates that cannot reach the brain and are subsequently cleared from the body.

Question 216

vaccination

Answer 216

Injection of a foreign substance, such as deactivated viruses or conjugated molecules of drugs of abuse like cocaine, in order to provoke the production of antibodies against the foreign substance.