Mod 6- Introduction to the Pharmacology of CNS Drugs

Question 1

First, it is clear that nearly all drugs with CNS effects act on
specific receptorsthatmodulate synaptic transmission.

A very few
agents such as _____________may have nonspecific
actions on membranes (although these exceptions are not
fully accepted), but even these non–receptor-mediated actions
result in demonstrable alterations in synaptic transmission.

Answer 1

general anesthetics and alcohol

Question 2

The membranes of nerve cells contain two types of channels
defined on the basis of the mechanisms controlling their gating
(opening and closing): _______________

Answer 2

voltage-gated and ligand-gated channels

Question 3

_____________ respond to changes in the membrane potential of the cell.

Answer 3

Voltage-gated channels

Question 4

The_____________ described in Chapter 14 for the heart is an example of the first type of channel. In nerve cells, these channels are concentrated on the initial segment and the axon and are responsible for the fast action potential, which transmits the signal from cell body to nerve terminal.

Answer 4

voltage-gated sodium channel

Question 5

There are many types of_______________ which act on a much slower time scale and modulate the rate at which the neuron discharges.

Answer 5

** voltage-sensitive calcium and potassium channels** on the cell body, dendrites, and initial segment,

Note : For example, some types of potassium channels opened by depolarization of the cell result in slowing of further depolarization and act as a brake to limit further action potential discharge.

Question 6

Neurotransmitters exert their effects on neurons by binding to
two distinct classes of receptor.

Answer 6

1. Ligand-gated channels or ionotropic receptors
2. Metabotropic receptors

Question 7

The first class is referred to as
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

The receptor
consists of subunits, and binding of ligand directly opens the
channel,which is anintegral parts of the receptor complex (see
Figure 22–6 ).

These channels are insensitive or only weakly sensitive
to membrane potential. Activation of these channels typically results in a brief (a few milliseconds to tens of milliseconds) opening
of the channel. Ligand-gated channels are responsible for fast
synaptic transmission typical of hierarchical pathways in the CNS
(see following text).

Answer 7

ligand-gated channels , or ionotropic receptors.

Question 8

The second class of neurotransmitter receptor is referred to as
\_\_\_\_\_\_\_\_\_\_\_\_\_.

These are seven-transmembrane G
protein-coupled receptors of the type described in Chapter 2 . The
binding of neurotransmitter to this type of receptor does not result
in the direct gating of a channel.

Rather, binding to the receptor
engages a G protein, which results in the production of second messengers
that modulate voltage-gated channels. These interactions
can occur entirely with the plane of the membrane and are referred
to as membrane-delimited pathways

Answer 8

metabotropic receptors

Question 9

In this case,
the G protein (often the βγ subunit) interacts directly with the
voltage-gated ion channel.

In general, two types of voltage-gated ion
channels are the targets of this type of signaling: _______ and ___________

Answer 9

**calcium **channels
and potassium channels.

Question 10

When G proteins interact with________________ they inhibit channel function. This mechanism accounts
for the presynaptic inhibition that occurs when presynaptic
metabotropic receptors are activated.

Answer 10

calcium
channels,

Question 11

In contrast with G proteins when these receptors
are postsynaptic, they activate (cause the opening of )_________________, resulting in a slow postsynaptic inhibition.

Answer 11

potassium
channels

Question 12

Metabotropic
receptors can also **modulate voltage-gated channel**s less directly by
the \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ ( Figure 21–2 D).

Answer 12

generation of diffusible second messengers

Question 13

_______________ ( Figure 21–2 D).

A classic example Metabotropic

receptors can also modulate voltage-gated channels less directly is provided by the______________which generates cAMP via the activation of adenylyl cyclase (see

Chapter 2 ).

Answer 13

β adrenoceptor,

Question 14

Whereas membrane-delimited actions occur within microdomains in the membrane, second messenger-mediated effects can occur over considerable distances.

Finally, an important consequence of the involvement of G proteins in receptor signaling is that, in contrast to the brief effect of ionotropic receptors, the effects of metabotropic receptor activation can last_____________

Metabotropic receptors predominate in the diffuse neuronal systems in the CNS (see below).

Answer 14

tens of seconds to minutes.

Mataba!

Mabagal kasi Mataba!!!

Question 15

The events involved in synaptic
transmission can be summarized as follows.

Answer 15

An action potential in the presynaptic fiber propagates into the **synaptic terminalandactivates voltage-sensitive calciumchannels in themembrane of the terminal** (see Figure 6–3 ).

The calcium channels

• *responsible for the release of transmitter** are generally resistant **to the calcium channel-blocking agentsdiscussed in Chapter 12 (verapamil, etc) but aresensitive to blockade by certain marine toxins**
• *and metal ions** (see Tables 21–1 and 12–4 ).

Calcium flows into the terminal, and the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane.

The transmitter contained in the vesicles is released into the
synaptic cleft and diffuses to the receptors on the postsynaptic membrane.

** Binding of the transmitter to its receptorcauses abrief change **in membrane conductance (permeability to ions) of the postsynaptic cell. The time delay from the arrival of the presynaptic action potential to the onset of the postsynaptic response is approximately

Question 16

This is the
resting membrane potential of the neuron.

Answer 16

–70 mV

Question 17

Two types of pathways—
—impinge on the motor neuron.

Answer 17

excitatory and inhibitory

Question 18

When an excitatory pathway is stimulated, a ___________________is recorded.
This potential is due to the excitatory transmitter acting on an
ionotropic receptor, causing anincrease in cation permeability.
Changing the stimulus intensity to the pathway, and therefore the number of presynaptic fibers activated, results in a graded change in the size of the depolarization. When a sufficient number of excitatory fibers are activated, the excitatory postsynaptic potential depolarizes the postsynaptic cell to threshold, and an all-or-none
action potential is generated.

Answer 18

small depolarizationor excitatory postsynaptic potential (EPSP)

Question 19

When an inhibitory pathway is stimulated, the postsynaptic
membraneishyperpolarizedowing to theselective opening of
______________,producing aninhibitory postsynaptic potential
(IPSP) ( Figure 21–4 ).

However, because the equilibrium
potential for chloride is only slightly more negative than the resting potential (∼ –65 mV), the hyperpolarization is small and** contributes only modestly to the inhibitory action.**

Answer 19

chloride channels

Question 20

A second type of inhibition is_____________
It was first described for sensory fibers entering the spinal
cord, where excitatory synaptic terminals receive synapses called
axoaxonic synapses (described later). When activated, axoaxonic synapses reduce the amount of transmitter released from the terminals
of sensory fibers.

Answer 20

presynaptic inhibition.

Question 21

It is interesting that presynaptic inhibitory
receptors are **present on almost all presynaptic terminals in
the brain even though axoaxonic synapses appear to be restricted **to the _____________

In the brain, transmitter spills over to neighboring
synapses to activate the presynaptic receptors.

Answer 21

spinal cord.

Question 22

Drugs acting on the synthesis, storage, metabolism, and
release of neurotransmitters fall into the________________.

Answer 22

presynaptic category

Question 23

• *Synaptic transmission can be depressed by blockade of transmitter**
• *synthesis or storage.**

For example,____________depletes monoamine
synapses of transmitters by interfering with intracellular
storage. Blockade of transmitter catabolism inside the nerve terminal
can increase transmitter concentrations and has been
reported to increase the amount of transmitter released per
impulse.

Answer 23

reserpine

Question 24

Drugs can also alter the release of transmitters. The
stimulant _____________induces the release of catecholamines
from adrenergic synapses

Answer 24

amphetamine

Question 25

__________
causes the release of the peptide substance P from sensory neurons, and **__________________ **blocks the release of transmitters.

Answer 25

Capsaicin

** tetanus toxin**

Question 26

After a
transmitter has been released into the synaptic cleft, its action is
terminated either by uptake or by degradation.

For most neurotransmitters,
there are uptake mechanisms into the synaptic
terminaland also intosurrounding neuroglia.____________for
example, blocks the uptake of catecholamines at adrenergic synapses
and thus potentiates the action of these amines.

Answer 26

Cocaine, f

Question 27

However,
____________ is inactivated by enzymatic degradation, not
reuptake.

Answer 27

acetylcholine

**Note : **Anticholinesterases **block the degradation of acetylcholine **and thereby prolong its action.

No uptake mechanism has been found for any of the numerous CNS peptides, and it has yet to be demonstrated whether specific enzymatic degradation terminates the action of peptide transmitters.

Question 28

In the postsynaptic region, the____________ provides
the primary site of drug action. Drugs can act either as neurotransmitter
agonists, such as the opioids, which mimic the
action of enkephalin, or they can block receptor function.

Answer 28

** transmitter receptor**

Question 29

______________ is a common mechanism of action for CNS
drugs.

An example is strychnine’s blockade of the receptor for the
inhibitory transmitter glycine. This block, which underlies
strychnine’s convulsant action, illustrates how the blockade of
inhibitory processes results in excitation.

Answer 29

Receptor antagonism

Question 30

Drugs can also act
directlyon theion channel of ionotropic receptors. For example,
_______________- can enter and block the channel of many excitatory
ionotropic receptors.

Answer 30

barbiturates

Question 31

In the case of metabotropic receptors, drugs
can act at any of the steps downstream of the receptor.

Perhaps
the best example is provided by the___________ which can
modify neurotransmitter responses mediated through the secondmessenger
cAMP.

Answer 31

methylxanthines,

Note: At high concentrations, the methylxanthines

elevate the level of cAMP by blocking its metabolism and thereby
prolong its action.

Question 32

_____________ are the best documented example of such
retrograde signaling.

Answer 32

Endocannabinoids

Question 33

Most of the neuronal systems in the CNS can be divided into two
broad categories:

Answer 33

hierarchical systems and nonspecific or diffuse
neuronal systems.

Question 34

_____________ include all the pathways directly involved in sensory perception and motor control.

The pathways are generally clearly delineated, being composed of large myelinated fibers that can often conduct action potentials at a rate of more than 50 m/s.

The information is typically phasic and occurs in bursts of action potentials. In sensory systems, the information is processed sequentially by successive integrations at each relay nucleus on its way to the cortex. A lesion at any link incapacitates the system. Within each nucleus and in the cortex, there are two types of cells: relay or projection neurons and local circuit neurons ( Figure 21–6 A). The projection neurons that form the interconnecting pathways transmit signals over long distances. The cell bodies are relatively large, and their axons emit collaterals that arborize extensively in the vicinity of the neuron. These neurons are excitatory, and their synaptic influences, which involve ionotropic receptors, are very short-lived.

Answer 34

Hierarchical systems

Question 35

The excitatory transmitter released from these cells is, in most
instances, ______________

Answer 35

glutamate.

Question 36

Local circuit neurons are typically smaller
than projection neurons, and their axons arborize in the immediate
vicinity of the cell body. Most of these neurons are inhibitory,
and they release either ______________

Answer 36

GABA or glycine.

Question 37

They synapse primarily on the cell body of the projection neurons but can also synapse on the dendrites of projection neurons as well as with each other. Two common types of pathways for these neurons ( Figure 21–6 A) include______________ and _____________.

Answer 37

recurrent feedback pathways and feed-forward pathways.

Question 38

Although there is a great variety of synaptic connections in
these hierarchical systems, the fact that a limited number of transmitters
are used by these neurons indicates that any major pharmacologic
manipulation of this system will have a profound effect
on the overall excitability of the CNS.

Question 39

For instance, selectively
blocking GABA A receptors with a drug such as_______________ results
in generalized convulsions. Thus, although the mechanism of
action of picrotoxin is specific in blocking the effects of GABA,
the overall functional effect appears to be quite nonspecific,
because GABA-mediated synaptic inhibition is so widely utilized
in the brain.

Answer 39

** picrotoxin**

Question 40

Neuronal systems that contain one of the monoamines—
norepinephrine, dopamine, or 5-hydroxytryptamine (serotonin)—provide examples in this category.

Certain other pathways
emanating from the reticular formation and possibly some
peptide-containing pathways also fall into this category. These
systems differ in fundamental ways from the hierarchical systems,
and the noradrenergic systems serve to illustrate the differences.

Answer 40

Nonspecific or Diffuse Neuronal Systems

Question 41

Noradrenergic cell bodies are found primarily in a compact cell group called the locus caeruleus located in the caudal pontine central gray matter. The number of neurons in this cell group is small, approximately 1500 on each side of the brain in the rat.

Because these axons are fine and unmyelinated, they conduct very slowly, at about 0.5 m/s. The axons branch repeatedly and are extraordinarily divergent.

Branches from the same neuron can innervate several functionally different parts of the CNS.

In the neocortex, these fibers have a tangential organization and therefore can monosynaptically influence large areas of cortex.

The pattern of innervation by noradrenergic fibers in the cortex and nuclei of the hierarchical systems is diffuse, and these fibers form a very small percentage of the total number in the area.

In addition, the axons are studded with periodic enlargements called varicosities, which contain large numbers of vesicles.

In some instances, these varicosities do not form synaptic contacts, suggesting that norepinephrine may be released in a rather diffuse manner, as occurs with the noradrenergic autonomic innervation of smooth muscle. This indicates that the **cellular targets of these systems are determined largely by the location of the receptors **rather than by the location of the release sites.

Finally, most neurotransmitters
utilized by diffuse neuronal systems, including
norepinephrine, act—perhaps exclusively—on metabotropic
receptors and therefore initiate long-lasting synaptic effects.
Based on these observations, it is clear that the monoamine systems cannot be conveying topographically specific types of information; rather, vast areas of the CNS must be affected
simultaneously and in a rather uniform way. It is not surprising,
then, that these systems have been implicated in such global functions
as sleeping and waking, attention, appetite, and emotional
states.

Question 42

The amino acids of primary interest to the pharmacologist fall
into two categories: the acidic amino acid _____________ and the neutral amino acids )_____________ and _______________.

Answer 42

glutamate

glycine and GABA.

Question 43

Excitatory synaptic transmission is mediated by______________, which is present in very high concentrations in excitatory synaptic vesicles (∼100 mM).

Answer 43

glutamate

Question 44

Glutamate is released into the synaptic cleft by_______________( Figure 21–7 ). The released glutamate acts on postsynaptic glutamate receptors and is cleared by glutamate transporters present on surrounding glia.

Answer 44

Ca 2+ -dependent exocytosis

Question 45

In glia, glutamate is converted to glutamine by __________________, released from the glia, taken up by the nerve terminal, and converted back to glutamate by the enzyme glutaminase.

Answer 45

glutamine synthetase

Question 46

The high concentration of glutamate in synaptic vesicles is achieved by the ___________________

Answer 46

vesicular glutamate transporter (VGLUT).

Question 47

The high concentration of glutamate in synaptic vesicles is achieved by the __________________

Answer 47

vesicular glutamate transporter (VGLUT).

Question 48

Almost all neurons that have been tested are strongly excited by

glutamate. This excitation is caused by the activation of both
* *ionotropic and metabotropic receptors**, which have been extensively characterized by molecular cloning.

The ionotropic receptors
can be further divided into three subtypes based on the action
of selective agonists:_________, __________ and ____________.

Answer 48

1. α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA),
2. kainic acid (KA),
3. and N -methyl-D-aspartate (NMDA)

Question 49

All the ionotropic receptors are composed of four subunits.
______________, which are present on all neurons, are
heterotetramers assembled from four subunits (GluA1–GluA4).
The majority of AMPA receptors contain the GluA2 subunit and
are permeable to Na + and K + , but not to Ca 2+ . Some AMPA receptors,
typically present on inhibitory interneurons, lack the GluA2
subunit and are also permeable to Ca 2+ .

Answer 49

AMPA receptors

Question 50

_______________ are not as uniformly distributed as AMPA
receptors, being expressed at high levels in the hippocampus, cerebellum,
and spinal cord.

They are formed from a number of subunit
combinations (GluK1–GluK5). Although GluK4 and GluK5
are unable to form channels on their own, their presence in the receptor changes the receptor’s affinity and kinetics. Similar to AMPA receptors, kainate receptors are permeable to Na + and K +
and in some subunit combinations can also be permeable to Ca 2+ .

Answer 50

Kainate receptors

Question 51

________________ are as ubiquitous as AMPA receptors, being present on essentially all neurons in the CNS.

• all these require the presence of the subunit GluN1.
• The channel also contains one or two NR2 subunits (GluN2A–GluN2D).
  *

Answer 51

NMDA receptors

• Unlike AMPA and kainate receptors, all NMDA receptors are highly permeable to Ca 2+ as well as to Na + and K + . NMDA receptor function is controlled in a number of intriguing ways.

Question 52

In addition
to glutamate binding, the channel also requires the binding
of glycine to a separate site.

Question 53

Another key difference between AMPA and kainate receptors on the one hand, and NMDA receptors on the other, is that AMPA and kainate receptor activation results in channel _______________, whereas NMDA receptor activation does not.

Answer 53

opening at resting membrane potential

Note: This is due to the voltagedependent block of the NMDA pore by extracellular Mg 2+ . When the neuron is strongly depolarized, as occurs with intense activation of the synapse or by activation of neighboring synapses, Mg 2+ is expelled and the channel opens.

Question 54

Thus, there are two requirements for NMDA receptor channel opening: Glutamate must bind the receptor__________ and the __________________.

Answer 54

1. Glutamate must bind the receptor
2. membrane must be depolarized