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Mind and
Brain
Psychopharmacology
Chapter 4
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Chapter Preview
 Principles
 Sites
of Psychopharmacology
of Drug Action
 Neurotransmitters
and Neuromodulators
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Routes of Administration

Intravenous (IV) Injection – injection of a substance directly into a vein.

Intraperitoneal (IP) Injection – injection of a substance into the
peritoneal cavity, the space that surrounds the stomach, intestines, liver,
and other abdominal organs.

Intramuscular (IM) Injection – injection of a substance into a muscle.

Subcutaneous (SC) Injection – injection of a substance into the space
beneath the skin

Oral Administration – administration of a substance into the mouth so
that it is swallowed.

Sublingual Administration – administration of a substance by placing
it beneath the tongue.
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Routes of Administration

Intrarectal Administration – administration of a substance
into the rectum.

Inhalation – administration of a vaporous substance into the
lungs.

Topical Administration – administration of a substance
directly onto the skin or mucous membrane.

Insufflation – sniffing drugs; contacts mucous membranes
of the nasal passages; sniffing not same as inhalation!

Intracerebral Administration – administration of a
substance directly into the brain.

Intracerebroventricular (ICV) Administration –
administration of a substance into one of the cerebral
ventricles.
Thinking about routes of drug
administration..
What
advantage is there to using a
cannula to put the drug directly into
the brain?
Copyright © 2006 by Allyn and Bacon
+ Figure 4.5 Drug Affects on Synaptic
Transmission
Monoamines
Acetylcholine
Amino Acids
Neurotransmitters
Soluble Gases
Peptides
Lipids
Nucleosides
+
Neurotransmitters and
Neuromodulators

Neurotransmitters have 2 general effects on postsynaptic
membranes

EPSP (depolarization)


IPSP (hyperpolarization)


Glutamate
GABA, glycine (spinal cord and lower brainstem)
Most of the activity of local circuits of neurons involves
balances between the excitatory and inhibitory effects of
Glutamate and GABA (info transmitted within the brain)

All sensory organs transmit information to the brain through
axons whose terminals release glutamate (except pain)
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Neurotransmitters and
Neuromodulators

All other neurotransmitters have modulating effects rather than
information-transmitting effects

Secretion of Ach activates the cerebral cortex and facilitates
learning

But the information that is learned and remembered is
transmitted by neurons that secrete glutamate and GABA

Secretion of NA increases vigilance and enhances readiness to act

Secretion of 5-HT (serotonin) suppresses certain categories of
species-typical behaviors and reduces the likelihood that the
animal acts impulsively

Secretion of DA (dopamine) activates voluntary movements (does
not specify which movements) or reinforces ongoing behaviors
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ACh

Acetylcholine (ACh)


Primary neurotransmitter secreted by efferent axons of the PNS.

All muscular movement accomplished by release of ACh

ACh found in the ganglia of the autonomic nervous system

ACh found at the target organs of the parasympathetic branch
of ANS
Major concentrations of ACh in the CNS include:

Dorsolateral Pons (role in REM sleep)

Basal Forebrain (role in learning)

Medial Septum (role in memory)
Figure 4.9 Acetylcholinergic Pathways in a Rat Brain
REM sleep
(basal
forebrain)
learning
memory
+ Figure 4.5 Drug Affects on Synaptic
Transmission
+
ACh


Nicotinic Receptor – an ionotropic ACh receptor that is stimulated
by nicotine and blocked by curare.

Muscle fibers, which must be able to contract rapidly, contain
the ionotropic nicotinic receptors

Some nicotinic receptors found at axoaxonic synapses in the
brain, where they produce presynaptic facilitation (nicotine
addiction)
Muscarinic Receptor – a metabotropic ACh receptor that is
stimulated by muscarine and blocked by atropine.

While the CNS contains both types of receptors, the muscarinic
receptors predominate
+ Figure 4.5 Drug Affects on Synaptic
Transmission
+
Monoamines

The Monoamines

A class of amines that includes indolamine, such as serotonin; and
catecholamines, such as dopamine, norepinephrine, and
epinephrine.

See Table 4.1
Catecholamines
Indolamines
Dopamine
Serotonin
Norepinephrine
Epinephrine
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DA

Dopamine (DA)

A catecholamine synthesized from L-DOPA.

DA can produce both EPSP and IPSP depending on the
postsynaptic receptor.

Functions:


Movement, attention, learning, reinforcing effects of drugs of
abuse
Major CNS dopaminergic systems include (originate in
midbrain):

Nigrostriatal System (role in movement)

Mesolimbic System (role in reinforcement/reward)

Mesocortical System (role in short-term memory, planning,
and problem solving)
Figure 4.13 Dopaminergic Pathways in a Rat Brain
Nigrostrial = cell bodies in substantia nigra send axons to striatum = movement (parkinson’s)
Mesolimbic = VTA to limbic system including NA, AMYG, & HIP (NA important for rewarding
effects of stimuli including drugs of abuse)
Mesocortical = VTA to prefrontal cortex (short-term memories, planning and problem solving)
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Parkinson’s Disease

Degeneration of DA neurons that connect the substantia
nigra with the caudate nucleus

Characterized by:


Tremors, rigidity of the limbs, poor balance, difficulty initiating
movements
Treatment: L-DOPA, DA precursor

L-DOPA passes the BBB, unlike DA

Increased DA to be released by surviving DA neurons
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DA

Dopamine receptors

Several different types

All metabotropic

2 most common:

D1 receptors


Exclusively postsynaptic
D2 receptors

Found both presynaptically and postsynaptically
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DA


Agonists:

Cocaine – blocks DA reuptake

Amphetamine – causes transporter to run in reverse

Methylphenidate (ritalin) – blocks DA reuptake
May be involved in Schizophrenia

Hallucinations, delusions, disruption of normal, logical thought

Drugs – chlorpromazine blocks D2 receptors
+ Figure 4.5 Drug Affects on Synaptic
Transmission
+
Catecholamines


Norepinephrine (NE) – one of the catecholamines

a neurotransmitter found in the brain and in the sympathetic
division of the ANS.

noradrenalin
Epinephrine – one of the catecholamines

a hormone secreted by the adrenal medulla; serves also as a
neurotransmitter in the brain.

adrenalin
+
NE

Almost every region of the brain receives input from
noradrenergic neurons

The cell bodies of the most important noradrenergic system
are located in the locus coerulus

Locus Coeruleus (LC) – a dark-colored group of
noradrenergic cell bodies located in the pons near the
rostral end of the floor of the fourth ventricle.
Figure 4.16 Noradrenergic Pathways in a Rat Brain
Increased vigilance, attentiveness to events in the environment
+
NE

Most neuron that release NE do not do
so at terminal buttons but through
axonal varicosities

Axonal Varicosities – beadlike
swellings of the axonal branches,
contains synaptic vesicles and
releases a neurotransmitter or
neuromodulator.
+
NE

Adrenergic receptors (all sensitive to NE and E)

β1- and β2-adrenergic receptors

α1- and α2-adrenergic receptors

All are metabotropic, coupled to G proteins that control
production of second messengers

All are found in various organs in addition to the brain

Adrenergic receptors produce both excitatory and inhibitory
effects but, in general, the behavioral effects of NE release are
excitatory
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5-HT

Serotonin (5-HT)

An indolamine neurotransmitter; also called 5-hydroxytryptamine.

Behavioral effects are complex


Regulation of mood

Control of eating, sleep and arousal

Regulation of pain

Dreaming
Most important clusters of serotonergic cell bodies are found in the
dorsal and medial raphe nuclei
Figure 4.18 Serotonergic Pathways in a Rat Brain
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5-HT

Like NE, 5-HT is released from varicosities rather than terminal
buttons

There are least 9 different types of 5-HT receptors

5-HT1A-1B, 5-HT1D-1F, 5-HT2A-2C and 5-HT3

all are metabotropic except the 5-HT3 receptor, which is
ionotropic

5-HT3 receptor controls a chloride channel, which means it
produces IPSPs

Drugs that inhibit the reuptake of 5-HT (SSRIs) treat mental illness


Fluoxetine – treats depression
Fenfluramine – treats obesity
+
5-HT

Several hallucinogenic drugs produce their effects by
interacting with 5-HT transmission

LSD – distortions of visual perceptions


direct agonist for 5-HT2A
MDMA (ecstasy) – NE and 5-HT agonist

Excitatory and hallucinogenic effects

Causes NE and 5-HT transporters to backwards

Can damage 5-HT neurons and cause cognitive deficits
+
GABA
Glutamate
Amino Acids
Glysine
+
Glutamate

Glutamate

An amino acid; the most important excitatory neurotransmitter in
the brain.

In addition to producing PSPs by activating postsynaptic
receptors, glutamate (and GABA) have direct excitatory and
inhibitory effects on axons; they raise or lower the threshold of
excitation, thus affecting the rate at which action potentials occur
+
Glutamate

Glutamate receptors

4 major types of glutamate receptors: 3 are ionotropic and named
after the artificial ligands that stimulate them. The other is
metabotropic (about 8 different subtypes)
1.
Metabotropic Glutamate Receptor – a category of metabotropic
receptors that are sensitive to glutamate.
2.
AMPA Receptor – an ionotropic glutamate receptor that controls
a sodium channel; stimulated by AMPA; most common.
3.
Kainate Receptor – an ionotropic glutamate receptor that
controls a sodium channel; stimulated by kainic acid.
4.
NMDA Receptor – a specialized ionotropic glutamate receptor
that controls a calcium channel that is normally blocked by
Mg2+ ions; contains at least 6 different binding sites.
+Figure 4.19 NMDA Receptor
decreased
Increased
Indirect
antagonist
4 binding sites on exterior and 2
binding sites deep in ion channel
•When channel is open both Na and
Ca ions move inside the cell, causes
depolarization
•Ca also serves as 2nd messenger
and activate enzymes important for
learning and memory
•Must also have glycine binding for
channel to open
•Also Mg ion must not be attached to
Mg binding site
•Mg repelled if membrane is
partially depolarized
•Need glutamate & depolarization
•Voltage and NTS-dependent ion
channel
+
Glutamate


PCP – angel dust

PCP, when attached to its binding site, prevents Ca from passing
into the ion channel

Not a natural ligand (not produced in the brain)
Alcohol serves as an antagonist of NMDA receptors
+
GABA

GABA (gamma-aminobutyric acid)


An amino acid; the most important inhibitory neurotransmitter
in the brain.
Two types of GABA receptors

GABAA – ionotropic; controls a chloride channel


Complex; contains at least 5 different binding sites
GABAB – metabotropic; controls a potassium channel

Can be both a postsynaptic receptor and a presynaptic
autoreceptor
+ Figure 4.20 GABA
A
Receptor
•Barbiturates, steroids and
benzodiazepines all promote
activity of GABA receptor (indirect
agonists)
•Picrotoxin inhibits activity of
GABA receptor (indirect
antagonist)
+
Glycine

Glycine


An amino acid; an important inhibitory neurotransmitter in the
lower brain stem and spinal cord.
Glycine receptor

Ionotropic; controls a chloride channel
+
Peptides
 Peptides






2 or more amino acids linked together by peptide bonds
Released from all parts of the terminal button, not just from
active zone (only portion released into synaptic cleft
Others act on receptors belonging to neighboring cells
Most serve as neuromodulators; but some act as
neurotransmitters
Once released, they are destroyed by enzymes (no reuptake or recycling)
Sometimes co-released with a ‘classical’ neurotransmitter
+
Peptides
 Peptides


Endogenous Opioids
 A class of peptides secreted by the brain that act like
opiates (opium, morphine, heroin).
 Enkephalin – one of the endogenous opioids.
Opiate receptors
 At least 3 different types: μ(mu), δ(delta) and κ(kappa)
* Opioid refers to endogenous chemicals and opiates refers to drugs
+
Peptides
 Activation




of opiate receptors
Analgesia
Inhibits species-typical defensive response such as fleeing
and hiding
Simulates a system of neurons involved in reinforcement
(reward)
Naloxone – a drug that blocks opiate receptors; reverse
opiate intoxication.
+
Lipids
 Lipids

Endocannabinoids
 Endogenous ligand for cannabinoid receptors
 CB1 and CB2
 Both are metabotropic
 CB1 receptors found in brain (frontal cortex, anterior
cingulate cortex, basal ganglia, cerebellum,
hypothalamus and hippocampus; very low levels in the
brainstem)
 CB2 receptors found outside the brain, in cells of the
immune system
 CB1 receptors serve as presynaptic heteroreceptors
+
Endocannabinoids

Binds with THC, the active ingredient of marijuana.
 THC
 Analgesia, sedation, simulates appetite, reduces
nausea (cancer drugs), relieves asthma attacks,
decreases pressure in eye (glaucoma), reduces
symptoms of certain motor disorders
 Interferes with concentration and memory, alters
visual and auditory perception, and distorts
perceptions of the passage of time
 Anandamide
– the first cannabinoid to be
discovered.
 2-arachidonyl
glycerol (2-AG)
+
Nucleosides
Compounds that consist of a sugar molecule bound with a
purine or pyrimidine base.
 Adenosine – a nucleoside; a combination of ribose and
adenine; serves as a neuromodulator in the brain.
 Adenosine receptors are coupled to G proteins and open
potassium channels (IPSP)
 Caffeine – a drug that blocks adenosine receptors.
 Prolonged use of caffeine leads to a moderate amount of
tolerance
 Withdrawal symptoms – headaches, drowsiness,
difficulty concentrating
 Caffeine does not produce compulsive drug-taking
behaviors
 Lab animals will not self administer caffeine
+
Soluble Gases

Soluble Gases



NO and CO
Nitric Oxide (NO) – a gas produced by cells in the nervous
system; used as a means of communication between cells.

Released by diffusion as soon as it is produced

Triggers production of second messengers (cyclic GMP) in
adjacent cells
Functions:

Control of muscles in the wall of the intestines

Dilates blood vessels in brain

Stimulates the changes in blood vessels that produce penile
erections

May play a role in learning
+

Table 4.4!!!