DRUG AND SUBSTANCE ABUSE

ANATOMY AND PHYSIOLOGY OF ADDICTION

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NERVOUS SYSTEM
1.CENTRAL NERVOUS SYSTEM.

2.PERIPHERAL NERVOUS SYSTEM.

A. AUTONOMIC NERVOUS SYSTEM.
i. SYMPATHETIC SYSTEM.
ii. PARASYMPATHETIC SYSTEM.
B. SOMATIC NERVOUS SYSTEM.
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Neuronal structure

(receiving)

(sending)

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 The Neuron: How the Brains
Messaging System Works
Dendrites

Cell body Axon

(the cells life
support
center) Terminal
branches of
axon
Neuronal Impulse

Myelin
sheath

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Donald Bliss, MAPB, Medical Illustration
Brain regions and their functions
Certain parts of the brain govern specific functions.
For example, the cerebellum is involved with coordination; the
hippocampus with memory.
Nerve cells (neurons) are the basic unit of communication in the
brain.
Information is relayed from one area of the brain to other areas
through complex circuits of interconnected neurons.
Information via electrical impulses transmitted from one neuron to
many others is done through a process called neurotransmission.

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Neurotransmission
information is communicated in the brain via a process called
neurotransmission.
Neurotransmission involves a variety of chemical substances called
neurotransmitters.
Neurotransmitters are endogenous chemicals which transmit signals from
a neuron to a target cell across the synapse.
Major neurotransmitters:
glutamate, aspartame
Monoamines: dopamine (DA), epinephrine (adrenaline), serotonin,
acetylcholine, adenosine, nitric oxide.

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 One such neurotransmitter is called dopamine.
In the normal communication process, dopamine is released by a
neuron into the synapse (the small gap between neurons).
The dopamine then binds with specialized proteins called dopamine
receptors on the neighboring neuron, thereby sending a signal to
that neuron.
After the signal is sent to the neighboring neuron, dopamine is
transported back to the neuron from which it was released by
another specialized protein, the dopamine transporter
Drugs of abuse are able to interfere with this normal communication
process in the brain.

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 What is schematically illustrated in the previous slide is a nerve
terminal (top), the synaptic cleft or space between the neurons,
and the post-synaptic or receiving portion of a dendrite on a
neighboring neuron.
Dopamine is contained in vesicles (round storage sites) in the
nerve terminal; dopamine receptors are present on the
receiving (bottom) neuron.

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NEUROTRANSMITTERS
EXCITATORY TRANSMITTERS.
GLUTAMATE, ASPARTATE.
INHIBITORY TRANSMITTERS.
GABA, GLYCINE.
OTHERS.
NORADRENALINE, ADRENALINE, DOPAMINE, SEROTONIN,
ACTYLCHOLINE, HISTAMINE, ENDOCANNOBINOIDS -
ENDOGENOUS OPIOID PEPTIDES - ENKEPHALINS,
ENDORPHINS, DYNORPHINS.

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Below, you will find a pictoral summary of the behaviors that are
controlled by dopamine, serotonin, and norepinephrine.

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As neurotransmitters, each one of these molecules undergo a similar life
cycle:
1.Synthesis: Neurotransmitters are synthesized by the enzymatic
transformation of precursors.
2.Storage: They are packaged inside synaptic vesicles. These vesicles vary in
size, depending on the size of the neurotransmitter.
3.Release: The neurotransmitters are released from the presynaptic terminal by
exocytosis and diffuse across the synaptic cleft to the postsynaptic membrane
4.Binding: The neurotransmitters bind to receptor proteins imbedded in the
postsynaptic cell's membrane.
5.Inactivation: The neurotransmitter is degraded either by being broken down
enzymatically, or reused by active reuptake in which case the cycle begins again

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How do drugs affect neurotransmitters
Similar to other psychoactive drugs, drugs of abuse alter the brains normal balance and
level of biochemical activity.
This can include;
i. mimicking the action of naturally occurring neurotransmitters - Some
substances imitate natural neuromediators and take their place on their receptors.
Morphine, for example, binds to the receptors for endorphin (a natural "morphine"
produced by the brain), while nicotine binds to the receptors for acetylcholine.
ii. blocking neurotransmitter action
iii. altering the normal chemical actions that mediate the transmission of information within
the brain.
iv. Other substances increase the secretion of natural neuromediators. Cocaine, for
example, mainly increases the amount of dopamine in the synapses, while ecstasy
mainly increases the amount of serotonin.
The ultimate effect is to either elevate or depress activity in different brain regions.
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Drugs can be Imposters of
Brain Messages

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How are drugs able to affect brain chemicals?
Often, the chemical structure of drugs is similar to brain chemicals or
neurotransmitters.
Similarity in structure allows them to be recognized by neurons and to
alter normal brain messages.
Illustrated in the previous slide is THC, the active ingredient found in
marijuana.
Its chemical structure is highly similar to anandamide, which is
involved in a variety of functions including regulation of pain,
appetite, memory, and mood.

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YOUR BRAIN ON DRUGS

All addictive drugs produce their effects by altering the

synaptic activity.
Drugs can alter important brain areas. Brain areas
affected by drug abuse include reward circuit which
controls:
ability to feel pleasure
Feeling pleasure motivates us to repeat behavior
responsible for our perception of other emotions, both
positive and negative
forebrain, the thinking center of the brain, powers our ability
to think, plan, solve problems, and make decisions.
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THE REWARD PATHWAY
One pathway important to understanding the effects of drugs on the
brain is called the reward pathway.
The reward pathway involves several parts of the brain: the ventral
tegmental area (VTA), the nucleus accumbens, and the prefrontal
cortex.
When activated by a rewarding stimulus (e.g., food, water, sex),
information travels from the VTA to the nucleus accumbens and then
up to the prefrontal cortex.
What separates drugs of abuse from other psychoactive drugs is that
these drugs act, at least in part, on those areas of the brain that
mediate feelings of pleasure and reward.
Inducing activity in the so-called brain reward system gives drugs of
abuse positive reinforcing actions that provoke and support their
continued use and abuse. 19
 The nucleus accumbens definitely plays a central role in the reward circuit.
Its operation is based chiefly on two essential neurotransmitters: dopamine,
which promotes desire, and serotonin, whose effects include satiety and
inhibition.
But the nucleus accumbens does not work in isolation.
It maintains close relations with other centres involved in the mechanisms of
pleasure, and in particular, with the ventral tegmental area (VTA).
It is the neurons of the VTA that synthesize dopamine, which their axons
then send to the nucleus accumbens. The VTA is also influenced by
endorphins whose receptors are targeted by opiate drugs such as heroin and
morphine..

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 Another structure involved in pleasure mechanisms is the prefrontal
cortex, whose role in planning and motivating action is well established.
The prefrontal cortex is a significant relay in the reward circuit and also
is modulated by dopamine.
The locus coeruleus, an alarm centre of the brain and packed with
norepinephrine, is another brain structure that plays an important role
in drug addiction.
When stimulated by a lack of the drug in question, the locus coeruleus
drives the addict to do anything necessary to obtain a fix.

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THE MESOLIMBIC DOPAMINERGIC REWARD PATHWAY

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 TYPES OF REWARD SYSTEMS
Reward system is of 2 types.
1. Natural reward system.
2. Artificial reward system.

NATURAL rewarding stimulus (e.g., food, water, sex,

nurture) or ARTIFICIAL rewarding stimulus (e.g., drugs),
information travels from the VTA to the nucleus accumbens and
then up to the prefrontal cortex.

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 Movement

Motivation

Dopamine

Addiction Reward & well-being 24

REWARD DEFICIENCY
Prolonged drug use causes the dopamine neurons in the
reward pathway to cease functioning.
This state of dopamine deficiency causes the user to
experience chronic feelings of anxiety, depression and an
inability to just feel good.
The person can only feel normal when under the
influence of the drug.

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 How we get addicted to drugs:
The master brain chemical of addiction
Dopamine
-transmits all of the pleasure signals
Drugs modify activity of various brain chemicals that cross
pathways in the brain; dopamine could be the end result of
all the pathways
Dopamine overload (esp. feelings of euphoria and bliss)
Nearly all drugs of abuse directly or indirectly increase
dopamine in the pleasure and motivation pathways and in so
doing, alter the normal communication between neurons.
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 When a signal comes down the axon, dopamine (shown in orange)
is released into the synapse.
It then crosses the synaptic cleft to the second neuron, where it
binds to and stimulates dopamine receptors (shown in blue),
generating a signal in the second neuron.
The dopamine is then released from the receptor and crosses back
to the first neuron where it is picked up by dopamine transporters
(reuptake molecules; shown in purple) for re-use.

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dopamine
transporters

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Cocaine and neurotransmission
Drugs of abuse are able to interfere with this normal
communication process in the brain.
Cocaine, for example, blocks the removal of dopamine from
the synapse by binding to the dopamine transporters.
This results in a buildup of dopamine in the synapse. In turn,
this causes a continuous stimulation of receiving neurons,
probably responsible for the euphoria reported by cocaine
abusers.
Cocaine blocks the reuptake of dopamine

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 When a person snorts, smokes, or injects cocaine, it travels
to the brain via the bloodstream. Although it reaches all
areas of the brain, its euphoric effects are mediated in a few
specific areas, especially those associated with the reward
pathway.
These are highlighted with the turquoise sprinkles in the
next slide; the VTA, the nucleus accumbens, and the caudate
nucleus (lighter turquoise since the caudate is inside the
hemisphere).
Cocaine accumulation in other areas such as the caudate
nucleus can explain other effects such as increased
stereotypic behaviors (pacing, nail-biting, scratching, etc.).

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 The next slide shows how cocaine is able to alter activity in the
synapse.
Cocaine (shown in green), attaches to dopamine transporters
(shown in purple), thereby blocking dopamine from being taken
back up by the first neuron. Cocaine binds to the uptake pumps and
prevents them from removing dopamine from the synapse. This
results in more dopamine in the synapse, and more dopamine
receptors are activated.
Thus dopamine can continue to stimulate (maybe over-stimulate)
the receptors of the second neuron because it remains in the
synapse for a longer period of time.
This duration of stimulation and amount of dopamine in the
synapse is far greater than what normally occurs when a person
engages in an enjoyable activity (e.g., eating, sex, etc), and is what
produces cocaines intense euphoria and potential for abuse. 32
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 When dopamine binds to its receptor, another protein called a G-
protein (in pink) moves up close to the dopamine receptor.
The G-protein signals an enzyme to produce cyclic adenosine
monophosphate (cAMP) molecules (in green) inside the cell.
[Sometimes the signal can decrease production of cAMP, depending
on the kind of dopamine receptor and G-protein present.]
cAMP controls many important functions in the cell including the
ability of the cell to generate electrical impulses.

Increased cAMP produced in post-synaptic cell

The increased activation of dopamine receptors causes increased
production of cAMP inside the post-synaptic cell. This causes many
changes inside the cell that lead to abnormal firing patterns.
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 As a result of cocaine's actions in the nucleus accumbens
(the sprinkles of cocaine in the nuc. acc.), there are increased
impulses leaving the nucleus accumbens to activate the
reward system.
with continued use of cocaine, the body relies on this drug to
maintain rewarding feelings.
The person is no longer able to feel the positive
reinforcement or pleasurable feelings of natural rewards
(food, water, sex).

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OPIATES
When a person injects heroin or morphine, it too travels quickly to the
brain.
The VTA, nucleus accumbens, caudate nucleus and thalamus are
highlighted.
The opiates bind to opiate receptors that are concentrated in areas within
the reward system.
The action of opiates in the thalamus contributes to their ability to
produce analgesia.

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 Opiates binding to opiate receptors in the nucleus accumbens: increased
dopamine release
Opiates activate the reward system using the nucleus accumbens as an
example.
The action is a little more complicated than cocaine's because more than two
neurons are involved.
Three neurons participate in opiate action: the dopamine terminal, another
terminal (on the right) containing a different neurotransmitter (probably
GABA), and the post-synaptic cell containing dopamine receptors.
Opiates bind to opiate receptors (green) on the neighboring terminal and this
sends a signal to the dopamine terminal to release more dopamine.
one theory is that opiate receptor activation decreases GABA release.
GABA is a neurotransmitter which normally inhibits dopamine release, so
dopamine release is increased (if there is less GABA therefore there is more
dopamine 41
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Opiate binding in nucleus accumbens and activation of the
reward pathway
As a result of opiate actions in the nucleus accumbens , there
are increased impulses leaving the nucleus accumbens to
activate the reward system.
As with cocaine, continued use of opiates makes the body
rely on the presence of the drug to maintain rewarding
feelings and other normal behaviors. The person is no longer
able to feel the benefits of natural rewards (food, water, sex)
and can't function normally without the drug present.

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Marijuana
When a person smokes marijuana, the active ingredient, a
cannabinoid called tetrahydrocannabinol (THC), travels quickly to the
brain.
The VTA, nucleus accumbens, caudate nucleus, hippocampus, and
cerebellum are highlighted. THC binds to THC receptors that are
concentrated in areas within the reward system as well as these
other areas.
The action of THC in the hippocampus explains its ability to interfere
with memory and actions in the cerebellum are responsible for its
ability to cause uncoordination and loss of balance.
THC, is the chemical responsible for most of marijuana's
psychological effects. It acts much like the cannabinoid chemicals
made naturally by the body 45
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THC binding to THC receptors in the nucleus accumbens: increased dopamine
release
Over the last few years, there has been intense study to discover where and
how THC works.
One theory is that it acts in a similar way to opiates.
The same three neurons are probably involved: the dopamine terminal,
another terminal (on the right) containing a different neurotransmitter
(probably GABA), and the post-synaptic cell containing dopamine receptors.
THC binds to THC receptors (magenta) on the neighboring terminal and this
sends a signal to the dopamine terminal to release more dopamine.
Again, it is probably a presynaptic receptor on GABA interneurons that
controls dopamine release.

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THC binding in nucleus accumbens and activation of the reward
pathway
As a result of THC actions in the nucleus accumbens, there are
increased impulses leaving the nucleus accumbens to activate the
reward system.
Scientists still don't know how the continued use of marijuana alters
the reward system. This is an area of intense research by
neuroscientists.

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Overall summary: these drugs of abuse all activate the
reward system via increasing dopamine neurotransmission
In this next slide, the binding of all three drugs is shown in
one of the reward areas, the nucleus accumbens.
Each drug increases the activity of the reward pathway by
increasing dopamine transmission.
This happens even though the drugs act by different
mechanisms.
Because of the way our brains are designed, and because
these drugs activate a particular brain pathway for reward,
they have the ability to be abused.

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 Natural rewards stimulate dopamine neurotransmission. Eating something
that you enjoy or being stimulated sexually can cause dopamine levels to
increase.
Nearly all drugs of abuse increase dopamine neurotransmission.
It is because drugs activate these brain regionsusually more effectively and
for longer periods of time than natural rewardsthat they have an inherent
risk of being abused.

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DOPAMINE IS THE LINK IN ADDICTION
Addictive drugs are biochemically quite different
Activate different neurotransmitter systems
Produce different psychoactive effects
Heroin acts on the opiate system
Nicotine acts on the cholinergic system
Cocaine acts on dopaminergic & noradrenergic systems
All either stimulate dopamine release (heroin,
nicotine) or enhance dopamine action (cocaine) in
the nucleus accumbens.

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 But Dopamine is only Part of the Story
Scientific research has shown that other neurotransmitter
systems are also affected:
Serotonin
Regulates mood, sleep, etc.
Glutamate
Regulates learning and memory, etc.

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MEASURING BRAIN ACTIVITY IN RESPONSE TO DRUG USE
Position Emission Tomography (PET) measures emissions from radioactively
labeled chemicals that have been injected into the bloodstream, and uses the
data to produce images of the distribution of the chemicals in the body.
In drug abuse research, PET is being used for a variety of purposes including:
i. to identify the brain sites where drugs and naturally occurring
neurotransmitters act;
ii. to show how quickly drugs reach and activate receptors;
iii. to determine how long drugs occupy these receptors; and
iv. to find out how long they take to leave the brain.
v. to show brain changes following chronic drug abuse, during withdrawal
from drug use, and during the experience of drug craving.
vi. In addition, PET can be used to assess the effects of pharmacological and
behavioral therapies for drug addiction on the brain.
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 Cocaine has other actions in the brain in addition to activating the brains
reward circuitry. Using brain imaging technologies, such as PET scans, scientists
can see how cocaine actually affects brain function in people.
PET allows scientists to see which areas of the brain are more or less active by
measuring the amount of glucose that is used by different brain regions.
Glucose is the main energy source for the brain. provides energy to each
neuron so it can perform work.
When brain regions are more active, they will use more glucose and when they
are less active they will use less.
The amount of glucose that is used by the brain can be measured with PET
scans.

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Positron emission tomography (PET) scan of a
person using cocaine

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 The left scan is taken from a normal, awake person. The red color
shows the highest level of glucose utilization (yellow represents less
utilization and blue indicated the least).
The right scan is taken from someone who is on cocaine. The loss of
red areas in the right scan compared to the left (normal) scan
indicates that the brain is using less glucose and therefore is less
active. This reduction in activity results in disruption of many brain
functions.

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Implication?

Brain changes resulting from

prolonged use of drugs
may compromise
mental AND motor function.

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Their Brains

Get Rewired
by Drug Use

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