The document summarizes drug abuse and addiction from a neurobiological perspective. It discusses how repetitive drug use leads to adaptive changes in the brain, especially in brain circuits involved in reward and motivation. This can make drug use compulsive and difficult to stop. All addictive drugs increase dopamine levels in the brain's reward system, hijacking the brain's natural reinforcement pathways and conditioning drug-seeking behavior. Long-term drug use can cause lasting changes in the structure and function of the brain that contribute to addiction. However, treatment and abstinence can allow the brain to partially recover over time.

1. Drug Abuse - Structural
& Functional Changes
in Brain and Current
Treatment
Dr Lateef
M Khan,
Asst Prof.
Dept
Of
Pharmacology
College of
Medicine
King
Abdul
Aziz
University
Jeddah

2. Drug abuse
• Use of drugs in the ways that are not medically approved.
 Why the drugs are abused?
• Because they cause strong feelings of euphoria or alter
perception.
• However, repetitive exposure induces widespread adaptive
changes in the brain.
• As a consequence drug use may become compulsive—the
hallmark of addiction.

3. Dependence versus Addiction
 The older term "Physical dependence" is now mean as
Dependence.
 Whereas "Psychological dependence" is more simply called
Addiction.
 Every addictive drug causes its own characteristic spectrum of
acute effects, but all have in common that they induce strong
feelings of euphoria and reward.
 With repetitive exposure, addictive drugs induce adaptive
changes such as tolerance (i.e., escalation of dose to maintain
effect)

4. Drug abuse
• Drug abuse can lead to drug dependence or addiction.
• Drug dependence means that a person needs a drug to
function normally. Abruptly stopping the drug leads to
withdrawal symptoms.
• Drug addiction is the compulsive use of a substance, despite
its negative or dangerous effects.

6. Two Decades of Neurobiological
Research Have
Brought Us A New Understanding
of
Drug Abuse and Addiction, Their
Complexity and their Solutions

7. Research has revealed that addiction affects the
brain circuits involved in reward, motivation,
memory, and inhibitory control.
When these circuits are disrupted, capacity of a
person to freely choose and not to use drugs even
when it means losing everything is lost.
In fact, the inability to stop use of drugs is the
real meaning of addiction, like riding a car with
no brakes.

8. Characteristics Of Addictive Behavior
Reinforcement
•Produces pleasurable state
Compulsion or Craving
 Loss of Control
 Cannot block impulse to do behavior
Escalation
 More and more
 Negative Consequences
 Continues despite its harmful effects.

9. Development Of Addiction
 Often starts to bring pleasure or to avoid pain.
 Harmless or even beneficial if done in moderation.**
 Examples of addictive behaviors:
Gambling.
Compulsive Exercising.
Work Addiction.
Sex and love addiction.
Compulsive buying or shopping.
Internet addiction.
 Characteristics of people with addiction
Genetics, Trouble - Stress, risk-takers

10. affects
your
brain
in 3
main
areas The limbic system control our emotional responses, feeling pleasure
when we eat chocolate. The good feelings motivate - to repeat the
behavior,

11. Addiction is a developmental disease that usually begins in
adolescence. For example, 67 percent of those who try marijuana
for the first time are between the ages of 12 and 17.
Prevention efforts are therefore of primary importance—to
stop drug abuse before it ever starts.

12. Research shows that brain development continues throughout adolescence
and into early adulthood.

13. The prefrontal cortex
(white circle), which
governs judgment and
decision-making
functions, is the last part
of the brain to develop.
This may help explain why
teens, who are more prone
to participating in risk-
taking behavior, are
particularly vulnerable to
drug abuse

14. Adolescents’ brains are “wired” differently than adults.
Because the prefrontal cortex is one of the last areas of the brain to mature,
adolescents tend to use other areas of the brain – in this case emotional areas –
when making decisions.
In contrast, the prefrontal cortex, involved in reasoning and it is activated in the
adult brain.

15. Given the different physiology of adolescents’ brains, do they
react differently to substances of abuse?
Research findings point to “yes.”

16.  Animal studies show a
difference in response to drugs
of abuse in early-exposed
“adolescents.”
Rats first exposed to
nicotine as adolescents self-
administer nicotine more
often and in higher total
doses than rats first exposed
as adults.

17. Self-administration of drugs
in laboratory animals.
The pump delivers drug solution
through a catheter implanted into
a vein.
The rat will learn to press the
lever which causes activation of
the infusion pump by the
program circuitry.

18. The level of dopamine receptors in a person’s brain can influence
whether they “like or dislike” the effects of a particular drug.
It was assumed that variation in the number of
dopamine receptors in a person’s brain could
influence their response to drug exposure.
To test this, human subjects were given the
stimulant methylphenidate .
Their brains’ were imaged using PET.
They were asked whether they liked or disliked
the drug’s effects.
Those subjects who had high levels of
dopamine receptors found the experience
unpleasant, while those with lower levels of
dopamine found it more pleasurable.
This suggests that individual differences
in levels of dopamine function can
influence a person’s susceptibility to
continued drug abuse.

19. Studies have shown that
40-60 percent of the
predisposition to addiction
can be attributed to genetics

20. The prevalence of
addiction to illicit
drugs (left) and to
nicotine (right) is
higher in patients
who also suffer from
mental illnesses.

21. The converse is also
true: substance
abusers experience
higher rates of other
mental illnesses than
the general
population.

23. Theories of Drug Addiction
 McKim (1997) describes models of why people become
addicted to drugs, or engage in substance abuse:
 The physical dependency model
 The positive reinforcement model
The presence of withdrawal symptoms led to the idea that
the avoidance of withdrawal symptoms was the reason
people continued to self-administer drugs. This is the
essence of the physical dependency model

24. Physical Dependency Model
 After repeated
exposure to certain
drugs, withdrawal
symptoms appear if the
drug is discontinued.
 Therefore they are the
opposite of the effects
of the drug.
Effects of
heroin
Heroin withdrawal
symptoms
Euphoria Dysphoria
Constipation Diarrhoea & cramps
Relaxation Agitation

25. Negative reinforcement
 Withdrawal effects are unpleasant and reduction in
these effects would therefore constitute negative
reinforcement.
 Negative reinforcement could explain why addicts
continue to take the drug.
 Cocaine does not produce physical dependency
(tolerance and withdrawal symptoms) but it is more
addictive than heroin.

26. Negative reinforcement – Cont’d
 Reduction in withdrawal symptoms does not explain why
people take drugs in the first place.
 Negative reinforcement may account for initial drug
taking in some situations. For example, someone who is
suffering from unpleasant emotions may experience a
reduction in these feelings (i.e. negative reinforcement)
following drug administration

27. Positive reinforcement
 The most likely reason for drug taking involves
positive reinforcement.
 Positive Reinforcement Model
 Addictive drugs are positive reinforcers
 Behaviors associated with taking an addictive drug
(i.e. injecting or smoking it) will increase in
probability.
 One way of testing this claim is to examine the
reinforcing properties of drugs in animals

29. Drugs and Brain Reinforcement Systems
 Why humans self-administer potentially lethal drugs ?
 These chemicals activate the reinforcement system in the
brain.
 This system is normally activated by natural reinforcers such
as food, water, sex etc.
 Reinforcers are thought to increase the effect of dopamine at
receptors in the mesolimbic system which originates in the
ventral tegmental area and terminates in the nucleus
accumbens

30. Mesolimbic dopamine system as the prime target of addictive drugs.
This system originates in the ventral tegmental area (VTA), a tiny structure at the tip of the
brain stem, which projects to the nucleus accumbens, the amygdala, the hippocampus, and
the prefrontal cortex
Most projection neurons of the VTA are dopamine-producing neurons.
When the dopamine neurons of the VTA begin to fire in bursts, large quantities of dopamine
are released in the nucleus accumbens and the prefrontal cortex
Electrical stimulation of the VTA result in release of Dopamine and established the central
role of the mesolimbic dopamine system in reward processing. Systemic administration of
drugs of abuse causes release of dopamine
Addictive Drugs
Increase the Level
of Dopamine:
Reinforcement

31. Drugs and Brain Reinforcement Systems
 Cocaine is thought to cause a massive and rapid
activation of dopamine receptors in this system.
Cocaine users report that the effects are much more
intense than those produced by powerful reinforcers
such as sexual orgasm.
 All Reinforcers share one physiological effect: They
increase the release of dopamine (DA) in the nucleus
accumbens. This effect can be produced by addictive
drugs such as amphetamine, cocaine, opiates, nicotine,
alcohol, PCP, and cannabis as well as natural
reinforcers such as food, water and sexual contact.

32. Cocaaine and amphetamine increase
activation of dopamine (DA) receptors
and they act on VTA.
ismesocorticolimbic systemIf the
damaged most reinforcing drugs loose
their reinforcing effects.

33. 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.
Dopamine is a brain chemical involved in many different functions
including movement, motivation, reward — and addiction.

35. Dopamine
The brain’s reward system
It’s like chocolate
for the brain
How you feel when something good
happens—maybe your team wins a
game or you're praised for
something you've done well—that's
your limbic system at work.
Because natural pleasures in our
lives are necessary for survival, the
limbic system creates an appetite
that drives you to seek out those
things.
The first time someone uses a drug
of abuse, he or she experiences
unnaturally intense feelings of
pleasure. The reward circuitry is
activated—with dopamine carrying
the message.

36. Nerve terminal
Synaptic cleft or
space between the
neurons
 Post-synaptic portion
of a dendrite on a
neighboring neuron.
How neurotransmission works specifically
for dopamine

37. Dopamine release into
the synapse.
It then crosses the
synaptic cleft to the second
neuron, where it binds to
and stimulates dopamine
receptors
The dopamine is then
released from the receptor
and crosses back to the
first neuron where it is
picked up by dopamine
transporters - reuptake - for
re-use

38. By
flooding
it with
dopamine
Drugs
hijack the
reward system

39. /serotonin
Vmat
transporter
stimulation
DA/5HT
How some drugs of abuse cause dopamine release:
• opioids narcotics (activate opioid receptors)
• nicotine (activate nicotine receptors)
• marijuana (activate cannabinoid receptors)
• caffeine
• alcohol (activate GABA receptors; an inhibitory transmitter)
Drug :
• cocaine
• ritalin
vesicle Neuronal terminal

40. Opiate Link in
Brain Reward Circuitry
From Scientific American Medicine Online, 2000.From Bozarth, 1987.

42. Release DA from vesicles and reverse
transporter
Drug Types:
•Amphetamines
-methamphetamine
-MDMA (Ecstasy)
Vmat
transporter
serotonin/
DA/5HT

43. 0
100
200
300
400
500
600
700
800
900
1000
1100
0 1 2 3 4 5 hr
Time After Amphetamine
%ofBasalRelease
DA
DOPAC
HVA
Accumbens AMPHETAMINE
0
100
200
300
400
0 1 2 3 4 5 hr
Time After Cocaine
%ofBasalRelease
DA
DOPAC
HVA
Accumbens
COCAINE
0
100
150
200
250
0 1 2 3 hr
Time After Nicotine
%ofBasalRelease
Accumbens
Caudate
NICOTINE
Source: Di Chiara and Imperato
Effects of Drugs on Dopamine Release
100
150
200
250
0 1 2 3 4hr
Time After Ethanol
%ofBasalRelease 0.25
0.5
1
2.5
Accumbens
0
Dose (g/kg ip)
ETHANOL
Much greater
Activity than any
Other drug of abuse
-causes neurotoxicity

44. How does someone get addicted
to drugs?
Because of the extra dopamine, the
brain chemistry changes
The brain stops making enough of its
own dopamine
Without enough dopamine, the user
feels flat, depressed, and lifeless
The user needs more and more drugs
to feel good
The brain’s changes make the user
need the drug just to feel normal
Even if it’s ruining their life

45. Addiction is similar to other chronic diseases.
Glucose uptake in the brain and
heart - both addiction and heart
disease produce observable changes
in organ function.
The healthy organ shows greater
activity (reds and yellows) than the
diseased organ.
In drug addiction, the frontal
cortex, which is a part of the brain
associated with judgment and
decision-making, is significantly
affected.
Like heart disease, drug addiction
can be prevented and treated
successfully.
If left untreated, however, its
effects can last a lifetime

46. METH Suppresses Expression of DAT
(note: duration of use/3-20 yrs)

47. (PET) images show similar changes in brain dopamine receptors
resulting from addiction to different substances.
The reward and motor circuit
contain DA 2 receptors .
The brains of addicted
individuals show a less intense
signal, indicating lower levels of D2
receptors.
This reduction results from
repeated over-stimulation of the
dopamine receptors.
Brain adaptations such as this
contribute to the compulsion to
abuse drugs.

48. Comparison Subject METH Abuser
Dopamine Transporter Loss After
Heavy Methamphetamine Use
(PET analysis)

49. Methamphetamine abuse decreases dopamine transporter activity and compromises
mental function.

50. MOTOR FUNCTION
• Slowed gait
•Impaired balance
• Impairment correlates with damage
to dopamine system

51. Is There Recovery?
• Good News: After 2 years some
of the dopamine deficits are
recovering
• Bad News: Functional deficits
persist
• What does this mean???

52. Reward System in Addiction
Cocaine
Food
METH
Alcohol
Ability to Experience
Rewards Is Damaged
treated
More
Less

53. Get Rewired
by Drug Use
Their Brains…

54. Drug abuse changes both the structure of
the brain and its functioning.
Research in humans and in animal models
demonstrates that repeated exposure to drugs
of abuse alters brain function and behavior.
Therefore, early intervention is key—before
brain changes take hold and drug abuse
becomes compulsive.

55. Drug addiction, like other chronic diseases requires
long-term treatment to help people get to a point
where they can manage their recovery and regain their
lives.

56. Relapse is common
and similar across these
illnesses (as is
adherence to
medication).
Thus, drug addiction
should be treated like
any other chronic
illness.

57. The odds of remaining
abstinent rise if patients
have been abstinent for 1
to 3 years.
After 3 years, the
recovery remain high
and stable.
 Therefore, as with
other chronic diseases,
addiction requires an
ongoing and active
disease management
strategy.

58. It takes time, but the brain can recover.
Images of dopamine transporter
(DAT) binding in three brains:
 Healthy control (top) - strong
concentration of dopamine
transporters.
 Methamphetamine abuser one
month after discontinuing drug
abuse (middle) dramatic drop in
DAT binding.
 Methamphetamine abuser after 14
months of abstinence (bottom) -
allows a near-full return of DAT
binding to normal levels.

60. Basic research has led to the
identification of several potential
medications for drug addiction.
In addition to already approved
medications for treatment of opiate
addiction (e.g., methadone,
buprenorphine)
 New approaches - Cannabinoid
receptor system (CB1) is currently
being targeted for medications to treat
nicotine, alcohol and other drug
addictions, as well as obesity.
 Drug metabolism can also be a
factor in addiction susceptibility by
altering the pharmacokinetics and
reinforcing effects of drugs.

61. Smokers who are poor metabolizers of nicotine
smoke less and may be less vulnerable to addiction.
Medications can be developed to take advantage of
this quality.
Corticotropin releasing factor (CRF) antagonists are
being explored as possible medications as they inhibit the
stress response and the resultant drug

62. Aim of addiction
treatment is to help
people to achieve
abstinence
Secondary support services, in
addition to behavioral and
pharmacological treatment help
to connect people to needed
social, medical, and
employment services, to get
their lives back on track.

63. Conclusion
 Drugs of abuse stimulates the reward pathway in the human brain -
leading to addiction.
 Drugs of abuse can be compared with virus.
 Viruses and drugs of abuse are both foreign to humans.
 Viruses enter an animal’s cells and use the pre-existing cell “machinery”
to synthesize more viruses, thus promoting their own survival.
 As the viruses infect more and more cells, the organism may become sick
 Drugs of abuse take the advantage of an organism in a similar fashion
 These drugs enter the human brain, use and modify cell function in the
important brain structures - the reward pathway and promote its constant
use leading to modifications in behavior.