This presentation is about drug addiction. It provide good information and knowledge to the Public.

1. Adnan Khan
PhD Scholar
(Pharmacology)
Quaid-i-Azam University Islamabad
Dated: 21-10-2018
DRUG ADDICTION

2. CONTENTS
 INTRODUCTION
 NEUROBIOLOGY OF DRUG
ADDICTION
 DOPAMINERGIC PATHWAYS
 ROLE OF DOPAMINE IN DRUG
ADDICTION
 THE MECHANISTIC CLASSIFICATION
OF DRUGS OF ABUSE.
 DRUG USE TO TREAT DRUG
ADDICTION
2

3. DEFINITION
 Addiction is a medical condition or neurological
disease characterized by compulsive engagement
in rewarding stimuli, despite adverse
consequences.
OR
• Addiction is a complex disease of the brain and
body that involves compulsive use of one or more
substances despite serious health and social
consequences.
Bartum G. ketzung et al”Basic and clinical pharmacology” 12th
Edition, New York: McGraw-Hill Medical Companies, 2012;
3

4. Why drug addiction is neurological
disease ? Or why it is a disease?
4

5. It is disease because of four reasons.
 Structural and functional changes in the brain.
 Detrimental
 Having a set of sign and symptoms
 Abnormal test
5

6. POSITRON EMISSION TOMOGRAPHY
OF THE BRAIN
The neurobiology of behaviour gone awry Nora D. Volkow & Ting-Kai Li
Nature Reviews Neuroscience 5, 963-970 (December 2004).6

7. IMPORTANT TERMINOLOGY
7

8. http://hamrah.co/en/pages/what-is-addiction
TYPES OF ADDICTION
8

9. TYPES OF SUBSTANCE ADDICTION
COCAINE ADDICTION
MARIJUANA ADDICTION.
NICOTINE ADDICTION
PRESCRIPTION DRUG
ADDICTION.
ALCHOL ADDICTION
HEROIN ADDICTION
9

10. http://hamrah.co/en/pages/behavioral-addiction-types
TYPES OF BEHVIORAL
ADDICTION
10

11. SIGNS OF DRUG ADDICTION
ABUSE DESPITE HARM
DRUG TOLERANCE
APPETITE CHANGE
11
COMPULSIVE TALKING
WITH DRAWAL SYMPTOMS
MOOD SWINGS
LOSS OF INTEREST IN FAMILY,
SCHOOL OR WORK LIFE

12. MENTAL SYMTOMS OF ADDICTION
http://hamrah.co/en/pages/mental symptoms of-addiction-
12

13. FACTORS CONTRIBUTING TO
ADDICTION
http://hamrah.co/en/pages/ factors contributing to drug
addiction-
13

14. CYCLE OF ADDICTION
Tolerance
Despair
http://hamrah.co/en/pages/ factors contributing to drug
addiction-
14

15. WITHDRAWAL SYMPTOMS
WITHDRAWAL SYMPTOMS
http://hamrah.co/wp-content/uploads/2015/09/1-2-Defining-
behavior-addiction.jpg15

16. 16
DRUGS OF ABUSE AND THEIR POTENTIAL
HAZARDS
Goodman and Gilman’s, the pharmacological basis of therapeutics, 11th
edition

17. SCHEDULES OF CONTROLLED DRUGS
17

18. NEUROBIOLOGY OF DRUG
ADDICTION
18

19. REWARD
 Reward is the attractive and motivational property of a
stimulus that induces appetitive behavior also known
as approach behavior.
REWARD
19

20. TYPES OF REWARD
REWARD
PRIMARY
REWARD
INTRINSIC
REWARD
EXTRINSIC
REWARD
20
•FOOD
•WATER
•SEX
•FOOD
•WATER
•LOVE
•MONEY
•GAMBLING
•SHOPPING

21. NEUROBIOLOGY OF REWARD SYSTEM
REWARD SYSTEM
• The reward system is a group of neural
structures responsible for
a) Incentive salience (i.e., "wanting" or
desire),
b) Pleasure (i.e., "liking" or hedonic value),
c) Positive reinforcement (i.e., learning).
21

22. ANATOMY OF REWARD SYSTEM
 The reward system includes the
1) Ventral Tegmental Area (VTA)
2) Nucleus Accumbens (NA)
3) Prefrontal cortex (PFC)
22

23. BRAIN REWARD CIRCUITRY
Bartum G. ketzung et al”Basic and clinical pharmacology” 12th Edition,
New York: McGraw-Hill Medical Companies, 2012;23

24. Transcriptional and epigenetic mechanisms of addiction Alfred J.
Robison & Eric J. Nestler Nature Reviews Neuroscience 12, 623-
637 (November 2011)
BRAIN REWARD CIRCUITRY
24

25. http://www.buzzle.com/articles/structure-and-function-of-the-
nucleus-accumbens.html
BRAIN REWARD CIRCUITRY
25

26. DOPAMINERGIC PATHWAY
INVOLVED IN DRUG
ADDICTION
26

27. DOPAMINERGIC PATHWAYS
 Dopaminergic pathways, sometimes called
dopaminergic projections, are neural pathways
in the brain that transmit the neurotransmitter
dopamine from one region of the brain to
another.
27

28. TYPES OF DOPAMINERGIC
PATHWAYS
DOPAMINERGI
C PATHWAYS
MESOCORTICOLIMBIC
PROJECTION
NIGROSTRIATAL
PATHWAY
MESOLIMBIC
PATHWAY
MESOCORTICAL
PATHWAY
TUBERO
INFUNDIBULAR
PATHWAY
28

29. http://www.sovhealth.com/addiction/brain-awareness-week-
addiction-brains-reward-system/29

30. MESOLIMBIC PATHWAY
 The mesolimbic pathway, sometimes referred to as
the reward pathway, is a dopaminergic pathway in
the brain.
 The pathway connects the ventral tegmental area,
which is located in the midbrain, to the nucleus
accumbens. The mesolimbic pathway releases
dopamine into the nucleus accumbens, where it
affects motivation for rewarding stimuli.
 It is the most significant neural pathway in the brain
in which changes occur in all known forms of
addiction.
30

31. MESOLIMBIC PATHWAY
VTA
NUCLEUS
ACCUMBENS
REWARD
31

32. ROLE OF DOPAMINE IN
DRUG ADDICTION
32

33.  Dopamine in the mesolimbic system appears to play a
primary role in the expression of “reward,” but
excessive dopaminergic stimulation may lead to
pathologic reinforcement such that behavior may
become compulsive and no longer under control
 Most types of reward increase the level of dopamine in
the brain.
33
THE DOPAMINE HYPOTHESIS OFADDICTION

34. 34
 Addictive drugs, by directly increasing dopamine,
would generate a strong but inappropriate learning
signal, thus hijacking the reward system and leading to
pathologic reinforcement.
 As a consequence, behavior becomes compulsive; that
is decisions are no longer planned and under control,
but automatic, which is the hallmark of addiction.
THE DOPAMINE HYPOTHESISOFADDICTION

35. DRUG OF ABUSE INCREASE
DOPAMINE LEVEL
http://www.druglibrary.org/schaffer/heroin/ase/chap_4.html
35

36. THE MECHANISTIC CLASSIFICATION
OF DRUGS OF ABUSE.
Bartum G. ketzung et al”Basic and clinical pharmacology” 12th Edition,
New York: McGraw-Hill Medical Companies, 2012;36

37. NEUROPHARMACOLOGIC CLASSIFICATION OF
ADDICTIVE DRUGS BY PRIMARY TARGET
Bartum G. ketzung et al”Basic and clinical pharmacology” 12th
Edition, New York: McGraw-Hill Medical Companies, 2012;
37

38. DRUGS THAT ACTIVATE G IO -
COUPLED RECEPTORS
38

39. OPIODS
 Opioids is a modern term, which is used to designate all
substances, both natural and synthetic, that bind to opioid
receptors (including antagonists).
 Opioids comprise a large family of endogenous and
exogenous agonists at three G protein-coupled
receptors: the μ, κ, and δ opioid receptors
 Opioids are the most potent analgesics in clinical use;
however, their powerful rewarding properties can lead to
addiction. The scientific challenge is to retain analgesic
potency while limiting the development of tolerance,
dependence, and addiction. Both rewarding and analgesic
actions of opioids depend upon actions at the mu opioid
(MOP) receptor.
39

40. 40
 Systemic opioid reward requires MOP receptor function in the
midbrain ventral tegmental area (VTA) which contains
dopaminergic neurons. VTA dopaminergic neurons are
implicated in various aspects of reward including reward
prediction error, working memory, and incentive salience.
 In the VTA, for example, μ-opioid receptors are selectively
expressed on GABA neurons (which they inhibit), whereas κ-
opioid receptors are expressed on and inhibit dopamine neurons.
 This may explain why μ-opioid agonists cause euphoria, whereas
κ agonists induce dysphoria.
 In the VTA, μ opioids cause an inhibition of GABAergic
inhibitory interneuron, which leads eventually to a disinhibition
of dopamine neurons.
OPIODS

41. 41
OPIOD AND REWARD PATHWAY
https://www.studyblue.com/notes/note/n/biobasis-
flashcards/deck/1141080
OPIODS

42. 42
OPIOD AND REWARD PATHWAY
Opioid receptors: distinct roles in mood disorders Pierre-Eric Lutz, Brigitte L.
Kieffer, Trends in Neuroscience, Volume 36, Issue 3, p195–206, March 201

43.  The most commonly abused μ opioids include
morphine, heroin (diacetylmorphine, which is rapidly
metabolized to morphine), codeine, and oxycodone.
Meperidine abuse is common among health
professionals.
 All of these drugs induce strong tolerance and
dependence.
43
EXAMPLE OF OPIODS

44. OPIODS AND TOLERANCE
44
 Several hypotheses are given about how tolerance
develops, including
1. Opioid receptor phosphorylation (which
would change the receptor conformation).
2. Functional decoupling of receptors from G-
proteins (leading to receptor desensitization).
3. μ-opioid receptor internalization or receptor
down-regulation (reducing the number of
available receptors for morphine to act on).
4. Up regulation of the cAMP pathway (a counter
regulatory mechanism to opioid effects).

45. 45
OPIODS WITHDRAWAL SYNDROME

46. TREATMENT OF OPIOD ADDICTION
46
NALOXONE
OPIOD
OVERDOSE
METHADONE
SUBSTITUTION
THERAPY FOR
OPIOD ADDICT
BUPRENORPHINE
SUBSTITUTION
THERAPY FOR
OPIOD ADDICT

47. CANNABINOIDS
47
 A cannabinoid is one of a class of diverse chemical
compounds that acts on cannabinoid receptors in cells that
alter neurotransmitter release in the brain.
 There are two known types of cannabinoid receptors,
termed CB1 and CB2.
 The cannabinoid receptor type 1, often abbreviated as
CB1, is a G protein-coupled cannabinoid receptor located
primarily in the central and peripheral nervous system.
 The cannabinoid receptor type 2, abbreviated as CB2, is a
G protein-coupled receptor located in the immune system.

48. 48
 Both CB1 and CB2 receptors couple to inhibitory G
proteins (i.e., they all inhibit adenylyl cyclase).
 Ligands for these receptor proteins include the
Endogenous cannabinoids like 2-arachidonyl
glycerol (2-AG) and anandamide (produced naturally
in the body and Exogenous cannabinoids like the
phytocannabinoids (found in cannabis and some other
plants), and synthetic cannabinoids (manufactured
artificially).
CANNABINOIDS

49. 4949
 Exogenous cannabinoids, e.g. in marijuana , include
several pharmacologically active substances including
D 9 -tetrahydrocannabinol
 (THC) , a powerful psychoactive substance. Like
opioids, THC causes disinhibition of dopamine
neurons, mainly by pre-synaptic inhibition of GABA
neurons in the VTA.
CANNABINOIDS

50. 50
http://www.leafscience.com/2015/10/23/cannabinoids/
CANNABINOIDS

51. 51
CANNABINOIDS AND REWARD PATHWAY
Nature Medicine 12, 281 - 283 (2006

52. MARIJUANA WITHDRAWAL SYNDROME
52 Goodman and Gilman’s, the pharmacological basis of therapeutics, 11th
edition

53. HALLUCINOGENS
53
 A hallucinogen is a psychoactive agent which can cause
hallucinations, perceptual anomalies, and other substantial
subjective changes in thoughts, emotion, and
consciousness.
 LSD, mescaline, and psilocybin are commonly called
hallucinogens because of their ability to alter consciousness
such that the individual senses things that are not present.
 Hallucinogen induce often an unpredictable way,
perceptual symptoms, including shape and color distortion.
Psychosis-like manifestations (depersonalization,
hallucinations, distorted time perception) have led some to
classify these drugs as psychotomimetics.

54. 54
 They also produce somatic symptoms (dizziness,
nausea, paresthesias, and blurred vision).
 Additional studies show that these drugs also fail to
stimulate dopamine release, further supporting the idea
that only drugs that activate the mesolimbic dopamine
system are addictive. Instead, hallucinogens increase
glutamate release in the cortex, presumably by
enhancing excitatory afferent input via presynaptic
serotonin receptors (e.g., 5HT 2A ) from the thalamus.
HALLUCINOGENS

55. 55
 LSD, lysergic acid diethylamide, is perhaps the most
commonly considered drug in the hallucinogen class.
LSD was first created from ergot in 1938 by Dr. Albert
Hoffman.
 The main molecular target of LSD and other
hallucinogens is the 5-HT 2A receptor. This receptor
couples to G proteins of the G q type and generates
inositol trisphosphate (IP 3 ), leading to a release of
intracellular calcium.
HALLUCINOGENS

56. 56
Vollenweider, F.X. & Kometer, M. (2010). The neurobiology of psychedelic
drugs: implications for the treatment of mood disorders. Nature Reviews:
Neuroscience, 11: 642-51

57. DRUG THAT BIND TO
IONOTROPIC RECEPTOR ON
ION CHANNEL
57

58. NICOTINE
• Nicotine is a potent parasympathomimetic
alkaloid found in the nightshade family of plants
(Solanaceae).
• Nicotine is found in the leaves of tobacco plant
Nicotiana tabacum.
• Nicotine is a nicotinic acetylcholine receptor
(nAChR) agonist.
58

59. 59
Nicotine remains important, because:
 It is 2nd only to caffeine as the most widely used
CNS stimulant
 It 2nd only to alcohol as the most abused drug.
NICOTINE

60. NICOTINE
 Nicotine activates nicotinic receptors (particularly
α4β2 nicotinic receptors) on neurons that
innervate the ventral tegmental area and within
the mesolimbic pathway where it appears to
cause the release of dopamine.
 These actions are largely responsible for the
strongly reinforcing effects of nicotine, which
often occur in the absence of euphoria
60

61. 61
 Electrophysiological evidence suggests that
homomeric nAChRs made exclusively of α7 subunits
also contribute to the reinforcing effects of nicotine.
 These receptors are mainly expressed on synaptic
terminals of excitatory afferents projecting onto the
dopamine neurons.
 They also contribute to nicotine-evoked dopamine
release and the long-term changes induced by the
drugs related to addiction (e.g., long-term synaptic
potentiation of excitatory inputs).

62. MECHANISM ACTION OF NICOTINE
https://openi.nlm.nih.gov/gridquery.php?simResults=P
MC3028205_dhps-2-039f1&que62

63. 63
NICOTINE
http://www.coachbh-phd.com/sample-page/science-my-job/

64. NICOTINE WITHDRAWAL SYNDROME
64
Goodman and Gilman’s, the pharmacological basis of therapeutics, 11th
edition

65. 65
TREATMENT OF NICOTINE ADDICTION
65
NICOTINE
REPLACEMENT
THERAPY
e.g. Chewing gum,
Transdermal patch
BUPROPION VARENICLINE

66. BENZODIAZEPINES
66
 Benzodiazepines are commonly prescribed as anxiolytics
and sleep medications.
 They represent a moderate risk for abuse, which has to be
weighed against their beneficial effects.
 Benzodiazepines are abused by some persons for their
euphoriant effects.
 Benzodiazepines includes Alprazolam, Clonazepam
Diazepam Lorazepam,Temazepam, Bromazepam etc.

67. 67
 The targets for benzodiazepine actions are the
γ-amino butyric acid (GABA A) receptors. (Note:
GABA is the major inhibitory neurotransmitter).
 In the central nervous system (CNS).] The GABAA
receptors are composed of a combination of five α, β,
and γ subunits that span the postsynaptic membrane.
 GABA receptors on dopamine neurons of the VTA
lack α 1 , a subunit isoform that is present in GABA
neurons nearby (i.e., interneurons).
BENZODIAZEPINES

68. 68
 The rewarding effects of benzodiazepines are,
therefore, mediated by α 1 -containing GABA A
receptors expressed on VTA neurons.
 GABA is no longer released, and benzodiazepines lose
their effect on dopamine neurons, ultimately leading to
disinhibition of the dopamine neurons.
BENZODIAZEPINES

69. BENZODIAZEPINES AND REWARD PATHWAY
69
Beyond classical benzodiazepines: novel therapeutic potential of GABAA
receptor subtypes Nature Reviews Drug Discovery

70. 70
BENZODIAZEPINES WITHDRAWAL SYNDROME
Goodman and Gilman’s, the pharmacological basis of therapeutics, 11th
edition

71. 7171
TREATMENT OF BENZODIAZEPINES ADDICTION
71
FLUMAZENIL BUSPIRONE

72. ALCOHOL
72
 Alcohol (ethanol) is regularly used by a majority of the
population in many Western countries.
 Although only a minority becomes dependent and addicted,
abuse is a very serious public health problem because of the
many diseases associated with alcoholism.
 The pharmacology of alcohol is complex, and no single
receptor mediates all of its effects. On the contrary, alcohol
alters the function of several receptors and cellular
functions, including GABA A receptors, Kir3/GIRK
channels, adenosine reuptake (through ENT1), glycine
receptor, NMDA receptor, and 5-HT 3 receptor. They are
all, with the exception of ENT1, either ionotropic receptors
or ion channels.

73. 73
 It is not clear which of these targets is responsible for
the increase of dopamine release from the mesolimbic
reward system.
 The inhibition of ENT1 is probably not responsible for
the rewarding effects (ENT1 knockout mice drink
more than controls) but seems to be involved in
alcohol dependence through an accumulation of
adenosine, stimulation of adenosine A 2 receptors, and
ensuing enhanced CREB signaling.
ALCOHOL

74. 74
ALCOHOLAND REWARD PATHWAY
74
Pharmacogenetic approaches to the treatment of alcohol addiction Markus Heilig,
David Goldman, Wade Berrettini & Charles P. O'Brien Nature Reviews Neuroscience
12, 670-684 (November 2011)

75. ALCOHOL WITHDRAWAL SYNDROME
75 https://www.pinterest.com/pin/34480753372928904/

76. 767676
TREATMENT OF ALCHOLADDICTION
76
BENZODIAZEPINES
(Oxazepam , Lorazepam) ACAMPROSATE

77. DRUG THAT BIND TO TRANSPORTERS
OF BIOGENIC AMINES
77

78. COCAINE
 Cocaine, also known as coke, is a strong
stimulant mostly used as a recreational drug.
 It is commonly snorted, inhaled, or injected into
the veins.
 It is obtained from the plant Erythroxylum coca
family Erythroxylaceae.
78

79. 79
 Cocaine is addictive due to its effect on the
reward pathway in the brain. After a short period
of use, there is a high risk that dependence will
occur.
COCAINE

80. COCAINE AND REWARD CIRCUIT
 In the central nervous system, cocaine blocks the
uptake of dopamine, nor adrenaline, and
serotonin through their respective transporters.
 The block of the dopamine transporter (DAT), by
increasing dopamine concentrations in the
nucleus accumbens, has been implicated in the
rewarding effects of cocaine.
80

81. 81
• Initially cocaine produces the intense euphoria by
prolongation of dopaminergic effects in the
brain’s pleasure system (limbic system).
• Chronic intake of cocaine depletes dopamine.
• This depletion triggers the vicious cycle of
craving for cocaine that temporarily relieves
severe depression.
COCAINE AND REWARD CIRCUIT

82. COCAINE AND REWARD CIRCUIT
Bartum G. ketzung et al”Basic and clinical pharmacology” 12th
Edition, New York: McGraw-Hill Medical Companies, 2012;82

83. COCAINE
83
 Behavioral effects result from powerful
stimulation of cortex and brain stem.
 Cocaine acutely increase mental awareness and
produces a feeling of well-being and euphoria
similar to that produced by amphetamine.
 Like amphetamine, cocaine can produce
hallucinations and delusions of paranoia or
grandiosity.
 Cocaine increases motor activity, and at high
doses, it causes tremors and convulsions,
followed by respiratory and vasomotor
depression.

84. WITHDRAWAL SYNDROME
84
Goodman and Gilman’s, the pharmacological basis of therapeutics,
11th edition

85. HARM RELATED TO DRUG ABUSE
85
LEGAL ISSUES
DRUG USE AND ACCIDENTS
SOCIAL PROBLEMS
DRUG USE AND CRIMES
MEDICAL PROBLEMS

86. STRATEGIES TO CONTROL DRUG
ABUSE
86
SOCIAL SUPPORT
DRUG EDUCATION
DETOXIFICATION
REHABILITATION
PRIMARY PREVENTION
SECONDARY PREVENTION

87. DRUG USE TO TREAT DRUG ADDICTION
Bartum G. ketzung et al”Basic and clinical pharmacology” 12th
Edition, New York: McGraw-Hill Medical Companies, 2012;
87

88. REFRENCES
 http://www.centeronaddiction.org/about
 Dreyer JL (2010). "New insights into the roles
of microRNAs in drug addiction and
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 Malenka RC, Nestler EJ, Hyman SE (2009).
"Chapter 10: Neural and Neuroendocrine
Control of the Internal Milieu". In Sydor A,
Brown RY. Molecular Neuropharmacology: A
Foundation for Clinical Neuroscience (2nd
ed.). New York: McGraw-Hill Medical. p. 266.
ISBN 978-0-07-148127-4.
88

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89

90.  Tritsch, NX; Ding, JB; Sabatini, BL (Oct 2012).
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 Goodman and Gilman's, the pharmacological basis of
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 Betram G ketzung, basic and clinical pharmacology,
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 Howland, R. D., Mycek, M. J., Harvey, R. A., &
Champe, P. C. (2006). Lippincott's illustrated reviews:
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 Rang and Dale’s, pharmacology, 6th edition.
CONT…..
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CONT…..

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 Koch T, Höllt V (2008). "Role of receptor
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CONT…..

93. 93