Here is a concise and conceptual view of Drug Addiction,explaining how physiologically and psychologically a person become addict,also what are the chemical changes in which part of brain responsible for addiction.

1. DRUG ADDICTION

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2. BSc., Pharm.D, RPh.
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3. Definitions:

 Drug Abuse:
• Drug abuse is any recurrent use of drug that is illegal
or causes harm to individual.
• Using a drug as a habit
• Use of a drug to an extent that it produces
impairment of social, psychological or physiological
functioning.
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4. Definitions:

 Tolerance:
Reduction in pharmacological effects on repeated
administration of drug, requiring escalation of dose to
maintain same effects.
 Physical Dependence:
The state of response to a drug whereby removal of
the drug evokes unpleasant symptoms, usually the
opposite of drug effects.
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5. Definitions:

 Withdrawal Symptoms ( Abstinence Syndrome) :
• Signs and symptoms that follows the abrupt
discontinuation or reduction in the use of a
substance or after blockage of the actions of a
substance with antagonists.
• Tend to be opposite to original effects of drug.
• Evidence of physical or psychological dependence.
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6. Definitions:

 Psychological Dependence:
The state of response to a drug whereby the drug
taker feels compelled to use the drug and suffers
anxiety if doesn’t take drug.
 Reinforcement:
Refers to the capacity of drugs to produce Hedonic
(pleasureable) effects that make user wish to take them
again. (Reward of Drug)
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7. Definitions:

 Drug Addicition :
Drug addiction is a chronic, relapsing disorder in
which compulsive drug-seeking and drug-taking
behavior persists despite serious negative
consequences.
 The Stages of Addiction
• Exposure
• Compulsion
• Loss of control
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9. How does a brain become
addicted….???

• A person takes a drug of abuse.
• Drug activates the same brain circuits as do behaviors
linked to survival, such as eating, bonding and sex.
• The drug causes a surge in levels of a brain chemical called
dopamine, which results in feelings of pleasure. The brain
remembers this pleasure and wants it repeated.
• Just as food is linked to survival in day-to-day living, drugs
begin to take on the same significance for the addict. The
need to obtain and take drugs becomes more important
than any other need, including truly vital behaviors like
eating. The addict no longer seeks the drug for pleasure, but
for relieving distress.
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10. How does a brain become
addicted….???

 Acutely, addictive drugs are both
• rewarding (i.e., interpreted by the brain as intrinsically
positive) and
• reinforcing (i.e.,behaviors associated with drug use tend
to be repeated).
• With repeated use, however, addictive drugs produce
molecular changes that, within a vulnerable brain,
promote continued drug-taking behavior in a manner that
becomes increasingly difficult to control. The central
feature of addiction is compulsive drug use—the loss of
control over the apparently voluntary acts of drug
seeking and drug taking.
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11. Why do some people become addict
while others do not………???????????
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12. Biochemical Mechanism
Of Drug Addiction
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13. Where Drugs Act
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15. Medial Forebrain
Bundle

 • ventral tegmental area (VTA)
 • (lateral) hypothalamus (LH)
 • nucleus accumbens (NAc)
 • frontal cortex (FC) - key portions
 - prefrontal cortex (pfc)
 - orbitofrontal cortex (ofc)
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16. Dopaminergic
Mesolimbic Pathway

 A prevailing view is that the primary brain circuits relevant to
drug addiction (responsible for activation of neurochemical
reward pathways) involve dopaminergic mesolimbic pathways.
 The mesolimbic dopamine system extends from dopamine
(DA)1 -containing cell bodies within the ventral tegmental area
(VTA) in brainstem to the nucleus accumbens (NuAcc) (part of
the basal ganglia), prefrontal cortex and amygdala.
 The hypothesis is that many abused substances (except the
benzodiazepines) enhance dopamine release in
• nucleus accumbens or
• pre- frontal cortex or both.
(Ó 2000 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 25.)
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18. Dopaminergic
Mesolimbic Pathway

 Cocaine, for example, The primary mechanism of
action believed to be related to its misuse is the
inhibition of the dopamine transporter, which is
responsible for the reuptake of dopamine into the
presynaptic nerve terminal. Inhibition of the
dopamine transporter (DAT) increases the synaptic
concentrations of dopamine, enabling more
activation of DA receptors.
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22. 
Effects of Drugs on
Dopamine Release
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23. 1100
1000
900
800
700
600
500
400
300
200
100
0
Accumbens AMPHETAMINE
0 1 2 3 4 5 hr
Time After Amphetamine
% of Basal Release
DA
DOPAC
HVA
250
200
150
100
0
NICOTINE
0 1 2 3 hr
Time After Nicotine
% of Basal Release
Accumbens
Caudate
250
200
150
100
ETHANOL
0 1 2 3 4hr
Time After Ethanol
% of Basal Release
0.25
0.5
1
2.5
Accumbens
0
Dose (g/kg ip)
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24. 
Natural Rewards Elevate
Dopamine Levels
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25. 200
150
100
50
0
FOOD
0 60 120 180
Time (min)
% of Basal DA Output
NAc shell
Empty
Box Feeding
Source: Di Chiara et al.
200
150
100
DA Concentration (% Baseline)
Scr
SEX
Mounts
Intromissions
Ejaculations
15
10
5
0
Copulation Frequency
Sample
Number
ScrScr
BasFemale 1 Present
Scr
Female 2 Present
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Source: Fiorino and Phillips
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26. Dopaminergic
Mesolimbic Pathway

 NEUROCHEMICAL REWARD PATHWAY
• The mesolimbic dopamine system, including its
projections to the nucleus accumbens, and local
GABAergic afferents, has been most clearly
associated with the habit-forming aspects of drugs of
abuse.
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27. Dopaminergic
Mesolimbic Pathway

 ANTI-REWARD SYSTEMS
• Negative reinforcement (in the form of dysphoric
affective and physical withdrawal symptoms) plays
an important.
• Hence, cessation of drug-taking results in physical
and affective motivation to take drug again and
again.
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28. Dopaminergic
Mesolimbic Pathway

Effets of chronic Drug Use
• Studies have showed that chronic administration of
drugs of abuse, among many other changes, induces
higher levels of tyrosine hydroxylase (TH), the rate-limiting
enzyme in dopamine synthesis.
• Chronic drug exposure causes:
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29. Dopaminergic
Mesolimbic Pathway

• decreased levels of neurofilament (NF) proteins
(major structural determinants of neurons)
• increased glial fibrillary acidic protein (GFAP),
which are major structural determinants of glia
within the VTA.
• Together, these neuroadaptations identified in the
VTA are suggestive of a state of neuronal injury
• reductions in NF proteins in the VTA might result in
reductions in the caliber of the neuronal processes
and possibly an overall decrease in their size.
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31. 
Biochemical Mechanism
of Drug Addiction
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33. Mechanism Of drug
Addiction

Since each addictive drug has a specific molecular target to
activate mesolimbic system,
Three classes can be distinguished:
First Group,binds Gio-coupled
receptors,eg.,Opioids,Canbinoids,LSD etc.
Second group,binds to Ion
Channels,eg.,Nicotine,Alcohol,BZD.
Third group,binds to transporters of biogenic
amines,eg.,Cocaine,amphetamine
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34. Mechanism Of drug
Addiction

The Common
Signaling Pathway
of All these drugs is:
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35. Mechanism Of drug
Addiction

Activation Of Dopamine receptors D1 D5
Activation of G Protien G s
Activation of Adenyl Cyclase
AC converts ATP into cAMP
Causes phosphorylation of cAMP dependent Protein Kinase A,DARPP-32 ( 32kDa-Dopamine
and cAMP regulated Phosphoprotein)
This phosphorylated DARPP-32 act as an inhibitor of Protein Phosphatase(dec. cAMP) such as
protein phosphatase-1 and Calcineurin
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36. Mechanism Of drug
Addiction
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Thus acting parallel to PK and Inc Phosphorylation
An amplifying mechanism.
On chronc administration these drugs inc, activity of AC in nAcc;
Morphine,for example, dec. AC
Dec. in AC leads to secondary rise in AC expression
Inc. AC exp. Leads to tolerance
On cessation of morphine excessive cAMP production occurs (withdrawal Symptoms)
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37. Mechanism Of drug
Addiction

Chronic treatment inc. amount of not only AC itself but also of other components of signaling
pathways i.e. G proteins and various PKs.
This inc. in cAMP leads to inc. in cAMP dep. PKs which control the activity of :
Ion channels (making cells more excitable)
Various Enzymes
Transcription factors ( particularly cAMP response element-binding protein CREB is
upregulated in nAcc)
CREB plays Key role in var. cAMP sig. pathways.
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38. 
And After all these
changes what
Happens………????????
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41. REFERENCES

 H.P RANG, et al.RANG AND DALE’S Pharmacology.6th edition.Churchill
livingstone.2007
 Betram G. KATZUNG.Basic and Clinincal Pharmacology.10th edition.Mc Graw
Hill.2007
 Goodman & Gillman’s Manual of Pharmacology and Therapeautics.Laurence
L.Brunton, Keith L.Parker edis.Mc Graw Hill.USA.2008
 Jennifer Chao and Eric J. Nestler. MOLECULAR NEUROBIOLOGY OF DRUG
ADDICTION. Department of Psychiatry and Center for Basic Neuroscience, The
University of Texas,Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas,
Texas.2004
 Robinson TE, Berridge KC. 2003. Addiction.Annu. Rev. Psychol. 54:25–53
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allostasis.Neuropsychopharmacology 24:97–129
 Nestler EJ, Aghajanian GK. 1997. Molecular and cellular basis of addiction. Science
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 Nestler EJ. 2001. Molecular basis of longterm plasticity underlying addiction. Nat.
 Rev. Neurosci. 2:119–28
 Foote SL, Bloom FE, Aston-Jones G.1983. Nucleus locus ceruleus: new evidence of
anatomical and physiological specificity. Physiol. Rev. 63:844–914
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