2. What is Drug Addiction?
Modern definition of Addiction (Jaffe):
“a behavioral pattern of drug use, characterized by
1) overwhelming involvement with the use of a drug
(compulsive use)
2) the securing of its supply (compulsive drug-seeking), &
3) a high tendency to relapse after withdrawal”
3. Jellinek Typology: Subspecies
of Alcoholism
• Alpha: Psychologically-driven substance use that
may or may not lead to neuroadaptation
• Beta: Continuous heavy drinking resulting in
physical problems
• Gamma: Classic loss of control type of symptom
profile
• Delta: Inability to stop drinking; continual
drinking to avoid withdrawal symptoms
• Epsilon: Binge/episodic pattern of drinking
4. Cloninger et al.: Type I and II
• Type I:
• Mild to severe alcohol use
• Relatively high socioeconomic status
• Maternal alcohol use
• No criminality among fathers
• More responsive to environmental influence
• Relatively mild alcohol problems
• Late age of onset (>25 years)
• Type II:
• Positive family history of alcohol use
• Severe alcohol problems
• Other drug use
• Early onset (<25 years)
5. Babor: Type A and B
• Type A:
• Late age of onset
• Fewer childhood behavior problems
• Less psychopathology
• Type B:
• Childhood behavior problems
• Family history of alcohol use
• Early onset of alcohol problems
• More psychopathology
• More life stress
• More chronic treatment history
6. A Story
-
-
-
-
-
-
-
-
-
- Environment,
vulnerability.
choice, decision
making.
Pleasure & reward.
Motivation.
Acute abuse.
Learning,
Conditioning &
reinforcement.
Compulsive behavior.
Chronic, regular use.
Craving, with cues &
stress.
Relapse
Nurobiological
Explanation:
-Genetic aspects.
- Neuroanatomical
regions related to the
functions.
-Synaptic system:
NTS,
receptors,
Molecular changes
neuroadaptation.
-Signal transduction,
chr. ,gene,& proteins.
8. vulnerability
Env.factors—100% of cases
Genetic factors for addiction 30-60%
Drug iduced effects with some genetic factors–
100% of cases
Mary etal., neurobiology of addiction, nature neuroscience, vol8, 1450-1457
,november 2005
9. G X E
Interaction
Risk Factors for Alcoholism or
Drug Dependence
GENETIC
Specific
genes
ENVIRONMENTAL
Family, Peers
Workplace
Comorbidity
Early onset
10. The Development of
Addiction: Genetics
Inheritability has been found to range from 40-
60%
Some variability between: gender and substances
Specifically:
4-fold increased risk in 1st degree relatives
4-fold increased risk also in adopted away
children
11. Genetics: Pedigree
● Monozygotic twins have higher concordance of
addiction than dizygotic twins (the more genes
you share, the more similar your addiction
propensity)
● Men whose parents were alcoholics have an
increased likelihood of alcoholism even when
adopted and raised by non-alcoholic parents
from birth.
● specific alleles for the genes encode alcohol
dehydrogenase ADH1B and acetaldehyde
dehydrogenase ALDH 2 (enzymes involved in
metabolism of alcohol) are reportedly protective
against alcoholism
12. Genetics: The Genome
● A single nucleotide polymorphism in the gene
encoding fatty acid amide hydrolase has been
associated with increased recreational and problem
use of drugs or alcohol.
● A Leu7Pro polymorphism of the neuropeptide Y gene
has been correlated with increased alcohol
consumption
● Single nucleotide polymorphisms of the gene
encoding the mu-opioid receptor correlates with an
increased likelihood of heroin abuse
● Genes that affect metabolism of drugs/alcohol/nicotine
affect propensity for dependence
13. Genetics: The Genome
● Similarly polymorphisms in the genes for cytochrome P450
2A6 and 2D6 (enzymes involved in nicotine and opiod
metabolism respectively) are protective against nicotine
addiction.
.
● For example associations have been reported between
alcoholism and the genes for the GABA-A receptors,
GABRG3 and GABRA2 and between nicotine addiction and
the B3(beta3) nicotinic cholinergic receptor.
● The minor (A1) allele of the TaqIA D2 dopamine receptor
gene has been linked to severe alcoholism and
polysubstance dependence
14. Not everyone who takes a drug
once gets addicted to it.
Why?
● For one thing, some drugs seem to be
intrinsically more addicting than others.
● For another, some individuals may be
more impulsive by nature or have a
genetically dysfunctional reward
system.
15. Probability of becoming dependent when
you have tried a substance at least once
TOBACCO 32%
HEROINE 23%
COCAINE 17%
ALCOHOL 15%
STIMULANTS 11%
ANXIOLYTICS 9%
CANNABIS 9%
ANALGESIC 8%
INHALANTS 4%
16. Environmental factors
● Structural factors:-(low socioeconomic status,)
● Proximal factors:- ( parental drug use and
dependence, poor quality of parenting, parental depression,
sibling and peer influence, licensing laws)
● Distal factors:-drug availability, school, neighbourhood
characteristics, advertising and the media.
● Stress
18. SOCIOCULTURAL FACTORS
● Culture and Ethnic Background – Norms and religious
beliefs that govern the use of alcohol and drugs and ethnic
variations the body’s rate and efficiency of metabolizing
drugs and alcohol.
● Media/Advertising – Societal emphasis on immediate
gratification and glorification of the effects of alcohol and
drug use.
● Childhood Trauma (violent, sexual)
● Learning Disorders & ADD/ADHD
● Mental Illness
■ Depression
■ Bipolar Disorder
■ Psychosis
■ ADHD
19. Developmental factors
● Initial drug exposure during adolescence is associated
with more chronic use, more intensive use, and greater
risk of substance use disorder compared with initiation at
older age.
● Normal adolescent specific behaviors ( such as risk
taking, novelty seeking, high sensitivity to peer pressure)
increase the propensity of experimenting with legal and
illegal drugs, which might reflect incomplete
development of brain regions(e.g. myelination
of frontal lobe regions) involved in executive control and
motivation processes.
20. This imbalance leads to...
risk taking
low effort - high excitement activities
interest in novel stimuli
planned thinking
impulsiveness
PFC
The DeveDevelopmental factorslopment of
Addiction: Adolescence
Amygdala
NAc
21. Stages of Addiction
Jonkman S, Kenny PJ. Molecular, cellular, and structural mechanisms of cocaine addiction: a key role for microRNAs. Neuropsychopharmacology.
2013;38:198–211
23. Stages of Addiction
Impulse control disorders are characterized by three factors:
(1) an increasing sense of tension or arousal before committing an
impulsive act;
(2) pleasure, gratification, or relief at the time of committing the act; and
(3) regret, self-reproach, or guilt following the act .
In contrast, compulsive disorders are characterized by two factors:
(1) anxiety and stress before committing a compulsive repetitive
behaviour; and
(2) Relief from the stress by performing the compulsive behaviour.
Positive reinforcement (pleasure/gratification) is more closely associated
with impulse control disorders.
Negative reinforcement (relief of anxiety or relief of stress) is more
closely associated with compulsive disorders
24. Circuitry of impulsivity and
reward.
The “bottom-up” circuit that drives impulsivity is a loop with
projections from the ventral striatum to the thalamus, from the
thalamus to the ventro-medial prefrontal cortex (VMPFC), and
from the VMPFC back to the ventral striatum. This circuit is
usually modulated “top-down” from the prefrontal cortex (PFC).
If this top-down response inhibition system is inadequate or is
overcome by activity from the bottom-up ventral striatum,
impulsive behaviours may result
ACC
VMPFC
VENTRAL
SRIATUM
THALAMUS
25. Circuitry of compulsivity and
motor response inhibition
The “bottom-up” circuit that drives compulsivity is a loop with
projections from the dorsal striatum to the thalamus, from the
thalamus to the orbitofrontal cortex (OFC), and from the OFC back
to the dorsal striatum. This habit circuit can be modulated “top-
down” from the OFC, but if this top-down response inhibition
system is inadequate or is overcome by activity from the bottom-up
dorsal striatum, compulsive behaviors may result.
OFC DORSAL
SRIATUM
THALAMUS
26. Shifting from impulsivity to
compulsivity
Drug addiction provides a good example of the shift from impulsivity to
compulsivity that comes with migration from ventral to dorsal circuits.
With chronic substance use, compulsivity may develop as an individual’s
drive turns from seeking pleasure to seeking relief from distressing
symptoms of withdrawal and anticipation of obtaining the drug.
As an individual moves from an impulsive disorder to a mixed
compulsive/ impulsive disorder, there is a shift from positive to
negative reinforcement driving the motivated behaviour and
increasing control by automated prepotent responses. As these
arguments illustrate, drug addiction can best be conceptualized as a
disorder that progresses from impulsivity to compulsivity in a cycle
comprised of three stages:
30. Neural locations and functions
● PFC
● OFC
● Anterior
cingulate
-Executive, decision making and goal
directed functions
-Associative learning,
integration of emotion and drive,
Assessment of reward value;
cue and stress induced reinstatement
-Pleasure Vs Pain,
attentional processing,
emotional learning,
ascribing motivational values to cues.,
cue induced reinstatement.
31. Neural locations and functions
● Pre limbic cortex: the final common pathway for cue/drug
and stress induced craving, attention, working memory
● Amygdala
■ Basolateral-
● cue induced reinstatement,
● gateway for amygdala,
● emotional processing
■ Central nu + BNST(bed nucleus of the stria terminalis and central
nucleus of the amygdala) + Shell of Nu accumbens=
extended amygdala= brain stress system
● Drug/stress induced reinstatement.
32. Neural locations and functions
● Nucleus accumbens:
■ Core:
● output pathway from OFC/PFC,
● learning and conditioning;
● cue induced reinstatement.
■ Shell:
● reward responses,
● neuroadaptations,
● context based reinstatement,
33.
34. ● BRAIN PATHWAYS OF ADDICTION :
● 1. PATHWAY OF PRIMARY REWARD OR
DRUG REINFORCEMENT.
● 2. PATHWAYS OF RELAPSE :
● 1.CONDITIONED CUE - PATHWAY
● 2.DRUG PRIMED PATHWAY
● 3.STRESS PATHWAY
35. Brain Pathways of Reward and
Addiction
● Includes the hypothalamus, amygdala, hippocampus, nucleus accumbens
(NA), the ventral tegmental area (VTA), locus ceruleus and the prefrontal
cortex
Kauer JA, Malenka RC. Synaptic plasticity and addiction. Nat Rev Neurosci. 2007;8:844–858.
36. Mesolimbic pathway
The final common pathway of reinforcement and reward in the
brain is also hypothesized to be the mesolimbic dopamine
pathway .
“center of hedonic pleasure” of the brain and dopamine to be
the “neurotransmitter of hedonic pleasure.”
There are many natural ways to trigger mesolimbic dopamine
neurons to release dopamine, ranging from intellectual
accomplishments to athletic accomplishments, to enjoying a
good symphony, to experiencing an orgasm. These are
sometimes called “natural highs” .
The inputs to the mesolimbic pathway that mediate these natural
highs include a most incredible “pharmacy” of naturally
occurring substances ranging from the brain’s own
morphine/heroin (endorphins), to the brain’s own marijuana
(anandamide), to the brain’s own nicotine (acetylcholine), to the
brain’s own cocaine and amphetamine (dopamine itself).
38. • The numerous psychotropic drugs of abuse also have a
final common pathway of causing the mesolimbic pathway
to release dopamine, often in a manner more explosive
and pleasurable than that which occurs naturally.
• Also, it now appears that potentially maladaptive
behaviours as well as drugs can result in the release of
dopamine that in turn stimulates the reward system.
• Drugs bypass the brain’s own neurotransmitters and
directly stimulate the brain’s own receptors for these drugs,
causing dopamine to be released.
39. The Central Role of Dopamine
● Initially drives the reward pathway (phasic bursts) by
novelty.
● Provides baseline tonic drive for the whole reward
circuit.
● Involved in stimulus reward learning and stimulus
action learning.
● Provides motivational significance & incentive
salience to the reward cues.
● Error prediction signal for novelty, even later.
● The proposed reason for initial PFC hypo-function.
(PFC gating by dopamine)
The Reward Pathway
● All drugs of abuse increase dopamine levels in the brain reward
pathway although they often act through separate mechanism.
41. /serotonin
Vmat
transporter
stimulation
DA/5HT
Neuronal
terminal
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
42. • Release DA from vesicles and reverse
transporter
Drug Types:
• Amphetamines
-methamphetamine
-MDMA (Ecstasy)
Vmat
transporter
serotonin/
DA/5HT
DA/5HT
43. Neurobiological Substrates for the
Acute Reinforcing Effects of Drugs
of Abuse
Neurotransmitter
Dopamine
Opioid Peptides
GABA
Glutamate
Site
Ventral tegmental area, nucleus accumbens
Nucleus accumbens, amygdala, ventral
tegmental area
Amygdala, bed nucleus of stria terminalis
Nucleus accumbens
44. If the ventral tegmental area or nucleus
accumbens is lesioned, then animals will fail
to self-administer cocaine.
●
Extracellular dopamine release in the terminal
fields of the nucleus accumbens is significantly
enhanced during drug self-administration,
including psychostimulants, opiates, and
alcohol.
45. Converging Acute Actions of Drugs of Abuse on the
Ventral Tegmental Area and Nucleus Accumbens
From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.
46. ● Primary reinforcement by drugs of abuse engages a
widespread network of the brain's motivational pathways,
including cortical regions and limbic structures such as the
prefrontal cortex, amygdala, hippocampus, and
hypothalamus.
● For example, both acute and repeated cocaine administration
produce pronounced changes in neuronal stability in the
prefrontal cortex and changes in long-term potentiation in the
hippocampus.
● In vivo imaging studies in humans shows activation of
structures like VTA, NA, PREFRONTAL CORTEX, AMYGDALA
during drug reinforcement.
48. Learning Processes
Underlying Drug Addiction
(N. White, 1996)
● Amygdala-NAc (Incentive) – promotes
approach to and interaction with drug
related cues (produces behavior
unconsciously)
● Caudate-Putamen (Habit) – promotes
repetition of behaviors performed in the
presence of drug-related stimuli (produces
behavior unconsciously)
● Hippocampus (Declarative) – promotes
focusing of cognitive processes on drug
related situations (conscious)
50. Compulsion to seek & take the drug
natural rewards - release of DA
DA binds to receptors on post synaptic neuron
action potential is propagated - natural HIGH
DAT pumps DA back in to the cell (cocaine prevents it)
DA levels in the synapse increase
receiving neuron stimulated constantly - EUPHORIA
{alteration of brain circuits – natural rewards no longer produce high}
use of drug becomes obligatory
51. Loss of control in limiting intake
After cocaine use – DA levels fall below normal
low mood
to alleviate – uses drug again
52. Tolerance
Ch use of cocaine
Continuous above normal levels of DA
Reduction in no. of DA receptors
Larger amount of drug needed to get same HIGH
53. Pathways That Underlie Relapse
● In contrast to cocaine, for most drugs of abuse, there has
been little systematic study of the circuitry that underlies
relapse triggered by cues, stress, or drug-priming.
55. Conditioned Cue-Induced Relapse
● through a process of associative learning, previously
neutral stimuli acquire incentive-motivational properties
during repeated pairings with consumption of an abused
drug.
● These drug-associated stimuli subsequently elicit
subjective drug desire and physiological arousal in a
manner that perpetuates a return to further drug use which
will lead to relapse. :
● abstinent cocaine abusers report intense subjective
craving and autonomic arousal when exposed to cocaine-
paired stimuli, such as white powder, individuals with
whom they shared the cocaine-taking experience, and
other conditioned stimuli.
56. ● Particular interest has been the amygdala ( affective learning ).
● Lesions of the amygdala (basolateral amygdala) have no effect
on cocaine-taking during daily cocaine self-administration, but
these lesions completely abolish the reinstatement of cocaine-
seeking produced by cocaine-paired cues long after the
cessation of cocaine self-administration.
● Additional studies have demonstrated that the amygdalar
mediation of conditioned-cued reinstatement is dopamine-
dependent, in that intrabasolateral amygdala blockade of
dopamine D1 receptors abolishes cue-induced reinstatement,
while enhancing dopamine levels in the amygdala during cue
presentation will potentiate cocaine-seeking.
57. Drug-Primed Reinstatement
● The prelimbic cortex, nucleus accumbens core, and ventral
pallidum necessary for cocaine-primed reinstatement.
● One notable contrast in the neural circuitry underlying drug-
primed versus conditioned-cued reinstatement of cocaine-
seeking is the fact that amygdala inactivation has no effect on
cocaine-primed reinstatement. (no role of amygdala)
● Additional evidence suggests that other neurotransmitter
projections may drive cocaine-primed reinstatement, including
dopaminergic inputs to the infralimbic cortex and nucleus
accumbens shell.
● a critical role of cortical glutamatergic projections to the nucleus
accumbens has been established as a primary mechanism in
drug-primed reinstatement of drug-seeking.
58. Stress-Induced Reinstatement
● Prelimbic cortex , nucleus accumbens and extended amygdala
play a major role in sress induced reinstatement
● inactivation of extended amygdala structures, including the
central amygdala and bed nucleus of the stria terminalis, will
attenuate stress-induced reinstatement, while basolateral
amygdala inactivation fails to block stress-induced
reinstatement. (no role of basolateral amygdala in stress
induced reinstatement)
Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress- induced and pro-addictive behaviors. Brain Res.
2010;1314:44–55
59. The Stress Hormone Cycle
Hypothalamus
Pituitary
Gland
Adrenal
Glands
Kidneys
CRF
ACTH
CORTISOL
S
S
t
r
t
r
e
e
s
s
s
R
R
e
e
s
s
p
p
o
o
n
n
s
s
e
e
s
s
S
S
t
t
r
r
e
e
s
s
s
R
R
e
e
s
s
p
p
o
o
n
n
s
s
e
e
s
CRF:
Corticotropin
Releasing
Factor
62. CELLULAR AND MOLECULAR
SUBSTRATES OF ADDICTION:
● These changes are mainly focused Drug-induced
neuroadaptations in NA.
● (1) those associated with acute drug administration but are
short-lived,
● (2) those changes that augment with repeated administration
and gradually return to normal over the course of a few hours to
weeks, and
● (3) those adaptations that are stably manifested during drug
abstinence.
63. ● In NA most drugs of abuse induce immediate early gene
expression, including the transcriptional regulators c-fos
and NAC-1.
● And also upregulation of genes like narp, Arc, Homer1a.
● C-fos : cellular growth/differentiation.
● NAC-1 : increases dendritic spines.
● Arc : synaptic plasticity.
● Narp : synaptogenesis.
● Homer1a : post synaptic density.
Nestler EJ. Epigenetic mechanisms of drug addiction. Neuropharmacology. 2014;76
64.
65. ● The induction of cAMP response element binding
protein (CREB) by stimulating D1dopamine receptors not
only stimulates c-fos but also activates the synthesis of
ΔFosB, a transcriptional regulator that endures for days
to weeks after the last drug exposure.
● ΔFosB GluR2 and Cdk5.
● The cascade of events from dopamine D1 receptor
stimulation to increased expression of CREB----
ΔFosB----GluR2/Cdk5 is thought to be necessary for the
transition from social to compulsive drug use.
66. Dendritic spine density
● In addition to signaling and transcriptional events produced by the
repeated stimulation of D1receptors, the transition to addiction
involves the recruitment of cortical circuitry. These changes in
corticofugal glutamatergic input to the striatum
associated with repeated drug administration eventually leads to a
host of cellular adaptations in cortical and striatal cells, among the
most consistent of which are morphological changes
● in dendritic spine density.
● Repeated drug administration changes the synaptic plasticity.
● Actin cycling is increased.
● BDNF has been shown to influence many cellular processes
associated with neuroplasticity, including long-term potentiation
and spine morphology.
67. Sex Differences in the Addiction Process
Drug abuse and addiction are problems often attributed tomen, -
.women are also clearly affected
-
-
-
- Women more susceptible to drug addiction than men.
- Women tend to use drugs more days, get addicted in less time, and
greater severity of abuse.
women compared to men have higher levels of drug craving when
exposed to drug cues.
Women have greater activation, in stress induced, of the inferior
frontal cortex, left insula, dorsal anterior cingulate cortex, and right
posterior cingulate cortex
Women have greater activation of the anterior cingulate cortex, in
cues craving.
- Men have greater activation to cues craving of , the amygdala, insula,
ventral cingulate cortex, and orbitofrontal cortex .
68. Dopamine deprivation
produces:
Chronic unpleasant
feelings
Depression
Loss of motivation
The need to take
the drug to feel
better
Addicts now use
just to feel
“normal", not to
feel high
Over-stimulation leads to down-regulation of D2 dopamine
receptor.
The degree of this reduction lessens over time but is still
present a year and a half after withdrawal.
69. Recovery of Dopamine
Transporters
PET scan shows levels of dopamine transporters
Lower levels of dopamine transporters were associated with poorer
performance on tests of memory and motor skills
Impairments in motor skills and memory continued
Volkow, et al. 2001
70. Imaging- lessons learnt
1. PFC hypo-activity in addicted individuals
during working memory tasks.
2. Nu Ac core*, hippocampus and dorsal
striatum (long term) are involved in
learning during intoxication and learned
responses during craving.
72. Conclusion
Drug addiction represents a dramatic dysregulation of
motivational circuits that is caused by a combination of
exaggerated incentive salience and habit formation,
reward deficits and stress surfeits, and compromised
executive function in three stages.
The rewarding effects of drugs of abuse, development of
incentive salience, and development of drug-seeking
habits in the binge/intoxication stage involve changes in
dopamine and opioid peptides in the basal ganglia.
73. conclusion
The increases in negative emotional states and
dysphoric and stress-like responses in the
withdrawal/negative affect stage involve decreases in the
function of the dopamine component of the reward
system and recruitment of brain stress
neurotransmitters, such as corticotropin-releasing factor
and dynorphin, in the neurocircuitry of the extended
amygdala.
The craving and deficits in executive function in the so-
called preoccupation/anticipation stage involve the
dysregulation of key afferent projections from the
prefrontal cortex and insula, including glutamate, to the
basal ganglia and extended amygdala.
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psychostimulant addiction: the differences do matter. Nat Rev
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Becker JB, Perry AN, Westenbroek C. Sex differences in the neural
mechanisms mediating addiction: a new synthesis and hypothesis.
Biol Sex Differ. 2012;3:14.
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Bossert JM, Marchant NJ, Calu DJ, Shaham Y. The reinstatement
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