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The Neurobiology of Addiction
DR.VLN SEKHAR
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”
Drug addiction constitutes a chronic
central nervous system disorder,
characterized by recurrent episodes of
relapse in which individuals resume
drug-seeking and drug-taking
behaviour, even in the face of adverse
consequences and diminishing reward.
Neurobiology
How do drugs work in the brain?
Addiction
DRUG
Environment
Biology/Genes
Biology/
Environment
Interaction
Biology/Genes and Environment Play
Key Roles in Vulnerability
G X E
Interaction
Risk Factors for Alcoholism or
Drug Dependence
GENETIC ENVIRONMENTAL
G X E
Interaction
Risk Factors for Alcoholism or
Drug Dependence
GENETIC
Specific
genes
ENVIRONMENTAL
Family, Peers
Workplace
Comorbidity
Early onset
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
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
Genetics: The Genome
 In humans, several chromosomal regions have been
linked to substance use disorders , but only few
specific genes have been identified with polymorphism
that either predispose to or protect from drug
addiction.
 Some of these are polymorphism that interfere with
drug metabolism.
 For example, 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
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
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.
 Some of polymorphisms in genes that encode receptors that
mediate drug effects have also been associated with a higher
risk of 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
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.
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%
Environmental factors
Environmental factors that have been
consistently associated with the propensity to
self- administer drugs include –
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 might be a common feature in a wide variety of
environmental factors that increase the risk for drug abuse.
PARENTAL DRUG ABUSE
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
Developmental factors
 Normal developmental processes may result in higher risk for
drug use in certain life stages than others.
 Epidemiological data on patterns of drug use as well as animal
studies support the notion of critical developmental periods for
drug behaviour. Experimentation, as well as the process of
addiction, most often starts in adolescence , a period during
which the brain undergoes significant devolopmental changes.
 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.
 The back of brain matures first…
• sensory and physical activities favored over
complex, cognitive-demanding activities
• propensity toward risky, impulsive behaviors
This imbalance leads to...
risk taking
low effort - high excitement activities
interest in novel stimuli
planned thinking
impulsiveness
PFC
The
Development
of Addiction:
Adolescence
Amygdala
NAc
Add stress and alcohol/drug use...
PFC
Amygdala
NAc
The Development of Addiction:
Adolescence
Stages of Addiction
Stages of Addiction
From a psychiatric perspective, drug addiction has aspects of
both impulse control and compulsive disorders.
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
“Drug addiction" -Both impulse control
disorders and compulsive disorder
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 VENTRAL
VMPFC SRIATUM
THALAMUS
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
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. The
impulse to take a drug initially leads to great pleasure and satisfaction (a
“high”). If this happens infrequently, the behaviour may be a bit “naughty”
but will not necessarily progress to compulsivity. 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:
preoccupation/anticipation,
binge/intoxication, and
withdrawal/ negative affect
OFC
SCC
NAc
c VP
REWARD
PFC
ACG
INHIBITORY
CONTROL
MOTIVATION/
DRIVE
(saliency)
Brain Circuits Involved inBrain Circuits Involved in
Drug AddictionDrug Addiction
Hipp
Amyg
MEMORY/
LEARNING
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.
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.
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,
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
Brain Pathways of Reward and
Addiction
Located in the limbic system – functions
to monitor internal homeostasis,
mediate memory, mediate learning and
experience emotion
Includes the hypothalamus, amygdala,
hippocampus, nucleus accumbens
(NA), the ventral tegmental area (VTA),
locus ceruleus and the prefrontal cortex
The Reward Pathway
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).
 SO MESOLIMBIC PATHWAY IS ACTIVATED BY :
 NATURAL : FOOD, DRINKS, SEX.
 BEHAVIORS : eg: gambling.
 DRUGS : of abuse (hyperactivity)
 DISEASES : eg: psychosis, schizophrenia
( positive symptoms ).
Natural Rewards Elevate DopamineNatural Rewards Elevate Dopamine
LevelsLevels
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.
These are included in the impulsive–compulsive disorder
construct and include behaviours such as gambling, using the
internet, shopping, and even eating.
Drugs bypass the brain’s own neurotransmitters and directly
stimulate the brain’s own receptors for these drugs, causing
dopamine to be released.
The Reward Pathway
Dopamine is the primary
neurotransmitter of the reward pathway
All drugs of abuse increase dopamine
levels in the brain reward pathway
although they often act through
separate mechanisms
Drugs that are not abused have no
effect on dopamine concentrations in
the reward pathway
Dopamine Pathways
Functions
•reward (motivation)
•pleasure,euphoria
•motor function
(fine tuning)
•compulsion
•perserveration
•decision making
Serotonin Pathway
Functions
•mood
•memory
processing
•sleep
nucleus
accumbens
hippocampus
striatum
frontal
cortex
substantia
nigra/VTA
raphe
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)
/serotonin
Vmat
transporter
stimulationstimulation
DA/5HTDA/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)
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
• Release DA from vesicles and reverse
transporter
Drug Types:
• Amphetamines
-methamphetamine
-MDMA (Ecstasy)
Vmat
transporter
serotonin/
DA/5HTDA/5HT
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
 Extensive data using a variety of experimental
approaches have shown that mesolimbic
dopamine pathway activity is required for the
primary reinforcing effects of drugs of abuse.
 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.
Converging Acute Actions of Drugs of Abuse on the Ventral
Tegmental Area and Nucleus Accumbens
From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.
 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.
 Thus, it is clear that a complex pattern of brain activity
underlies drug reinforcement and the accompanying
cognitive and affective changes produced by drugs of abuse.
Nucleus
accumbens
Amphetamines
Opiates
THC
PCP
Ketamine
Nicotine
Alcohol
benzodiazepines
barbiturates
Dopamine
VTA
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)
Altered neural integration in addiction
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
Loss of control in limiting intake
After cocaine use – DA levels fall below normal
low mood
to alleviate – uses drug again
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
Pathways That Underlie Relapse
 Given the persistent nature of drug dependence, it is vital to
understand the long-lasting neuroadaptations that result in
relapse to compulsive drug use after periods of abstinence from
the abused substance
 Rapid advances have occurred over the last 10 years in
determining the neural circuitries that underlie various forms of
relapse using both animal models and in vivo brain imaging in
humans. In regards to different drugs of abuse, research on the
circuitry of relapse has primarily focused on cocaine.
 A schematic of the neurocircuitry for the reinstatement of
cocaine-seeking behaviour produced by conditioned cues,
drug-priming, and stress.
 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. While existing data
suggest that the circuitry mediating relapse across different
drugs of abuse shows some similarities, some evidence shows
Relapse circuits of addiction
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.
 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.
 Other brain regions involved in conditioned-cued
reinstatement include discrete subregions of the prefrontal
cortex and striatum.
 Pharmacological inactivation (either by sodium channel
blockade or GABA receptor agonists) of the dorsal medial
prefrontal cortex (anterior cingulate and prelimbic cortex),
the lateral orbitofrontal cortex, or the nucleus accumbens
core significantly attenuates cue-induced cocaine-
seeking.
 IN VIVO HUMAN imaging methods : cocaine-paired cues
have been shown to increase metabolic activation of the
amygdala, the anterior cingulate region of the cortex, the
nucleus accumbens, and the orbitofrontal cortex.
Because addiction is by definition “habitual,” recent
attention has turned to the study of drug-induced adaptive
changes in particular the dorsal striatum (caudate and
putamen), which are known to mediate habitual responses.
The caudate-putamen receives the densest innervation by
dopamine afferents.
In rodent models, extracellular dopamine in the caudate-
putamen is increased during response for a cocaine-
associated cue, while inactivation of the caudate-putamen
by pharmacological means blocks response for cocaine-
associated cues.
Positron emission tomography in cocaine-dependent
subjects during cue-induced craving have shown that
INCREASED dopamine in the caudate-putamen.
Clinical evidence has clearly established the ability of drug-
associated environmental cues (i.e., associated drug
paraphernalia or locations where a drug was previously
consumed) to elicit drug craving and consequently reinstate
drug-seeking and drug-taking.
Conditioned-cued responses have been demonstrated for a
variety of drugs of abuse, including psychostimulants,
opiates, nicotine, and alcohol.
EG: 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.
Drug-Primed Reinstatement
 Similar to conditioned-cued reinstatement, a number of studies
have examined drug-primed reinstatement in the animal model
of relapse
 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.
Stress-Induced Reinstatement
 Stress clearly plays a role in acquisition, maintenance, and
relapse with drugs of abuse.
 Controlled laboratory studies in human drug addicts have
shown that drug desire can be elicited with stressors and that
this stress-induced response predicts relapse.
 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)
The Stress Hormone Cycle
Hypothalamus
Pituitary
Gland
Adrenal
Glands
Kidneys
CRF
ACTH
CORTISOL
Stress ResponsesStress ResponsesStress ResponsesStress Response
CRF:
Corticotropin
Releasing
Factor
DRUG USEDRUG USE
(Self-Medication)(Self-Medication)
STRESSSTRESS
CRFCRF
AnxietyAnxiety
CRFCRF
AnxietyAnxiety
What Role Does Stress Play
In Initiating Drug Use?
ProlongedProlonged
DRUGDRUG
USEUSE
AbstinenceAbstinence
RELAPSERELAPSE
CRFCRF
AnxietyAnxiety
What Happens When A Person
Stops Taking A Drug?
 Other facets of the neural substrates of stress-induced
reinstatement include the findings that central infusions of
corticotropin-releasing factor (CRF) produce reinstatement,
while elimination of the corticosterone response by surgical
means or CRF receptor antagonists blocks stress-induced
reinstatement, as do noradrenergic α2 receptor agonists, such
as clonidine or lofexidine.
 stress may sensitize an individual to be more attentive to drug-
paired cues, increase the incentive salience of the cues, or
perhaps increase motivation to reduce negative affect states
through renewed drug use.
 A fertile area for new investigation is the question of how stress may
affect the ability of environmental cues to trigger drug-seeking.
 Stress-related induction of craving and relapse has been found to be
comparable to that produced by cocaine-paired cues, and stress and
cues may have significant interactions.
 Administration of the α-adrenergic receptor antagonist yohimbine
produced a modest increase in cocaine- or methamphetamine-
seeking in rats when administered alone.
 Yohimbine treatment has been shown to produce anxiety-like states
in humans and laboratory animals, presumably through its activation
of norepinephrine release. Yohimbine also has been reported to
induce subjective craving in drug-dependent subjects. When given
prior to conditioned cue-induced reinstatement in rats, yohimbine
pretreatment greatly potentiates cocaine-seeking maintained by the
previously cocaine-paired cues.
CELLULAR AND MOLECULAR
SUBSTRATES OF ADDICTION:
 These changes are mainly focused in NA.
 Drug-induced neuroadaptations in the nucleus accumbens can
be temporally segregated as
 (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.
 Each temporal category can contribute to the development of
addiction and the vulnerability to relapse.
 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.
 The induction of cAMP response element binding
protein (CREB) by stimulating D1 dopamine 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.
Dopamine receptor stimulation in NA
Activation of transcription factors (c-fos,NAC-1,CREB)
CREB protein
FosB
GluR2 and CDK5
Spine morphology,
glutamate homeostasis,
actin cycling
Synaptic plasticity
Vulnerability to relapse
Dendritic spine density
 In addition to signaling and transcriptional events produced by
the repeated stimulation of D1 receptors, 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.
 Interestingly, the changes in spine density can be either an
increase (e.g., with amphetamine-like psychostimulants) or a
decrease (e.g., µ opioid receptor drugs).
 These findings imply an underlying change in the mechanisms
of neuroplasticity that regulate spine density
Repeated drug administration changes the
synaptic plasticity.
Actin cycling is increased.
Actin are micro filaments .
Actin participates in many important cellular
processes, including muscle contraction, cell
motility, cell division and cytokinesis, vesicle
and organelle movement, cell signaling, and
the establishment and maintenance of
cell junctions and cell shape.
Actin cycling
It was recently shown that repeated
morphine or cocaine administration
produce an enduring and robust
increase in actin cycling, as measured
by elevations in F-actin in the presence
of increased actin disassembly due to
reduced phosphorylation of cofilin
 A final widely replicated cellular change produced by addictive drugs is
upregulated brain-derived neurotrophic factor (BDNF), which is produced
widely in many nuclei that have been identified as parts of the addiction
circuitry, including the ventral tegmental area, amygdala, and nucleus
accumbens
 BDNF is generally increased by acute drug administration and
appears to undergo further elevation during drug abstinence.
 BDNF has been shown to influence many cellular processes
associated with neuroplasticity, including long-term potentiation
and spine morphology.
 Therefore, these enduring changes in BDNF are thought to
contribute to the enduring neuroplasticity associated with repeated
drug use.
Animal Models for the Different Stages
of the Addiction Cycle
 Animal Models for the Binge/Intoxication Stage
1. Oral or intravenous drug self-administration
2. Brain stimulation reward
3. Place preference
 Animal models for the Withdrawal/Negative Affect Stage
1. Brain stimulation reward
2. Place aversion
 Animal Models for the Transition to Addiction
1. Dependence-induced drug taking
2. Escalation in drug self-administration with prolonged access
3. Drug taking despite aversive consequences
 Animal Models for the Preoccupation/Anticipation (“Craving”) Stage
1. Drug- induced reinstatement
2. Cue- induced reinstatement
3. Alcohol Deprivation Effect
4. Stress- induced reinstatement
Nucleus accumbens on MRI
Imaging- lessons learnt
1. PET, fMRI and sMRI has been used in
intoxication, cortical executive dys-
control, craving and withdrawal,
motivational salience paradigms.
2. DA changes in Nu Ac are most well
correlated with euphoria and high.
3. DA D2 receptor function predicts
predisposition to Addiction and
differential motivational salience.
4. OFC is hypoactive during withdrawal with
decreased DA D2 activity.
Imaging- lessons learnt
1. OFC is hyper metabolic during craving-
compulsivity?
2. OFC- DA mediated reward prediction with
stimuli.
3. PFC hypo-activity in addicted individuals
during working memory tasks.
4. Nu Ac core*, hippocampus and dorsal
striatum (long term) are involved in
learning during intoxication and learned
responses during craving.
Craving associated with D2 hypo function and OFC hyper activity
Strange “addictions”
• cell phone • internet
• television • shoes
• exercise .cars
• chocolate
DON’T FALL INTO LIFE LONG ADDICTION
Neurobiology of addiction
Neurobiology of addiction
Neurobiology of addiction

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Neurobiology of addiction

  • 1. The Neurobiology of Addiction DR.VLN SEKHAR
  • 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. Drug addiction constitutes a chronic central nervous system disorder, characterized by recurrent episodes of relapse in which individuals resume drug-seeking and drug-taking behaviour, even in the face of adverse consequences and diminishing reward.
  • 4. Neurobiology How do drugs work in the brain?
  • 6. G X E Interaction Risk Factors for Alcoholism or Drug Dependence GENETIC ENVIRONMENTAL
  • 7. G X E Interaction Risk Factors for Alcoholism or Drug Dependence GENETIC Specific genes ENVIRONMENTAL Family, Peers Workplace Comorbidity Early onset
  • 8. 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
  • 9. 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
  • 10. Genetics: The Genome  In humans, several chromosomal regions have been linked to substance use disorders , but only few specific genes have been identified with polymorphism that either predispose to or protect from drug addiction.  Some of these are polymorphism that interfere with drug metabolism.  For example, 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
  • 11. 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
  • 12. 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.  Some of polymorphisms in genes that encode receptors that mediate drug effects have also been associated with a higher risk of 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
  • 13.
  • 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 Environmental factors that have been consistently associated with the propensity to self- administer drugs include – 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 might be a common feature in a wide variety of environmental factors that increase the risk for drug abuse.
  • 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  Normal developmental processes may result in higher risk for drug use in certain life stages than others.  Epidemiological data on patterns of drug use as well as animal studies support the notion of critical developmental periods for drug behaviour. Experimentation, as well as the process of addiction, most often starts in adolescence , a period during which the brain undergoes significant devolopmental changes.  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.
  • 20.  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.  The back of brain matures first… • sensory and physical activities favored over complex, cognitive-demanding activities • propensity toward risky, impulsive behaviors
  • 21. This imbalance leads to... risk taking low effort - high excitement activities interest in novel stimuli planned thinking impulsiveness PFC The Development of Addiction: Adolescence Amygdala NAc
  • 22. Add stress and alcohol/drug use... PFC Amygdala NAc The Development of Addiction: Adolescence
  • 24. Stages of Addiction From a psychiatric perspective, drug addiction has aspects of both impulse control and compulsive disorders. 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
  • 25. “Drug addiction" -Both impulse control disorders and compulsive disorder
  • 26. 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 VENTRAL VMPFC SRIATUM THALAMUS
  • 27. 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
  • 28. 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. The impulse to take a drug initially leads to great pleasure and satisfaction (a “high”). If this happens infrequently, the behaviour may be a bit “naughty” but will not necessarily progress to compulsivity. 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: preoccupation/anticipation, binge/intoxication, and withdrawal/ negative affect
  • 29.
  • 30. OFC SCC NAc c VP REWARD PFC ACG INHIBITORY CONTROL MOTIVATION/ DRIVE (saliency) Brain Circuits Involved inBrain Circuits Involved in Drug AddictionDrug Addiction Hipp Amyg MEMORY/ LEARNING
  • 31.
  • 32. 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.
  • 33. 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.
  • 34. 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,
  • 35.
  • 36. 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
  • 37. Brain Pathways of Reward and Addiction Located in the limbic system – functions to monitor internal homeostasis, mediate memory, mediate learning and experience emotion Includes the hypothalamus, amygdala, hippocampus, nucleus accumbens (NA), the ventral tegmental area (VTA), locus ceruleus and the prefrontal cortex
  • 39. 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).
  • 40.  SO MESOLIMBIC PATHWAY IS ACTIVATED BY :  NATURAL : FOOD, DRINKS, SEX.  BEHAVIORS : eg: gambling.  DRUGS : of abuse (hyperactivity)  DISEASES : eg: psychosis, schizophrenia ( positive symptoms ).
  • 41. Natural Rewards Elevate DopamineNatural Rewards Elevate Dopamine LevelsLevels
  • 42. 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. These are included in the impulsive–compulsive disorder construct and include behaviours such as gambling, using the internet, shopping, and even eating. Drugs bypass the brain’s own neurotransmitters and directly stimulate the brain’s own receptors for these drugs, causing dopamine to be released.
  • 43. The Reward Pathway Dopamine is the primary neurotransmitter of the reward pathway All drugs of abuse increase dopamine levels in the brain reward pathway although they often act through separate mechanisms Drugs that are not abused have no effect on dopamine concentrations in the reward pathway
  • 44. Dopamine Pathways Functions •reward (motivation) •pleasure,euphoria •motor function (fine tuning) •compulsion •perserveration •decision making Serotonin Pathway Functions •mood •memory processing •sleep nucleus accumbens hippocampus striatum frontal cortex substantia nigra/VTA raphe
  • 45. 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)
  • 46. /serotonin Vmat transporter stimulationstimulation DA/5HTDA/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) 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
  • 47. • Release DA from vesicles and reverse transporter Drug Types: • Amphetamines -methamphetamine -MDMA (Ecstasy) Vmat transporter serotonin/ DA/5HTDA/5HT
  • 48. 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
  • 49.  Extensive data using a variety of experimental approaches have shown that mesolimbic dopamine pathway activity is required for the primary reinforcing effects of drugs of abuse.  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.
  • 50. Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.
  • 51.  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.  Thus, it is clear that a complex pattern of brain activity underlies drug reinforcement and the accompanying cognitive and affective changes produced by drugs of abuse.
  • 53.
  • 54. 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)
  • 56. 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
  • 57. Loss of control in limiting intake After cocaine use – DA levels fall below normal low mood to alleviate – uses drug again
  • 58. 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
  • 59. Pathways That Underlie Relapse  Given the persistent nature of drug dependence, it is vital to understand the long-lasting neuroadaptations that result in relapse to compulsive drug use after periods of abstinence from the abused substance  Rapid advances have occurred over the last 10 years in determining the neural circuitries that underlie various forms of relapse using both animal models and in vivo brain imaging in humans. In regards to different drugs of abuse, research on the circuitry of relapse has primarily focused on cocaine.  A schematic of the neurocircuitry for the reinstatement of cocaine-seeking behaviour produced by conditioned cues, drug-priming, and stress.  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. While existing data suggest that the circuitry mediating relapse across different drugs of abuse shows some similarities, some evidence shows
  • 60. Relapse circuits of addiction
  • 61. 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.
  • 62.  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.
  • 63.  Other brain regions involved in conditioned-cued reinstatement include discrete subregions of the prefrontal cortex and striatum.  Pharmacological inactivation (either by sodium channel blockade or GABA receptor agonists) of the dorsal medial prefrontal cortex (anterior cingulate and prelimbic cortex), the lateral orbitofrontal cortex, or the nucleus accumbens core significantly attenuates cue-induced cocaine- seeking.  IN VIVO HUMAN imaging methods : cocaine-paired cues have been shown to increase metabolic activation of the amygdala, the anterior cingulate region of the cortex, the nucleus accumbens, and the orbitofrontal cortex.
  • 64. Because addiction is by definition “habitual,” recent attention has turned to the study of drug-induced adaptive changes in particular the dorsal striatum (caudate and putamen), which are known to mediate habitual responses. The caudate-putamen receives the densest innervation by dopamine afferents. In rodent models, extracellular dopamine in the caudate- putamen is increased during response for a cocaine- associated cue, while inactivation of the caudate-putamen by pharmacological means blocks response for cocaine- associated cues. Positron emission tomography in cocaine-dependent subjects during cue-induced craving have shown that INCREASED dopamine in the caudate-putamen.
  • 65. Clinical evidence has clearly established the ability of drug- associated environmental cues (i.e., associated drug paraphernalia or locations where a drug was previously consumed) to elicit drug craving and consequently reinstate drug-seeking and drug-taking. Conditioned-cued responses have been demonstrated for a variety of drugs of abuse, including psychostimulants, opiates, nicotine, and alcohol. EG: 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.
  • 66. Drug-Primed Reinstatement  Similar to conditioned-cued reinstatement, a number of studies have examined drug-primed reinstatement in the animal model of relapse  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.
  • 67. Stress-Induced Reinstatement  Stress clearly plays a role in acquisition, maintenance, and relapse with drugs of abuse.  Controlled laboratory studies in human drug addicts have shown that drug desire can be elicited with stressors and that this stress-induced response predicts relapse.  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)
  • 68. The Stress Hormone Cycle Hypothalamus Pituitary Gland Adrenal Glands Kidneys CRF ACTH CORTISOL Stress ResponsesStress ResponsesStress ResponsesStress Response CRF: Corticotropin Releasing Factor
  • 71.  Other facets of the neural substrates of stress-induced reinstatement include the findings that central infusions of corticotropin-releasing factor (CRF) produce reinstatement, while elimination of the corticosterone response by surgical means or CRF receptor antagonists blocks stress-induced reinstatement, as do noradrenergic α2 receptor agonists, such as clonidine or lofexidine.  stress may sensitize an individual to be more attentive to drug- paired cues, increase the incentive salience of the cues, or perhaps increase motivation to reduce negative affect states through renewed drug use.
  • 72.  A fertile area for new investigation is the question of how stress may affect the ability of environmental cues to trigger drug-seeking.  Stress-related induction of craving and relapse has been found to be comparable to that produced by cocaine-paired cues, and stress and cues may have significant interactions.  Administration of the α-adrenergic receptor antagonist yohimbine produced a modest increase in cocaine- or methamphetamine- seeking in rats when administered alone.  Yohimbine treatment has been shown to produce anxiety-like states in humans and laboratory animals, presumably through its activation of norepinephrine release. Yohimbine also has been reported to induce subjective craving in drug-dependent subjects. When given prior to conditioned cue-induced reinstatement in rats, yohimbine pretreatment greatly potentiates cocaine-seeking maintained by the previously cocaine-paired cues.
  • 73. CELLULAR AND MOLECULAR SUBSTRATES OF ADDICTION:  These changes are mainly focused in NA.  Drug-induced neuroadaptations in the nucleus accumbens can be temporally segregated as  (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.  Each temporal category can contribute to the development of addiction and the vulnerability to relapse.
  • 74.  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.
  • 75.
  • 76.  The induction of cAMP response element binding protein (CREB) by stimulating D1 dopamine 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.
  • 77. Dopamine receptor stimulation in NA Activation of transcription factors (c-fos,NAC-1,CREB) CREB protein FosB GluR2 and CDK5 Spine morphology, glutamate homeostasis, actin cycling Synaptic plasticity Vulnerability to relapse
  • 78. Dendritic spine density  In addition to signaling and transcriptional events produced by the repeated stimulation of D1 receptors, 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.  Interestingly, the changes in spine density can be either an increase (e.g., with amphetamine-like psychostimulants) or a decrease (e.g., µ opioid receptor drugs).  These findings imply an underlying change in the mechanisms of neuroplasticity that regulate spine density
  • 79. Repeated drug administration changes the synaptic plasticity. Actin cycling is increased. Actin are micro filaments . Actin participates in many important cellular processes, including muscle contraction, cell motility, cell division and cytokinesis, vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape.
  • 80. Actin cycling It was recently shown that repeated morphine or cocaine administration produce an enduring and robust increase in actin cycling, as measured by elevations in F-actin in the presence of increased actin disassembly due to reduced phosphorylation of cofilin
  • 81.  A final widely replicated cellular change produced by addictive drugs is upregulated brain-derived neurotrophic factor (BDNF), which is produced widely in many nuclei that have been identified as parts of the addiction circuitry, including the ventral tegmental area, amygdala, and nucleus accumbens  BDNF is generally increased by acute drug administration and appears to undergo further elevation during drug abstinence.  BDNF has been shown to influence many cellular processes associated with neuroplasticity, including long-term potentiation and spine morphology.  Therefore, these enduring changes in BDNF are thought to contribute to the enduring neuroplasticity associated with repeated drug use.
  • 82. Animal Models for the Different Stages of the Addiction Cycle  Animal Models for the Binge/Intoxication Stage 1. Oral or intravenous drug self-administration 2. Brain stimulation reward 3. Place preference  Animal models for the Withdrawal/Negative Affect Stage 1. Brain stimulation reward 2. Place aversion  Animal Models for the Transition to Addiction 1. Dependence-induced drug taking 2. Escalation in drug self-administration with prolonged access 3. Drug taking despite aversive consequences  Animal Models for the Preoccupation/Anticipation (“Craving”) Stage 1. Drug- induced reinstatement 2. Cue- induced reinstatement 3. Alcohol Deprivation Effect 4. Stress- induced reinstatement
  • 84. Imaging- lessons learnt 1. PET, fMRI and sMRI has been used in intoxication, cortical executive dys- control, craving and withdrawal, motivational salience paradigms. 2. DA changes in Nu Ac are most well correlated with euphoria and high. 3. DA D2 receptor function predicts predisposition to Addiction and differential motivational salience. 4. OFC is hypoactive during withdrawal with decreased DA D2 activity.
  • 85. Imaging- lessons learnt 1. OFC is hyper metabolic during craving- compulsivity? 2. OFC- DA mediated reward prediction with stimuli. 3. PFC hypo-activity in addicted individuals during working memory tasks. 4. Nu Ac core*, hippocampus and dorsal striatum (long term) are involved in learning during intoxication and learned responses during craving.
  • 86. Craving associated with D2 hypo function and OFC hyper activity
  • 87. Strange “addictions” • cell phone • internet • television • shoes • exercise .cars • chocolate
  • 88. DON’T FALL INTO LIFE LONG ADDICTION

Editor's Notes

  1. Magnetic Resonance Imaging (MRI) Scans allow us to map the maturation of the brain. This slide illustrates brain development through early adulthood, with blue indicating the mature state. The prefrontal cortex (white circles), which governs judgment and decision-making functions, is the last part of the brain to develop. This may help explain why teens are prone to risk-taking, are particularly vulnerable to drug abuse, and why exposure to drugs at this critical time may affect propensity for future addiction.
  2. 041KoobG/NP/dia1c/040799pm
  3. Zorrilla ACNP 2001
  4. KoobG/NP/dia1/082205jh
  5. KoobG/NP/wor2/062802jh.ppt
  6. KoobG/NP/wor2/030104jh
  7. KoobG/MIND/dia1/053006jh