Transcript Slide 1

Original definition of addiction
Under Roman law, a formal giving over of a
debtor to a creditor by court sentence,
hence a binding over of a person to a
Later analogy: a person is bound over to
drug use, as a slave is to a master.
Implication: a loss of freedom of action of
the person so addicted
Essential features of definition
• Addictionj is a strongly established
pattern of repeated self-administration
of a drug
• in doses that reliably produce
reinforcing psychoactive effects
• great difficulty in achieving long-term
cessation of use despite adverse
effects and strong motivation to stop
Addiction is a disorder of drugtaking, not of drug action.
Passive exposure to a drug can
cause tolerance and physical
dependence, but these are not the
same as addiction.
Neurobiological concept of addiction as
proposed by NIDA, NIAAA and others:
“Addiction is a chronic relapsing brain
disease related to the chronic heavy use
of a mind-altering drug”
- to identify the locus and nature of the
brain disorder, and develop rationally
based medications to correct it
- identify predisposing biological factors
for targeting early prevention, including
biological measures (e.g., gene therapy)
Winger, Woods, et al. (2005):
“ Neuroscientific approaches to drug
addiction [are] based on the premise that
addiction…results from brain changes that
in turn result from chronic administration of
drugs of abuse. Alternative approach
views drug addiction as a behavioral
disorder in which drugs function as
preeminent reinforcers. [T]here is a
fundamental discrepancy between
these two approaches.”
Basic neurobiological concepts:
1. People use drugs because they derive some
benefit or pleasure [“reward”] from them, at least
2. “Opponent processes” produce “anti-reward”,
e.g., depression, craving, etc., even in acute use
3. Chronic heavy use leads to prolonged
adaptation that can produce tolerance and
physical dependence.
4. Neuroplasticity [“allostasis”] somehow removes
reward system from normal controls
Fig.?1 (A) Dysphoric feelings followed the initial euphoria in experimental subjects who smoked cocaine paste, even though the
concentration of cocaine in the plasma of the blood remained relatively high. The dysphoria is characterized by anxiety, depression.
(B) Average behavioral ratings after an intravenous infusion of cocaine, 0.6 mg/kg over 30 sec
George F. Koob : Neuropharmacology Volume 56, Supplement 1 2009 18 - 31
What is the “reward” mechanism?
Repeatedly demonstrated that all drugs
capable of causing dependence can
stimulate dopamine (DA)-releasing cells in
a midbrain area (the VTA) that sends
fibres to the nucleus accumbens (NAcc)
and the medial forebrain.
Extent of DA stimulation is proportional to
the dose, and to the speed with which the
drug concentration rises in the brain.
Rat brain
Pathways involved in reinforcement/”reward” system
Dopaminergic GABAergic Glutamatergic Orexinergic
(not shown: opioid, serotonin, noradrenergic,
cholinergic, endocannabinoid, others)
• Common assumption: the increased
release of DA either causes or
initiates the “rewarding effect” of these
• The same DA pathway is stimulated
by food-related cues, sexual cues,
other natural reinforcers
• Assumption: drugs “highjack” normal
reward mechanisms
Fig.?6 Neurocircuitry associated with the acute positive reinforcing effects of drugs of abuse and the negative reinforcement of
dependence and how it changes in the transition from non-dependent drug taking to dependent drug taking. Key elements...
George F. Koob: Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology Volume 56,
Supplement 1 2009 18 - 31
Apparent support for this concept:
DAR agonists (e.g., pramipexole) used in
treating Parkinson disease can cause
compulsive behaviors:
- compulsive gambling
- compulsive eating
- compulsive sex
- compulsive use of the drugs
themselves (Ambermoon et al., 2011)
Alternative hypothesis: VTA-NAcc DA path is not a
“reward” system, but an arousal system that
alerts the brain to important novel stimuli
● DA response occurs to rewarding, punishing, or
even motivationally neutral but intense stimuli
● DA neurons in VTA put out different patterns of
response to different kinds of stimuli (Schulz)
● with repeated exposure to same stimulus, DA
response fades, or shifts from actual “reward” to
cues that predict delivery of reward
● suggestion: DA system monitors match between
predicted reward and actual reward, serving as
basis for experience-based learning
Genetic factors in addiction
● clinical observations in alcoholism: family trees,
twin studies, adoption studies all demonstrate
role of genetic factors separate from “copy-cat”
● some evidence for genetic influence in other
addictions, but not yet explored as well as in
● is clearly multigenic, not monogenic in nature
● not strict causality, but increase in degree of risk
(child with high genetic load is at greater risk, but
may choose to abstain)
But a huge number of different genes (more
than 2,000 at present) are statistically
linked to alcoholism, that determine very
different traits in the offspring
 Some relate to sensitivity of the individual
to drug effects
 Some govern rate of metabolism of the
 Some relate to ability to develop adaptive
changes in response to drug actions
personality traits that somehow modify
readiness to use the drug
The genes involved encode for virtually all
parts of cell signalling systems.
Implication: the genes and their products
represent the cell machinery that enables
nerve cells to respond to all kinds of
stimuli, and thus permit all types of
adaptive change, both beneficial (e.g.,
learning, memory) and harmful (e.g.,
tolerance, physical dependence)
[Li et al., 2008]
More recently, emphasis has been on
genes governing personality traits that
somehow modify readiness to use the
drug, such as:
 impulsivity
 novelty-seeking
 psychosis
 mood disorders
= inability to postpone a
response even when it would be
advantageous to do so
● accompanied by genetically
determined reduction of D2/3
receptors in N Acc
● predicts easier acquisition of drugtaking: alcohol, cocaine, opioids, etc.
● High impulsivity
○ Low impulsivity
0crit, 3crit – number of criteria of addiction; LI, HI – low/high
impulsivity; LR, HR – low/high reactivity to novelty
But correlation between impulsivity and
cocaine use was not very striking.
Impulsivity also predicts other behavioral
changes unrelated to drug selfadministration (e.g., gambling)
Conclusion: Can not assume direct causal
link between impulsivity and drug addiction
Competing systems models of addiction
(Bechara, Bickel, Jentsch)
 Competition between impulsive system
(limbic system, concerned with immediate
outcomes) and executive system
(prefrontal cortex, concerned with rational
weighing of future outcomes)
 Addiction = dominance of impulsive
system over executive system
Examples of impaired executive functions found in
  working memory ( recall of past experience)
  risk evaluation
  response inhibition
  future discounting
  cognitive flexibility
Accompanied by  activation of prefrontal cortex, 
activation of N. accumbens, in imaging studies
Future discounting in addicted Ss
Future discounting (giving lesser value to
delayed reward than to immediate reward)
is another example of impaired executive
Greater future discounting is found in Ss
dependent on cocaine, tobacco, alcohol,
gambling, than in controls (Bickel et al)
Age-related change (from age 13 to
age 16) in cortical activation response
during visual memory task in
adolescents who acquired heavy
drinking during that time, compared
with those who remained abstinent.
[Those who became heavy drinkers
had smaller improvements in visual
memory accuracy and speed]
Squeglia et al., 2012
Factors influencing executive functioning in
parallel with PFC activity:
 Developmental stage: progressive
increase with age
 Cultural norms and demands
 Educational and work demands
 Brain injuries (traumatic, toxic, tumor,
radiation, etc. [but do these lead to
addiction ? Some evidence, but scanty]
Important omission of all biological
their failure to take into account
environmental influences that affect drug
use without changing genes or neuronal
- environmental novelty
- expectancies
- other closely similar behaviors when no
drugs are involved
Effect of novel environment on drug-related
dopaminergic activity
Novel environment (N) facilitates acquisition of cocaine selfadministration compared to home environment (H)
(Capriani et al. , 2007)
Effect of novel environment on drinking of
alcohol by rats
Effect of priming of expectancies and mood
on alcohol consumption
Stein, Goldman, Del Boca (2000)
Defining criteria of pathological gambling:
- Preoccupation with gambling
- Unsuccessful attempts to reduce or stop
- Need to gamble larger sums over time
- Attempts to recoup losses by gambling
even more
- Restlessness and irritability when trying to
reduce or stop
- Lying, stealing, etc., to cover losses
- Other forms of personal and family harm
“Binging” on sucrose by rat on restricted
Rats that binged on sucrose or chow show
Nx-precipitable withdrawal signs
Habitual over-eating (palatable food
binging) shares same neurobiological
- acutely, positive reinforcement
via DA activation
- withdrawal elicits anxiety, craving,
- changes in DA, ACh, enkephalin
release in N. accumbens
- claimed treatment with naltrexone
Effect of Naltrexone with and without
behavioral therapy
Anton et al., JAMA, 2006
Percentage abstinence (clean urine) at six months
in heroin addicts on extended-release Ntx
(adapted from Reece, 2012)
Study___ Ntx inj
Krupitsky #1
Krupitsky #2
Ntx oral
Influence of Mu receptor variant on effect of Naltrexone in
alcoholism (Oslin et al., 2003)
Major review of Mu receptor variants and
Ntx in alcoholism (Ray et al., 2012)
Many existing problems:
 conflicting results of large-scale trials
 effect size of receptor variant too small
 multiple genes contribute to overall effect
 different effects in treatment seekers and
 findings met with “considerable
enthusiasm as well as a healthy level of
What is the added (or subtracted) value of
to consider
several aspects:
the have
to the concept
of addiction?
1)Considerable gain
in knowledge of the
neurobiological mechanisms, including
drug-related and other behaviors
2)Hence, some mechanistic basis for
broadening the definition to include
pathological gambling, eating, etc,
3) Modest gain in treatment by drugs based
on knowledge of mechanisms
4) Substantial loss through narrowing basis
of research: great overemphasis on drug
actions at expense of behavioral and
social influences known to be important
5) Possible future gain through beginnings
of research on environmental modification
of genetic and neurobiological processes
Overall conclusion
Neurobiological studies have added only a
small extra value so far to the
understanding of addiction
But they offer hope of a larger “value added”
in the reasonably near future, if they direct
much more effort to studying brain
interactions with environmental influences