Addiction & Maladaptive Learning
Kate M. Wassum
Biology of Learning & Memory
May 18 2015
Addiction and maladaptive learning
Drug and Alcohol Addition
Drug Mechanisms of Action
Persistent Brain changes in addiction
Pathways to addiction
Allostasis theory of Addiction
• Behavioral Support
• Neural Mechanisms
• Limitations
• Incentive sensitization theory of addiction
• Behavioral Support
• Neural Mechanisms
• Limitations
• Aberrant Habits
• Behavioral Support
• Neural Mechanisms
• Limitations
• Multi-faceted view of addiction
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Addiction
www.drugabuse.gov
Drug and Alcohol Addiction
Addiction is a chronic, often relapsing brain disease that causes compulsive drug seeking and
use despite harmful consequences to the addicted individual and to those around him or her.
Although the initial decision to take drugs is voluntary for most people, the brain changes that
occur over time challenge a person’s self control and ability to resist intense impulses urging
them to take drugs.
Characterized by:
1.) compulsion to seek and take the drug
2.) loss of control in limiting intake
3.) emergence of negative emotional state (e.g., dysphoria, anxiety, irritability) when access to
the drug is prevented
Behavioral Addictions
Syndromes analogous to substance addiction, but with a behavioral focus other than ingestion
of a psychoactive substance.
Typically produce short-term reward that may engender persistent behavior despite
knowledge of adverse consequences, i.e., diminished control over the behavior.
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Pathological Gambling (DSM)
Kleptomania (DSM)
Compulsive buying
Pathological skin picking
Sexual addiction
Excessive Tanning
Computer/video game addiction
Internet addiction
1.) compulsion
2.) loss of control
3.) withdrawal
Compulsive Overeating
Binge-eating/compulsive overeating
• Uncontrollable recurrent and frequent episodes of eating unusually large amounts of food
• Repeatedly eating large amounts of food to the point of discomfort or illness
• Not followed by purging
• Often overweight or obese
• Guilt, shame, and distress about binge eating
Drug and Alcohol Addiction
Modeling Drug Addiction
• Escalation of intake
• Compulsion to take the drug despite negative consequences
• Drug craving
• Withdrawal state when off drug
• Relapse or ‘reinstatement’ of drug-seeking behavior
Drug and Alcohol Addiction
Most Common Abused Substances:
• Alcohol
• Bath Salts (Synthetic Cathinones)
• Club Drugs
• Cocaine
• Hallucinogens
• Heroin
• Inhalants
• K2/Spice ("Synthetic Marijuana")
• Marijuana
• MDMA (Ecstasy/Molly)
• Methamphetamine
• Prescription Drugs & Cold Medicines
• Salvia
• Steroids (Anabolic)
• Tobacco/Nicotine
Drug and Alcohol Addiction- Brain Mechanisms
Neurotransmitter
Dopamine
Serotonin
Norepinephrine
Distribution in the Central
Functions Affected
Nervous System
Midbrain, Ventral tegmental Reward Movement,
area (VTA), Cerebral cortex, Attention, Memory
Hypothalamus
Midbrain, VTA, Cerebral
cortex, Hypothalamus
Midbrain, VTA, Cerebral
cortex, Hypothalamus
Endogenous opioids
Widely distributed in brain
(endorphin and enkephalin) but regions vary in type of
receptors, Spinal cord
Acetylcholine
Hippocampus, Cerebral
cortex, Thalamus, Basal
ganglia, Cerebellum
Endogenous cannabinoids Cerebral cortex,
(anandamide)
Hippocampus, Thalamus,
Basal ganglia
Glutamate
Widely distributed in brain
Gamma-aminobutyric acid
(GABA)
Widely distributed in brain
Drugs That Affect It
Cocaine, Methamphetamine,
Amphetamine. In addition,
virtually all drugs of abuse
directly or indirectly augment
dopamine in the reward
pathway
Mood, Sleep, Sexual desire, MDMA (ecstasy), LSD,
Appetite
Cocaine
Cocaine, Methamphetamine,
Sensory processing,
Amphetamine
Movement, Sleep, Mood,
Memory, Anxiety
Analgesia, Sedation, Rate of Heroin, Morphine,
bodily functions, Mood
Prescription painkillers
(Oxycodone)
Memory, Arousal, Attention, Nicotine
Mood
Movement, Cognition and
memory
Marijuana
Neuron activity (increased
rate), Learning, Cognition,
Memory
Neuron activity (slowed),
Anxiety, Memory, Anesthesia
Ketamine, Phencyclidine,
Alcohol
Sedatives, Tranquilizers,
Alcohol
Drug and Alcohol Addiction- Brain Mechanisms
Dopamine
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Catecholamine
Neuromodulator
G-protein coupled receptors
D1 (and D1-like- D5) receptors
• Excitatory G-protein
D2 (and D2-like- D3,4) receptors
• Inhibitory G-protein
Cell bodies in Ventral Tegmental Area and
Substantia Nigra
Drug and Alcohol Addiction- Brain Mechanisms
Drug and Alcohol Addiction- Brain Mechanisms
Drug and Alcohol Addiction- Brain Mechanisms
Drug and Alcohol Addiction- Brain Mechanisms
Drug and Alcohol Addiction- Persistent Brain Changes
Wilbrecht et al 2013
Time-lapse images show wiring changes
in the brain cells of a live mouse over
multiple days.
green arrows = new spines
blue arrows = lost spines
yellow arrows =stable spines
Drug and Alcohol Addiction- Persistent Brain Changes
Liu et al 2005
Chronic Cocaine facilitates LTP in VTA DA cells
Drug and Alcohol Addiction- Persistent Brain Changes
Tomasi & Volkow 2013
Reduced striatal D2 receptor
binding and DA release
Drug and Alcohol Addiction- Persistent Brain Changes
Filbey et al 2014
Marijuana users- reduced OFC gray matter volume
Psychological
processes
of addiction
Psychological
Processes
of Addiction
If addiction is maladaptive learning and motivated behavior…
… how might it become maladaptive???
-Disrupted Homeostasis/need-based learning and motivation
-Usurped reinforcement processes (positive v. negative reinforcement)
-Inflated influence of cues relative to drug hedonic (i.e., high) effect
-Loss of cognitive control over drug seeking- maladaptive habit learning
Pathways to Addiction
Allostasis/Negative Reinforcement
‘Avoidance’; related to the homeostasis theory of motivation
Drug use causes counter adaptations (opponent-processes) that counter the euphoric effects of
the drug. These can become larger with repeated drug use such that the hedonic set point
decreases. Drug use is driven by negative reinforcement, the alleviation of the negative
symptoms of withdrawal.
Incentive Sensitization
‘Craving’; related to the incentive motivation theory of motivation
Repeated exposure to a addictive substance persistently change brain cells and circuits (ventral
striatal dopamine) that normally regulate the attribution of incentive salience to reward-paired
cues, without changing the ‘liking’ circuitry, such that a drug is ‘wanted’ excessively more than it
is ‘liked’ and cues in the environment trigger inappropriate cravings and drug motivation.
Aberrant Habit Learning
Drug seeking ‘Habits’; related to cognitive v. implicit control of reward seeking
In addiction drug-seeking behavior becomes compulsive and dominated by the habit S-R
system, perhaps by excessive recruit of habit learning mechanisms with a down regulation of
the circuitry underlying cognitive, flexible, goal-directed reward seeking leading to maladaptive
behavior
Allostasis theory of addiction
Koob et al. (2000+)
-Homeostasis
-Opponent-process
Counter-adaptation to maintain homeostasis
‘Anti-reward’: ↓ reward circuitry/↑ stress circuitry
-Allostasis
Process of maintaining stability, or "apparent stability
Change in hedonic set-point.
Solomon and Corbit (1974)
Allostasis theory of addiction
Koob et al. (2000+)
-Homeostasis
-Opponent-process
Counter-adaptation to maintain homeostasis
‘Anti-reward’: ↓ reward circuitry/↑ stress circuitry
-Allostasis
Process of maintaining stability, or "apparent stability
Change in hedonic set-point.
a
Mood
Hedonic setpoint
Drug
b
Allostatic point
Allostatic point
Allostasis theory of addiction
Reinforcer: increases performance of an instrumental action
Positive reinforcement → pleasant event
Negative reinforcement → removal of unpleasant event
Allostasis theory of addiction
Koob et al. (2000+)
Drug use is driven by negative reinforcement (the ‘dark side’ of addiction)
There is a desire/need to alleviate the negative hedonic state induced in withdrawal
Drug-seeking and -taking actions are negatively reinforced when they lead to alleviate of the
negative withdrawal state
Less about getting ‘high’ (positive reinforcement) and more about not feeling bad (negative
reinforcement, counteracting ‘anti-reward’ systems)
Allostasis theory of addiction
Koob 2006
Brain Stimulation reward threshold
Allostasis theory of addiction
Ahmed et al. (2002) & Jang et al (2013)
Allostasis theory of addiction
Roberts et al 2005 & Schulteis et al 1995
Allostasis and obesity
Johnson and Kenny (2010)
Allostasis & addiction: Brain Mechanisms
A process
B process
Allostasis & addiction: Brain Mechanisms
VTA DA Neuron Firing
Diana et al 1995
Morphine
Withdrawn
Allostasis & addiction: Brain Mechanisms
NAc
Weiss et al 1996
Allostasis & addiction: Brain Mechanisms
NAc
Cocaine-self administration
Twining et al 2014
quinine
Allostasis & addiction: Brain Mechanisms
Tomasi & Volkow 2013
Hypodopamine function in
human drug addicts
Allostasis & addiction: Brain Mechanisms
Wang et al 2012
Methamphetamine abusers those who maintain abstinence v. relapse
Stress System- CRF
Corticotrophin-Releasing Factor
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41 amino acid-containing peptide
Distributed throughout CNS
• Highest density of cells bodies in hypothalamic PVN, BNST
CRF1 and CRF2 receptors
Mediates the hormonal, autonomic and behavioral responses to stress
Stress System- CRF
Corticotrophin-Releasing Factor
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41 amino acid-containing peptide
Distributed throughout CNS
• Highest density of cells bodies in hypothalamic PVN, BNST
CRF1 and CRF2 receptors
Mediates the hormonal, autonomic and behavioral responses to stress
Allostasis & addiction: Brain Mechanisms
BNST
Olive et al 2002
Etoh-Control
Etoh-Etoh
Control-Control
Etoh
Etoh
Etoh
Etoh
Allostasis & addiction: Brain Mechanisms
Amygdala
Rodriguez et al 1997
Allostasis & addiction: Brain Mechanisms
Amygdala
Richter & Weiss 1999
Allostasis & addiction: Brain Mechanisms
Koob 2009
CRF antagonist (BNST) alleviates the negative phenotype of withdrawal from multiple drugs
Allostasis & addiction: Brain Mechanisms
Koob 2013
CRF1 antagonist
CRF1 antagonist
CRF1 antagonist
Allostasis & addiction: Brain Mechanisms
Twining et al 2014
Cocaine-self administration
CRF antagonist
quinine
Allostasis theory of addiction
Limitations:
• Brain stimulation reward threshold = hedonic setpoint??
• Drug-seeking is more heavily reinstated by A process type mechanisms that B-Process
• Withdrawal is maximal 1-2 days off drug, but relapse grows over weeks to months
• Addicts often relapse well after withdrawal
• “No doc, craving is when you want it—want it so bad you can almost taste it… but you ain’t
sick… sick is, well sick”
• Alternative/additional explanations for withdrawal-induced escalation of drug seeking
Incentive Sensitization theory of addiction
Berridge and Robinson (1998-2012)
Cues come to be associated with rewards (through Pavlovian learning).
In so doing they take on both the hedonic and motivational properties of the primary incentive,
such that they can both produce a hedonic reaction and motivate behavior.
These two processes are termed ‘liking’ (hedonic/emotional) and ‘wanting’ (incentive
motivation).
They normally go together, but they are dissociable brain processes.
In addiction, repeated exposure to a potentially addictive substance can (in susceptible
individuals and under particular circumstances) persistently change brain cells and circuits that
normally regulate the attribution of incentive salience that causes reward ‘wanting’ (ventral
striatal dopamine) without changing the ‘liking’ circuitry such that a drug is ‘wanted’
excessively more than it is ‘liked’ and cues in the environment trigger inappropriate cravings
and drug motivation.
Incentive Sensitization theory of addiction
Berridge and Robinson (1998-2012)
Initial Drug Use
Pleasure
Drug Addiction
Incentive Sensitization theory of addiction
Triggers
PIT measure of incentive motivation
Incentive Sensitization theory of addiction
Wyvell and Berridge (2001)
Amphetamine
pre-treatment
Incentive Sensitization theory of addiction
LeBlanc, Maidment & Ostlund (2013)
Pre-treatment
Incentive Sensitization theory of addiction
LeBlanc, Ostlund & Maidment (2012)
Cocaine-seeking
Action
Cocaine-taking
Action
Incentive Sensitization theory of addiction
Corbit & Janak (2007)
Etoh CS
Etoh Seeking
Incentive Sensitization theory of addiction
Martinovic et al 2014
PIT
Humans
Incentive Sensitization theory of addiction
Garbusow et al 2015
Humans
Incentive Sensitization theory of addiction
Hogarth et al 2014
PIT
Humans
Incentive Sensitization and overeating
Tetley et al. (2009)
Humans
This was significantly higher for over-weight individuals
(when controlling for pizza preference)
Sign-tracking measure of incentive motivation
Robinson & Flagel (2009)
Incentive Sensitization theory of addiction
Saunders & Robinson (2010, 2011)
Cocaine self-administration
Cue-induced reinstatement
Progressive Ratio
Drug-primed reinstatement
Incentive Sensitization theory of addiction- Brain Mechanisms
Fuchs et al. 2014
Cue-induced
reinstatement
Test
Cue-induced
reinstatement
Test
Incentive Sensitization theory of addiction- Brain Mechanisms
Ostlund et al. 2014
CS+
CS-
Saline
Cocaine
Incentive Sensitization theory of addiction- Brain Mechanisms
MSNs
Saddoris et al. 2011
Incentive Sensitization theory of addiction- Brain Mechanisms
Ciccocioppo et al (2001)
NAc
Incentive Sensitization theory of addiction- Brain Mechanisms
Dopamine Release
Wong et al. (2006)
Humans
Incentive Sensitization theory of addiction- Brain Mechanisms
Garbusow et al 2015
Human Alcoholics
Neural Mechanism of Incentive Motivation
CeN
NAc
MOTOR
Dopamine
CS+
Incentive Sensitization theory of addiction- Brain Mechanisms
Lu et al (2005)
Incentive Sensitization theory of addiction- Brain Mechanisms
Lu et al (2005)
Cue-induced reinstatement tests
Block ERK phosphorylation
Cue-induced reinstatement tests
Induced CeN ERK phosphorylation
Incentive Sensitization theory of addiction- Brain Mechanisms
CeN
plasticity
NAc
MOTOR
Cravings
Compulsions
Dopamine
CS+
Incentive Sensitization theory of addiction- Limitations
Limitations:
• Disentangling motivational impact of cue from direct response elicitation (S-R) in cueinduced reinstatement
• Other forms of relapse (e.g., stress)
• Escalation of drug seeking?
• Drug seeking despite known consequences (not enough evidence yet)
• Dopamine/ventral striatum-centric approach
Habits
Adams (1982)
Extinction
Reinforced
Dev
Non
Extended
Limited
Dev
Non
Extended
Training
Dev
Non
Limited
Training
Habits
Tricomi, Balleine & O’Doherty (2009)
Humans
Goal-directed actions v. Habitual responses
Goal-directed Actions
Habitual Responses
Reward Value-Dependent
Action-Outcome Learning
Reward Value-Independent
Stimulus-Response Learning
Devalue
Aberrant Habit theory of addiction
Dickinson, Everrit, Robbins, Balleine etc. (2000-2013)
Habits are the result of stimulus-response S-R learning (and S-R control of behavioral
performance, rather than cognitive R-O)
Habits develop normally with extended training
Addictive substances are particularly effective at engaging the neural processes that support
habit learning - leading to habit acceleration, aberrations in the strength or content of habit
Habits are thought to involve striatal dopamine, all addictive substances increase striatal
dopamine, psychostimulants in particular can cause long-term changes in striatal dopamine
signaling
Under normal conditions a habit can be ‘broken’ when conditions arise that warrant
deliberation (e.g., punishment)- here behavioral control reverts back to the cognitive system
In addiction drug-seeking behavior can become compulsive and dominated by the habit S-R
system with a down regulation of cognitive reward-seeking circuitry leading to maladaptive
behavior
Aberrant Habit theory of addiction
Stimuli or contexts
often present with
drug use
S
This is exacerbated by the effects of
drugs
Drugs may (via acting on dopamineespecially stimulants) accelerate this
reinforcement process
USap
drug
R
Drug-seeking action
Take drugs because of desire to get high
Aberrant Habit theory of addiction
S
USap
R
Negative consequences:
Overdose/illness
Negative consequences:
Incarceration
Aberrant Habit theory of addiction
Nelson and Killcross (2006)
Pre-treatment
Aberrant Habit theory of addiction
LeBlanc, Maidment & Ostlund (2013)
Pre-treatment
Pre-treatment
Aberrant Habit theory of addiction
Miles et al. (2003)
Aberrant Habit theory of addiction
Dickinson et al 2002
Aberrant Habit theory of addiction
Hogarth et al 2012
Humans
Compulsive over-eating and habit
Furlong et al. 2014
High-fat/sugar diet & Binge eating
Compulsive
over-eating and habit
Recall:
Habits
Neal et al. (2011)
Humans
Stress and Habits
Soares et al 2012
Two cohorts of medical students: one was under their normal academic activities
(controls), whereas the other included subjects that had just finished their long period
of preparation for the medical residence selection exam (chronic psychosocial stress).
Motivation Neurocircuitry: Striatum
Striatum
Motor control, Action selection, Motivation,
cue-reward associations, action-reward
learning, reinforcement learning
DLS
Habits
DMS
Cognitive
Action
NAc
NAs
Inputs: cortex (OFC, mPFC, sensorimotor),
limbic structures (amygdala, hippocampus),
thalamus,
substantia
nigra,
ventral
tegmental area
Outputs: Globus Pallidus
Striatal Loops
Dorsal Lateral Striatum (Putamen)
Dorsal Medial Striatum(Caudate)
Ventral Striatum- Nucleus Accumbens Core
Ventral Striatum- Nucleus Accumbens Shell
Aberrant Habit theory of addiction- Brain Mechanisms
Murray et al 2012
aDLS
pDMS
Dose of flupenthixol
Dose of flupenthixol
Aberrant
Habit
of addictionBrain
Mechanisms
Addiction
as theory
Aberrant
learning:
Habits
Corbit et al 2012
Aberrant
Habit
of addictionBrain
Mechanisms
Addiction
as theory
Aberrant
learning:
Habits
Soares et al 2012
Two cohorts of medical students: one was under their normal academic activities
(controls), whereas the other included subjects that had just finished their long period
of preparation for the medical residence selection exam (chronic psychosocial stress).
Stress-induced insensitivity to outcome devaluation is
reversible and associated with variations of the activation of
the corticostriatal networks
Aberrant
Habit
of overeatingMechanisms
Addiction
as theory
Aberrant
learning:Brain
Habits
Furlong et al. 2014
Addiction as Aberrant Habits- Limitations
Limitations:
• Pathological Craving
• Motivational Compulsion
• Flexible drug seeking is often required
• Withdrawal
Pathways to Addiction
Allostasis/Negative Reinforcement
‘Avoidance’
Incentive Sensitization
‘Craving’
Aberrant Habit Learning
Drug seeking ‘Habits’
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One size does not fit all
Different drugs different forms of addiction?
Stages of drug use, abuse, addiction
Phases of the drug-seeking and –taking process
Interaction of the psychological processes (and neural mechanisms) controlling addiction
Translation animal → human // human → animal
Framework for developing addiction pharmacotherapies