Lecture 2: Neurobiology of Addiction
Dopamine and Reward: Olds & Milner (1954): Rat study Electrical stimulation occurs when lever
is pressed. The rat went ‘crazy’ & repeatedly pressed the lever when electrode stimulated the septal
areas. Made something unpleasurable become pleasurable = created an addict. This study
encouraged the concept of a ‘reward centre’.
Brain Regions & Neuronal Pathways:
Neurons connect areas via pathways, and send and integrate information; neurons can be
long or short.
For example, the thalamus receives information about pain, this is then sent to the sensory
cortex. The reward pathway is activated when the individual receives or sees the possibility
of positive reinforcement.
Brain Transmission: Action potential (electrical impulse) travels down the axon towards the synaptic
terminal. The terminal makes a connection (synapse) with dendrite of neighbouring neuron, where it
transmits a neurochemical signal. Terminals can synapse onto dendrites, somata or axons!
Synaptic Transmission:
As an electrical impulse arrives at the terminal it triggers vesicles containing
neurotransmitters, to move towards and bond with the terminal membrane, released into
synaptic cleft, NT binds to specific protein receptor (lock & key) on membrane of a
neighbouring neuron
Neighbouring neurons release compounds called neuromodulators; which enhance or inhibit
the effects of NT’s, such as dopamine.
Neuromodulator example = endorphin. This binds to opiate receptors on the post synaptic
cell & thereby alter the effect of dopamine. Neighbouring neurons as neuromodulators are
ones surrounding the 2 involved in the neurotransmission. Endorphins are broken down by
enzymes (specialised protein).
Dopamine: In relation to addiction DA may play a role in many different processes that are relevant:
anhedonia, prediction error, salience/attention, cost/benefit computation, uncertainty processing,
incentive salience, energising/motivating behaviour – these are what dopamine rich brain areas
focus on.
So, DA is more concentrated in some brain areas than others; where they are concentrated, causes
previously mentioned behavioural manifestation.
The reward pathway: VTA (Ventral tegmental area) to the Nucleus accumbens onto the PFC.
Addictive stimulants e.g. alcohol & sex, electrically stimulate the VTA (this is where the
reward pathway begins). As the PFC is involved in reward, we know that all of these
outcomes will have higher functions in the brain.
Manufactured drugs impact this pathway they act as modulators of DA neurotransmission.
,The Action of Heroin
Heroin è brain: very rapid when injected or smoked
Enzymes convert heroin è morphine, which binds to opiate receptors (including parts of
cerebral cortex, the VTA, nucleus accumbens, thalamus, brainstem, and spinal cord)
In particular the reward pathway and the pain pathway (thalamus, brainstem, spinal cord);
this è analgesia (reduction in detection of pain)
Opiates binding to receptors in the nucleus accumbens (N Acc):
Morphine binds to opiate receptors on neuron A; causing it to decrease the release of GABA
(this inhibits DA release by neuron B). Consequently, neuron B now releases more DA than
normal. The released DA then binds to DA receptors on neuron C. Morphine is a
neuromodulator.
The Action of Cocaine: There are two forms of Cocaine:
Powdered (hydrochloride salt); which is snorted, takes a relatively slow route through the
nose heart lungs heart brain.
Freebase form (crack); which is smoked, takes a more rapid route through lungs heart
brain.
The faster the drug affects the brain, the more addictive the substance. Time between taking
the drug & experiencing the rewarding effects.
Cocaine reaches all areas of the brain but only binds to specific areas these are = VTA &
nucleus accumbens (reward pathways) & caudate nucleus (may explain other effects e.g.
increased stereotypic/repetitive behaviours e.g. pacing, nail-biting, scratching)
When cocaine is present, it binds to the uptake pumps and prevents them from transporting
DA back into the terminal Consequently, more DA builds up in the synaptic space and
causes a net increase in DA neurotransmission.
So, cocaine & heroin have different effects on the brain, yet are both highly addictive. This also
explains why they have different effects on the body.
Both Heroin & cocaine cause DA to stay in the system even longer (increased levels of DA);
but heroin acts on the neuromodulators and cocaine acts of the reuptakers.
Key Neuroanatomical Structures in Addiction:
1. Nucleus Accumbens & Central Nucleus of Amygdala: Involved in reward. Forebrain
structures involved in the rewarding effects of drugs of abuse and drives the binge
intoxication stage of addiction. Contains key reward neurotransmitters: dopamine and
opioid peptides
2. Extended Amygdala: involved in anti-reward system. Composed of central nucleus of the
amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial part of the
nucleus accumbens. Contains “brain stress” neurotransmitter, CRF that controls hormonal,
sympathetic, and behavioral responses to stressors, and is involved in the anti-reward
effects of drug dependence
, 3. Medial Prefrontal Cortex: neurobiological substrate for executive functions that are
compromised in drug dependence and play a key role in facilitating relapse. Contains major
glutamatergic projection to nucleus accumbens and amygdala.
Allostatic Model of Drug Addiction (Koob & Le Moal): A Framework for Addiction
Summary:
1. Binge Intoxication: Start taking or using in larger and larger quantities. This stage is thought
as the feel good stage; it is typically focused on positive reinforcing effects of drugs,
mediated by dopaminergic pathways in the medial forebrain. This stage involves serotonin;
opioid peptides and GABA. The change in dose is caused by a change in threshold; more
drugs needed to get the same effect.
2. Withdrawal/Negative Effect: This is thought of as the ‘dark side of addiction’. Involves the
hypoactivation (less than normal) of DA pathways, increased brain reward thresholds during
acute withdrawal (within system adaptations). Then, there is a recruitment of ‘anti-reward’
brain systems in amygdala involves corticotrophin releasing factor (CRF), dynorphin &
norepinephrine. This is thought of as a between systems adaptation.
Systems are visually involved in stress responses & activate to restore balance in the
chronic presence. This stage adds brain areas that make you feel bad in the absence
of the drug
3. Preoccupation/Anticipation: Negative feelings triggered by withdrawal = adaptational
changes in brain function via chronic drug use which allows for sensitivity to relapse & rapid
re-addiction. May be centred in deficits that develop in PFC (attention, memory, inhibition).
This stage is involved in change.
Positive Reinforcement Negative Reinforcement (withdrawal) Change in Cognitive Function
Allostatic Model:
Allostatic: Maintenance of stability outside the normal homeostatic range. An allostatic load is the
force the body has to cope with when these chronic resets occur.
This model was developed on the basis of opponent-process models; in this model system
parameters are continually reset across time in response to chronic demands on the body e.g.
getting used to reduced food intake.
After the first few experiences, the high isn’t as impacting anymore, and the low is more influential.
Allostatic load involves dealing with this; eventually in a position where the drug isn’t making you
feel good, only more low, people take more drugs to reach a normal level, not the high anymore
(addiction).
1. Initial positive reinforcing effects of drugs in brain rewards regions
2. Chronic use leading to down regulation of dopaminergic and hypo activity in brain reward
regions (within system adaptations: drug elicits an opposing, neutralising reaction within the
same system in which the drug elicits its primary and unconditioned reinforcing actions)
, 3. Recruitment of opponent processes based around HPA stress systems and CRF in
hypothalamus (between system adaptation: different neurobiological systems that one
initially activated by the drug are recruited)
Phase 1: Initial positive reinforcing effects of drugs in brain reward regions
Increase in extracellular dopamine levels
• Correlated with subjective feeling of ‘high’ and euphoria
• Related to speed of entry of drugs into brain; faster brain uptake associated with
greater reinforcing effects i.e. phasic vs tonic firing of DA
- Tonic firing: regular firing patterns
- Phasic firing: spontaneous bursts of activity
- Wannat et al (2010): severe exposure to addictive drugs = increase in tonic
DA firing. Recent studies suggest abused drugs similarly enhance phasic
events.
• Mimics responses to natural reinforcers, but at much higher concentration
Phase 2: Down-regulation of dopaminergic and hypoactivity in brain reward regions
Drug related cues can also increase DA release in the striatum and are associated with increased
drug administration in animals and humans, and correlate with self-report of craving in humans
Volkow et al. (2006) PET scans examine DA release in 18 cocaine-addicted individuals and correlate
this with self-report craving and addiction severity.
• Presented a cocaine-related video and video of natural scene across two days
• Cocaine video significantly increased DA release in the striatum
• DA change in the dorsal striatum significantly positively associated with addiction
severity and self-report of craving.
• Down regulation and hypoactivity in brain reward regions
Changes in DA and reward mediated regions:
• Significant reductions in DA D2 receptor availability (low DA), persisting months
after withdrawal
• Evidenced by reduced striatal DA release in response to psychostimulants in drug
abusers
• Reduced incentives for natural reinforcers due to increased thresholds for reward
• Increase in drug-seeking to compensate for increased reward thresholds e.g. shift
from using drugs to feel ‘high’ to using drugs to feel normal
Dopamine and Reward: Olds & Milner (1954): Rat study Electrical stimulation occurs when lever
is pressed. The rat went ‘crazy’ & repeatedly pressed the lever when electrode stimulated the septal
areas. Made something unpleasurable become pleasurable = created an addict. This study
encouraged the concept of a ‘reward centre’.
Brain Regions & Neuronal Pathways:
Neurons connect areas via pathways, and send and integrate information; neurons can be
long or short.
For example, the thalamus receives information about pain, this is then sent to the sensory
cortex. The reward pathway is activated when the individual receives or sees the possibility
of positive reinforcement.
Brain Transmission: Action potential (electrical impulse) travels down the axon towards the synaptic
terminal. The terminal makes a connection (synapse) with dendrite of neighbouring neuron, where it
transmits a neurochemical signal. Terminals can synapse onto dendrites, somata or axons!
Synaptic Transmission:
As an electrical impulse arrives at the terminal it triggers vesicles containing
neurotransmitters, to move towards and bond with the terminal membrane, released into
synaptic cleft, NT binds to specific protein receptor (lock & key) on membrane of a
neighbouring neuron
Neighbouring neurons release compounds called neuromodulators; which enhance or inhibit
the effects of NT’s, such as dopamine.
Neuromodulator example = endorphin. This binds to opiate receptors on the post synaptic
cell & thereby alter the effect of dopamine. Neighbouring neurons as neuromodulators are
ones surrounding the 2 involved in the neurotransmission. Endorphins are broken down by
enzymes (specialised protein).
Dopamine: In relation to addiction DA may play a role in many different processes that are relevant:
anhedonia, prediction error, salience/attention, cost/benefit computation, uncertainty processing,
incentive salience, energising/motivating behaviour – these are what dopamine rich brain areas
focus on.
So, DA is more concentrated in some brain areas than others; where they are concentrated, causes
previously mentioned behavioural manifestation.
The reward pathway: VTA (Ventral tegmental area) to the Nucleus accumbens onto the PFC.
Addictive stimulants e.g. alcohol & sex, electrically stimulate the VTA (this is where the
reward pathway begins). As the PFC is involved in reward, we know that all of these
outcomes will have higher functions in the brain.
Manufactured drugs impact this pathway they act as modulators of DA neurotransmission.
,The Action of Heroin
Heroin è brain: very rapid when injected or smoked
Enzymes convert heroin è morphine, which binds to opiate receptors (including parts of
cerebral cortex, the VTA, nucleus accumbens, thalamus, brainstem, and spinal cord)
In particular the reward pathway and the pain pathway (thalamus, brainstem, spinal cord);
this è analgesia (reduction in detection of pain)
Opiates binding to receptors in the nucleus accumbens (N Acc):
Morphine binds to opiate receptors on neuron A; causing it to decrease the release of GABA
(this inhibits DA release by neuron B). Consequently, neuron B now releases more DA than
normal. The released DA then binds to DA receptors on neuron C. Morphine is a
neuromodulator.
The Action of Cocaine: There are two forms of Cocaine:
Powdered (hydrochloride salt); which is snorted, takes a relatively slow route through the
nose heart lungs heart brain.
Freebase form (crack); which is smoked, takes a more rapid route through lungs heart
brain.
The faster the drug affects the brain, the more addictive the substance. Time between taking
the drug & experiencing the rewarding effects.
Cocaine reaches all areas of the brain but only binds to specific areas these are = VTA &
nucleus accumbens (reward pathways) & caudate nucleus (may explain other effects e.g.
increased stereotypic/repetitive behaviours e.g. pacing, nail-biting, scratching)
When cocaine is present, it binds to the uptake pumps and prevents them from transporting
DA back into the terminal Consequently, more DA builds up in the synaptic space and
causes a net increase in DA neurotransmission.
So, cocaine & heroin have different effects on the brain, yet are both highly addictive. This also
explains why they have different effects on the body.
Both Heroin & cocaine cause DA to stay in the system even longer (increased levels of DA);
but heroin acts on the neuromodulators and cocaine acts of the reuptakers.
Key Neuroanatomical Structures in Addiction:
1. Nucleus Accumbens & Central Nucleus of Amygdala: Involved in reward. Forebrain
structures involved in the rewarding effects of drugs of abuse and drives the binge
intoxication stage of addiction. Contains key reward neurotransmitters: dopamine and
opioid peptides
2. Extended Amygdala: involved in anti-reward system. Composed of central nucleus of the
amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial part of the
nucleus accumbens. Contains “brain stress” neurotransmitter, CRF that controls hormonal,
sympathetic, and behavioral responses to stressors, and is involved in the anti-reward
effects of drug dependence
, 3. Medial Prefrontal Cortex: neurobiological substrate for executive functions that are
compromised in drug dependence and play a key role in facilitating relapse. Contains major
glutamatergic projection to nucleus accumbens and amygdala.
Allostatic Model of Drug Addiction (Koob & Le Moal): A Framework for Addiction
Summary:
1. Binge Intoxication: Start taking or using in larger and larger quantities. This stage is thought
as the feel good stage; it is typically focused on positive reinforcing effects of drugs,
mediated by dopaminergic pathways in the medial forebrain. This stage involves serotonin;
opioid peptides and GABA. The change in dose is caused by a change in threshold; more
drugs needed to get the same effect.
2. Withdrawal/Negative Effect: This is thought of as the ‘dark side of addiction’. Involves the
hypoactivation (less than normal) of DA pathways, increased brain reward thresholds during
acute withdrawal (within system adaptations). Then, there is a recruitment of ‘anti-reward’
brain systems in amygdala involves corticotrophin releasing factor (CRF), dynorphin &
norepinephrine. This is thought of as a between systems adaptation.
Systems are visually involved in stress responses & activate to restore balance in the
chronic presence. This stage adds brain areas that make you feel bad in the absence
of the drug
3. Preoccupation/Anticipation: Negative feelings triggered by withdrawal = adaptational
changes in brain function via chronic drug use which allows for sensitivity to relapse & rapid
re-addiction. May be centred in deficits that develop in PFC (attention, memory, inhibition).
This stage is involved in change.
Positive Reinforcement Negative Reinforcement (withdrawal) Change in Cognitive Function
Allostatic Model:
Allostatic: Maintenance of stability outside the normal homeostatic range. An allostatic load is the
force the body has to cope with when these chronic resets occur.
This model was developed on the basis of opponent-process models; in this model system
parameters are continually reset across time in response to chronic demands on the body e.g.
getting used to reduced food intake.
After the first few experiences, the high isn’t as impacting anymore, and the low is more influential.
Allostatic load involves dealing with this; eventually in a position where the drug isn’t making you
feel good, only more low, people take more drugs to reach a normal level, not the high anymore
(addiction).
1. Initial positive reinforcing effects of drugs in brain rewards regions
2. Chronic use leading to down regulation of dopaminergic and hypo activity in brain reward
regions (within system adaptations: drug elicits an opposing, neutralising reaction within the
same system in which the drug elicits its primary and unconditioned reinforcing actions)
, 3. Recruitment of opponent processes based around HPA stress systems and CRF in
hypothalamus (between system adaptation: different neurobiological systems that one
initially activated by the drug are recruited)
Phase 1: Initial positive reinforcing effects of drugs in brain reward regions
Increase in extracellular dopamine levels
• Correlated with subjective feeling of ‘high’ and euphoria
• Related to speed of entry of drugs into brain; faster brain uptake associated with
greater reinforcing effects i.e. phasic vs tonic firing of DA
- Tonic firing: regular firing patterns
- Phasic firing: spontaneous bursts of activity
- Wannat et al (2010): severe exposure to addictive drugs = increase in tonic
DA firing. Recent studies suggest abused drugs similarly enhance phasic
events.
• Mimics responses to natural reinforcers, but at much higher concentration
Phase 2: Down-regulation of dopaminergic and hypoactivity in brain reward regions
Drug related cues can also increase DA release in the striatum and are associated with increased
drug administration in animals and humans, and correlate with self-report of craving in humans
Volkow et al. (2006) PET scans examine DA release in 18 cocaine-addicted individuals and correlate
this with self-report craving and addiction severity.
• Presented a cocaine-related video and video of natural scene across two days
• Cocaine video significantly increased DA release in the striatum
• DA change in the dorsal striatum significantly positively associated with addiction
severity and self-report of craving.
• Down regulation and hypoactivity in brain reward regions
Changes in DA and reward mediated regions:
• Significant reductions in DA D2 receptor availability (low DA), persisting months
after withdrawal
• Evidenced by reduced striatal DA release in response to psychostimulants in drug
abusers
• Reduced incentives for natural reinforcers due to increased thresholds for reward
• Increase in drug-seeking to compensate for increased reward thresholds e.g. shift
from using drugs to feel ‘high’ to using drugs to feel normal
