2. Lesion/ imaging studies establish important
brain circuits for specific behaviours.
But what of underlying neurobiological
processes that mediate behaviour?
3. Pharmacology – Behaviour
Understanding the mechanism of actions of drugs, provides
information on underlying neural processes that control specific
behaviours.
The natural reward system – hijacked by drugs of abuse
4. Where do drugs of abuse act?
Mesocorticolimbic pathway: ventral tegmental area → nucleus accumbens
ventral tegmental area → prefrontal cortex
Neurotransmitter - dopamine
PET
SCAN
5. Binding sites of cocaine following acute
administration
Striatum:
contains the
nucleus accumbens
Fowler et al (1989) Synapse 4: 371-377
6. How do we know this pathway
is involved in reward ?
Control group
Damage to the nucleus
accumbens decreases self- Damage to
nucleus
administration of heroin. accumbens
Mesocorticolimbic pathway
needed for drug to have a ANIMAL STUDIES:
rewarding effect. self-administration model
7. Natural reinforcers (e.g. food and sex) increase
extracellular Dopamine in the Nucleus Accumbens
% of Basal Release
FOOD 1100
% of Basal Release
1000
200
900
AMPHETAMINE
800
150 700
600
100 500
400
Empty 300
50 Box Feeding 200
100
0 0
0 60 120 180 0 1 2 3 4 5 hr
Time (min) Time After Amphetamine
Di Chiara et al.
All known addictive drugs activate this system
Drug of
Dopamine release
abuse Increased
in the Sensation
activation of
Natural mesocorticolimbic of reward
pathway
reward pathway
(dopamine levels measured by microdialysis)
8. Drugs of abuse maintain dopamine
release in the nucleus accumbens
shell after repeated exposure -
hijack the reward pathway.
naïve animals pre-exposed animals
9. The mesocorticolimbic dopamine system
Dopamine neurons projecting from ventral tegmental area (VTA)
to nucleus accumbens (NAcc) and prefrontal cortex (PFC)
Critical pathway for reward and reinforcement
mouse /rat
Natural reinforcers (e.g. food and sex)
increase release of extracellular DA in Nacc
10. The mesocorticolimbic dopamine system
All known addictive drugs activate this system
Behaviours leading to activation tend to be repeated (are reinforced)
Blockade of DA in this region attenuates most measurable reinforcing and
rewarding effects of addictive drugs
Activation by addictive drugs much more powerful and reliable than activation
by natural reinforcers (they hijack the system)
11. Psychomotor stimulants - cocaine and amphetamine
Potentiate monoaminergic transmission by inhibition of dopamine (DA),
serotonin (5-HT) and norepinephrine (NE) reuptake transporters
Cocaine blocks and inhibits transporter to prolong pool of extracellular DA
Amphetamine reverses transporter to increase extracellular DA levels
Action at dopamine
transporter (DAT)
most directly related to
reinforcing effects
Cocaine and amphetamine
extracellular DA in NAcc
12. Psychomotor stimulants - cocaine and amphetamine
Potentiate monoaminergic transmission by inhibition of dopamine (DA),
serotonin (5-HT) and noradrenaline (NE) reuptake transporters
But subjective effects probably mediated by action of drugs at other sites:
Feelings of euphoria, speeding etc.
through activation of this pathway
or actions at transporters located
elsewhere
In animal studies:
DAT transporter knockouts still show
some behavioural response to cocaine.
Only triple knockout (DAT, SERT and NET)
show no drug action
Extracellular 5-HT and NA
13. Opiates (e.g. morphine and heroin)
Act at endogenous opioid receptors (Gi/Go coupled)
Inhibitory - decrease adenylyl cyclase activity
- lead to open K+ channels, closed Na+ channels
Different subtypes on different cells in different brain regions (µ, κ, δ)
Most of morphine’s analgesic and rewarding properties are through actions at
µ (mu) receptors
Subjective effects:
Euphoria and intense rush with heroin compared to morphine due to route of
administration and entry to brain (seconds vs minutes)
Relaxing effects – inhibition of Noradrenergic pathways
Physical dependence – compensatory changes in these pathways (Week 7)
14. Opiates (e.g. morphine and heroin)
But also, as with other drugs of abuse also impact on function of the
Dopaminergic reward pathways
Reward and reinforcement by:
a) Disinhibition of DA neurons in VTA (DA neurons fire tonically but are
inhibted by GABA interneurons - µ receptor activation on GABA neurons
inhibits them from firing - relieving inhibition on DA neurons
b) Action at opiate receptors in the NAcc - independent of DA release (µ or δ)
DA neuron firing
DA DA release in NAcc
independent
action in NAcc
15. Normal reward system
Cortical control of VTA firing
PFC VTA
glu GABA
NAcc Dopamine
Opiate action in VTA to increased DA release
Disinhibition of DA neurons in VTA through inhibition of GABA interneuron
Morphine acts
at mu opioid
receptor inhibition
(inhibitory)
VTA
No inhibition
DA firing
NAcc
16. Alcohol (EtOH)
- GABAA agonist (inhibitory)
-NMDA antagonist (blocks excitation)
- also affects glycine, nicotinic & serotonin receptors
- Large doses inhibit functioning of most
voltage gated channels (sedation)
Subjective effects of EtOH
Low doses of alcohol - mild euphoria and anxiolytic effects
Higher doses - poor coordination, amnesia, sedation
Chronic alcoholism - Korsakoff’s Amnesia
(caused by neurodegeneration – not an effect of alcohol itself but thiamine deficiency)
17. Alcohol (EtOH)
Effects on Reward Circuitry
1) EtOH leads to increased DA release in NAcc
NMDA antagonism of cortical inputs to VTA may lead to increased DA release
in NAcc
PFC 1 firing
No excitation
2
alcohol No inhibition
3
DA firing
NAcc
1) Supression of cortical output
2) No activation of GABA interneuron
3) DA neuron disinhibited in VTA and able to fire
Ethanol rewarding effects blocked by DA receptor antagonists in NAcc
18. Alcohol (EtOH)
Effects on Reward Circuitry
2) Involvement of Opiate system
Naltrexone (an opiate antagonist)
- reduces EtOH self administration in animals
- used as a treatment to reduce EtOH consumption, relapse and
craving in alcoholics
(DA independent effects on reward)
19. Nicotine
Action at nicotinic acetylcholine receptors (nAChRs)
-Ligand gated ion channels located pre or post-synaptically
(present throughout brain, excitatory or modulatory)
-Presynaptic receptors - influx of Ca2+ - transmitter release
Unlike cocaine and opiates - powerfully reinforcing in absence of subjective
euphoria
Prolonged activation of nicotinic receptors leads to desensitization
first cigarette of day – subjective response
(rapid desensitization of receptors)
subsequent cigarettes – less obvious reported effects
(overnight – normalization of receptor state)
20. Nicotine
Effects on Reward Circuitry
Nicotine treatment increases DA release in the NAcc
Release of DA likely due to:
a) activation of ACh receptors on cell body in the VTA (increasing cell firing)
b) facilitation of DA release by pre-synaptic receptors in NAcc
Presynaptic
Postsynaptic activity
activity
DA release DA neuron firing
DA release in NAcc
Opiate system involvement
Both opiate and DA antagonists can block nicotine-induced behaviours and self
administration
(Naltrexone is on trial as a drug to aid smoking cessation)
21. Natural reward systems
Experiential – learn what, when and where rewards are likely.
Understanding actions of drugs of abuse – understand the reward system
Natural rewards Drugs
DA release in the NAcc More DA release in the NAcc
Behaviours associated
with stimuli are reinforced Drug taking is reinforced
We repeat those behaviours
But how do we get addicted?
22. Tolerance - diminishing effect of drug after repeated administration
- need more drug to get the same effect
HOMEOSTATIC -COMPENSATORY CHANGES
Dependence - physical or emotional - adaptive state
- homeostatic response to repeated drug administration
- unmasked by withdrawal (e.g. heroin - cold turkey)
Sensitization - repeated administration elicits escalating effects
- effect of psychostimulants (used in animal models)
ASSOCIATIVE LEARNING PROCESSES
Addiction - compulsive taking
- craving and relapse - persistent for many years
23. Physical dependence to opiates (Week 6 Lecture 2)
Chronic activation of opiate receptors leads to homeostatic mechanism that
compensates for the functional changes leading to tolerance and
physical dependence
Gs Gi
Locus coeruleus neurons - activated by multiple pathways,
ionotropic (e.g. glutamate) metabotropic (e.g. Gs coupled)
Acute morphine - acutely inhibits firing of LC neurons through Gi pathway
Gs
Gi
Chronic treatment - LC neurons return to their normal firing rates Gs Gi
(Gs pathway component upregulate to match Gi)
Gi
Withdrawal - dramatic increase in LC firing Gs
(In absence of Gi inhibiton Gs hypersensitive)
24. Physical Dependence to alcohol
Acute effects of alcohol
-agonist at GABAA receptor ( )
out
in
-antagonist at NMDA receptor ( )
Cells inhibited from firing Cl- Cl- Cl- Na+
Chronic alcohol
Down regulation of GABAA receptors out
Upregulation of NMDA receptors in
In presence of alcohol firing rates
Cl- Na+ Na+
return to normal
Withdrawal
in absence of alcohol out
balance shifts to excitation in
physical symptoms
- agitation, tremors, hypertension, seizures Na+ Na+ Na+ Na+ Na+
25. Emotional Dependence (e.g. psychomotor stimulants)
- dysphoria, anhedonia, anxiety on withdrawal
Compensatory changes in VTA / NAcc to lower DA transmission:
Blockade of reuptake - too much DA in NAcc synapses
Compensatory change - less DA release in NAcc
In presence of drug - normal DA function in NAcc
In absence of drug - not enough DA for natural rewarding stimuli
- anhedonia, dysphoria etc.
26. Emotional Dependence (e.g. psychomotor stimulants)
Neurobiological explanation:
Increased activity at D1 receptors (Gs coupled) in NAcc
Adenylyl cyclase – cAMP - PKA activation
Phosporylation of CREB (transcription factor)
Increased dynorphin (DYN) synthesis
(neuropeptide - endogenous opioid)
dynorphin released in VTA
acts at Kappa opioid R
Inhibits VTA neuron firing
and Nacc DA release
Less DA release in Nacc
27. Tolerance - diminishing effect of drug after repeated administration
- need more drug to get the same effect
HOMEOSTATIC -COMPENSATORY CHANGES
Dependence - physical or emotional - adaptive state
- homeostatic response to repeated drug administration
- unmasked by withdrawal (e.g. heroin - cold turkey)
Sensitization - repeated administration elicits escalating effects
- effect of psychostimulants (used in animal models)
ASSOCIATIVE LEARNING PROCESSES
Addiction - compulsive taking
- craving and relapse - persistent for many years
