mm emotion reward_2_2011
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Brain and BehaviourWeek 8 Lecture 2:
Addiction
Dr M J Morgan
Lesion/ imaging studies establish important brain circuits for specific behaviours.
But what of underlying neurobiological processes that mediate behaviour?
Pharmacology – BehaviourUnderstanding 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
Mesocorticolimbic pathway: ventral tegmental area nucleus accumbens ventral tegmental area prefrontal cortex
Neurotransmitter - dopamine
PETSCAN
Where do drugs of abuse act?
Binding sites of cocaine following acute administration
Fowler et al (1989) Synapse 4: 371-377
Striatum:contains the
nucleus accumbens
How do we know this pathwayis involved in reward ?
Damage to the nucleus accumbens decreases self-administration of heroin.
Mesocorticolimbic pathway needed for drug to have a rewarding effect.
Control group
Damage to nucleus accumbens
ANIMAL STUDIES: self-administration model
Natural reinforcers (e.g. food and sex) increaseextracellular Dopamine in the Nucleus Accumbens
All known addictive drugs activate this system
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EmptyBox Feeding
Di Chiara et al.
FOOD
Drug of abuse Dopamine release
in the mesocorticolimbic
pathway
Sensation of rewardNatural
reward
Increased activation of
pathway
(dopamine levels measured by microdialysis)
Drugs of abuse maintain dopamine release in the nucleus accumbens shell after repeated exposure - hijack the reward pathway.
pre-exposed animalsnaïve animals
The mesocorticolimbic dopamine systemDopamine 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
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)
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
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
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 (, , )
Most of morphine’s analgesic and rewarding properties are through actions at (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)
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 - 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 ( or )
DA independent action in NAcc
DA neuron firing
DA release in NAcc
Opiate action in VTA to increased DA releaseDisinhibition of DA neurons in VTA through inhibition of GABA interneuron
NAcc
Morphine acts at mu opioid receptor (inhibitory)
firingDANo inhibition
inhibition
Normal reward systemCortical control of VTA firing
PFC
NAcc
VTAglu GABA
Dopamine
VTA
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)
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
1) Supression of cortical output2) No activation of GABA interneuron3) DA neuron disinhibited in VTA and able to fire
Ethanol rewarding effects blocked by DA receptor antagonists in NAcc
PFC
NAcc
firingNo excitation
No inhibitionfiringDA
alcohol
1
3
2
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)
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)
NicotineEffects 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
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)
Presynaptic activity DA release
Postsynaptic activity
DA neuron firing
DA release in NAcc
Drugs
More DA release in the NAcc
Drug taking is reinforced
But how do we get addicted?
Natural rewards
DA release in the NAcc
Behaviours associated with stimuli are reinforced
We repeat those behaviours
Natural reward systems
Experiential – learn what, when and where rewards are likely.
Understanding actions of drugs of abuse – understand the reward system
Tolerance - diminishing effect of drug after repeated administration- need more drug to get the same effect
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)
Addiction - compulsive taking- craving and relapse - persistent for many years
HOMEOSTATIC -COMPENSATORY CHANGES
ASSOCIATIVE LEARNING PROCESSES
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
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
Chronic treatment - LC neurons return to their normal firing rates(Gs pathway component upregulate to match Gi)
Withdrawal - dramatic increase in LC firing(In absence of Gi inhibiton Gs hypersensitive)
Gs Gi
Gs
Gi
Gs Gi
Gi
Gs
Physical Dependence to alcohol
Acute effects of alcohol-agonist at GABAA receptor ( )-antagonist at NMDA receptor ( )
Cells inhibited from firing Cl- Na+
in
out
Cl- Cl-
Chronic alcoholDown regulation of GABAA receptorsUpregulation of NMDA receptors
In presence of alcohol firing ratesreturn to normal
Cl- Na+
in
out
Na+
Withdrawalin absence of alcoholbalance shifts to excitationphysical symptoms - agitation, tremors, hypertension, seizures Na+
in
out
Na+ Na+ Na+ Na+
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.
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 VTAacts at Kappa opioid R
Inhibits VTA neuron firingand Nacc DA release
Less DA release in Nacc
Tolerance - diminishing effect of drug after repeated administration- need more drug to get the same effect
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)
Addiction - compulsive taking- craving and relapse - persistent for many years
HOMEOSTATIC -COMPENSATORY CHANGES
ASSOCIATIVE LEARNING PROCESSES