Brain and BehaviourWeek 8 Lecture 2:AddictionDr M J Morgan
Lesion/ imaging studies establish importantbrain circuits for specific behaviours.But what of underlying neurobiologicalpr...
Pharmacology – BehaviourUnderstanding the mechanism of actions of drugs, providesinformation on underlying neural processe...
Where do drugs of abuse act?   Mesocorticolimbic pathway: ventral tegmental area → nucleus accumbens                      ...
Binding sites of cocaine following acute                    administration     Striatum:    contains thenucleus accumbens ...
How do we know this pathwayis involved in reward ?                                  Control groupDamage to the nucleusaccu...
Natural reinforcers (e.g. food and sex) increaseextracellular Dopamine in the Nucleus Accumbens                           ...
Drugs of abuse maintain dopaminerelease in the nucleus accumbensshell after repeated exposure -hijack the reward pathway.n...
The mesocorticolimbic dopamine systemDopamine neurons projecting from ventral tegmental area (VTA)to nucleus accumbens (NA...
The mesocorticolimbic dopamine systemAll known addictive drugs activate this systemBehaviours leading to activation tend t...
Psychomotor stimulants - cocaine and amphetaminePotentiate monoaminergic transmission by inhibition of dopamine (DA),serot...
Psychomotor stimulants - cocaine and amphetaminePotentiate monoaminergic transmission by inhibition of dopamine (DA),serot...
Opiates (e.g. morphine and heroin)Act at endogenous opioid receptors (Gi/Go coupled)    Inhibitory - decrease adenylyl cyc...
Opiates (e.g. morphine and heroin)But also, as with other drugs of abuse also impact on function of the    Dopaminergic re...
Normal reward systemCortical control of VTA firing                   PFC                               VTA                ...
Alcohol (EtOH)- GABAA agonist (inhibitory)-NMDA antagonist (blocks excitation)- also affects glycine, nicotinic & serotoni...
Alcohol (EtOH)Effects on Reward Circuitry1) EtOH leads to increased DA release in NAccNMDA antagonism of cortical inputs t...
Alcohol (EtOH)Effects on Reward Circuitry2) Involvement of Opiate systemNaltrexone (an opiate antagonist)        - reduces...
NicotineAction at nicotinic acetylcholine receptors (nAChRs)    -Ligand gated ion channels located pre or post-synapticall...
NicotineEffects on Reward CircuitryNicotine treatment increases DA release in the NAccRelease of DA likely due to:a) activ...
Natural reward systemsExperiential – learn what, when and where rewards are likely.Understanding actions of drugs of abuse...
Tolerance       - diminishing effect of drug after repeated administration                - need more drug to get the same...
Physical dependence to opiates (Week 6 Lecture 2)Chronic activation of opiate receptors leads to homeostatic mechanism tha...
Physical Dependence to alcoholAcute effects of alcohol-agonist at GABAA receptor ( )                                      ...
Emotional Dependence (e.g. psychomotor stimulants)- dysphoria, anhedonia, anxiety on withdrawalCompensatory changes in VTA...
Emotional Dependence (e.g. psychomotor stimulants)Neurobiological explanation:Increased activity at D1 receptors (Gs coupl...
Tolerance       - diminishing effect of drug after repeated administration                - need more drug to get the same...
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Mm emotion reward_2_2011

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Mm emotion reward_2_2011

  1. 1. Brain and BehaviourWeek 8 Lecture 2:AddictionDr M J Morgan
  2. 2. Lesion/ imaging studies establish importantbrain circuits for specific behaviours.But what of underlying neurobiologicalprocesses that mediate behaviour?
  3. 3. Pharmacology – BehaviourUnderstanding the mechanism of actions of drugs, providesinformation on underlying neural processes that control specificbehaviours.The natural reward system – hijacked by drugs of abuse
  4. 4. Where do drugs of abuse act? Mesocorticolimbic pathway: ventral tegmental area → nucleus accumbens ventral tegmental area → prefrontal cortex Neurotransmitter - dopamine PET SCAN
  5. 5. Binding sites of cocaine following acute administration Striatum: contains thenucleus accumbens Fowler et al (1989) Synapse 4: 371-377
  6. 6. How do we know this pathwayis involved in reward ? Control groupDamage to the nucleusaccumbens decreases self- Damage to nucleusadministration of heroin. accumbensMesocorticolimbic pathwayneeded for drug to have a ANIMAL STUDIES:rewarding effect. self-administration model
  7. 7. Natural reinforcers (e.g. food and sex) increaseextracellular 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 systemDrug of Dopamine releaseabuse Increased in the Sensation activation ofNatural mesocorticolimbic of reward pathwayreward pathway (dopamine levels measured by microdialysis)
  8. 8. Drugs of abuse maintain dopaminerelease in the nucleus accumbensshell after repeated exposure -hijack the reward pathway.naïve animals pre-exposed animals
  9. 9. 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 /ratNatural reinforcers (e.g. food and sex)increase release of extracellular DA in Nacc
  10. 10. The mesocorticolimbic dopamine systemAll known addictive drugs activate this systemBehaviours leading to activation tend to be repeated (are reinforced)Blockade of DA in this region attenuates most measurable reinforcing andrewarding effects of addictive drugsActivation by addictive drugs much more powerful and reliable than activationby natural reinforcers (they hijack the system)
  11. 11. Psychomotor stimulants - cocaine and amphetaminePotentiate monoaminergic transmission by inhibition of dopamine (DA),serotonin (5-HT) and norepinephrine (NE) reuptake transportersCocaine blocks and inhibits transporter to prolong pool of extracellular DAAmphetamine reverses transporter to increase extracellular DA levelsAction at dopaminetransporter (DAT)most directly related toreinforcing effects Cocaine and amphetamine extracellular DA in NAcc
  12. 12. Psychomotor stimulants - cocaine and amphetaminePotentiate monoaminergic transmission by inhibition of dopamine (DA),serotonin (5-HT) and noradrenaline (NE) reuptake transportersBut subjective effects probably mediated by action of drugs at other sites:Feelings of euphoria, speeding etc.through activation of this pathwayor actions at transporters locatedelsewhereIn animal studies:DAT transporter knockouts still showsome behavioural response to cocaine.Only triple knockout (DAT, SERT and NET)show no drug action Extracellular 5-HT and NA
  13. 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+ channelsDifferent 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) receptorsSubjective 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 pathwaysPhysical dependence – compensatory changes in these pathways (Week 7)
  14. 14. Opiates (e.g. morphine and heroin)But also, as with other drugs of abuse also impact on function of the Dopaminergic reward pathwaysReward 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 neuronsb) 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. 15. Normal reward systemCortical control of VTA firing PFC VTA glu GABA NAcc DopamineOpiate action in VTA to increased DA releaseDisinhibition 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. 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 EtOHLow doses of alcohol - mild euphoria and anxiolytic effectsHigher doses - poor coordination, amnesia, sedationChronic alcoholism - Korsakoff’s Amnesia(caused by neurodegeneration – not an effect of alcohol itself but thiamine deficiency)
  17. 17. Alcohol (EtOH)Effects on Reward Circuitry1) EtOH leads to increased DA release in NAccNMDA antagonism of cortical inputs to VTA may lead to increased DA releasein 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 fireEthanol rewarding effects blocked by DA receptor antagonists in NAcc
  18. 18. Alcohol (EtOH)Effects on Reward Circuitry2) Involvement of Opiate systemNaltrexone (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. 19. NicotineAction 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 releaseUnlike cocaine and opiates - powerfully reinforcing in absence of subjective euphoriaProlonged 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. 20. NicotineEffects on Reward CircuitryNicotine treatment increases DA release in the NAccRelease 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 NAccOpiate system involvementBoth opiate and DA antagonists can block nicotine-induced behaviours and self administration (Naltrexone is on trial as a drug to aid smoking cessation)
  21. 21. Natural reward systemsExperiential – 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. 22. Tolerance - diminishing effect of drug after repeated administration - need more drug to get the same effect HOMEOSTATIC -COMPENSATORY CHANGESDependence - 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 PROCESSESAddiction - compulsive taking - craving and relapse - persistent for many years
  23. 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 GiLocus 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 GiChronic treatment - LC neurons return to their normal firing rates Gs Gi (Gs pathway component upregulate to match Gi) GiWithdrawal - dramatic increase in LC firing Gs (In absence of Gi inhibiton Gs hypersensitive)
  24. 24. Physical Dependence to alcoholAcute effects of alcohol-agonist at GABAA receptor ( ) out   in-antagonist at NMDA receptor ( )Cells inhibited from firing Cl- Cl- Cl- Na+Chronic alcoholDown regulation of GABAA receptors out   Upregulation of NMDA receptors inIn presence of alcohol firing rates Cl- Na+ Na+ return to normalWithdrawalin absence of alcohol outbalance shifts to excitation inphysical symptoms- agitation, tremors, hypertension, seizures Na+ Na+ Na+ Na+ Na+
  25. 25. Emotional Dependence (e.g. psychomotor stimulants)- dysphoria, anhedonia, anxiety on withdrawalCompensatory changes in VTA / NAcc to lower DA transmission:Blockade of reuptake - too much DA in NAcc synapsesCompensatory change - less DA release in NAccIn presence of drug - normal DA function in NAccIn absence of drug - not enough DA for natural rewarding stimuli - anhedonia, dysphoria etc.
  26. 26. Emotional Dependence (e.g. psychomotor stimulants)Neurobiological explanation:Increased activity at D1 receptors (Gs coupled) in NAccAdenylyl cyclase – cAMP - PKA activationPhosporylation of CREB (transcription factor)Increased dynorphin (DYN) synthesis(neuropeptide - endogenous opioid)dynorphin released in VTAacts at Kappa opioid RInhibits VTA neuron firingand Nacc DA releaseLess DA release in Nacc
  27. 27. Tolerance - diminishing effect of drug after repeated administration - need more drug to get the same effect HOMEOSTATIC -COMPENSATORY CHANGESDependence - 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 PROCESSESAddiction - compulsive taking - craving and relapse - persistent for many years

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