Lecture 4 - Dopamine, Drugs and Reward Flashcards
What are the 3 Dopamine Pathways in the CNS
- Nigrostriatal Pathway - Motor Regulation
- last lecture
- Substantia Nigra Compacta -> Basal Ganglia - Mesolimbic Pathway - Reward, euphoria, intense emotions
- VTA -> Nucleus Accumbens
- this lecture - Mesocortical Pathway - personality, perseverance, compulsion
- VTA -> Prefrontal Cortex
- this lecture
Outline the Ventral Tegmental Area (VTA)
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- In midbrain (mesencephalon)
- Medial (inside of) SNc (substantia nigra)
- Involved in reward & learning, intense emotions, goal-driven behaviour
What % of Dopaminergic Neurons are in the Mesolimbic and Mesocortical Pathways?
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50-60% of all dopamingergic neurons
- there are dopaminergic neurons elsewhere, but most are here
- Neurons for dopamine
Outline the Mesolimbic pathway
- Starts at VTA
- Dopamine neurons origin is here - Projects mainly to Nuclues Accumbens
What does GABA do to Dopamine in mesolimbic pathway
GABAergic interneurons within VTA provide long lasting (tonic) inhibition of DA neurons
What other inputs are them in the Mesolimbic Pathway
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- Glutamate (From cortex)
- Acetylcholine (ACH)
- Involved in Reward signalling, learning and goal-directed behaviour
What happens to the mesolimbic pathway during reward?
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- See an actual reward, or just a cue that indicates a reward will be coming
- Increases VTA dopaminergic neuron firing
or - Lack of actual/ expected reward
- decreased firing
- Results in increase/ decrease in Nuclues Accumbens Shell DA levels
Important for reward0based learning and goal-driven behaviour
What is DA sensitivity linked to?
- Nurture: Linked to personality traits like extraversion, sensation-seeking, reward seeking
- Nature: just biology
What did Di Chiara et al (1999) do?
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Looked at amount of DA in NAc Shell during food and sex
- when the food box is empty, dopamine isnt firing too much, as soon as food arrives, the dopamine shoots up in the brain
- During sex there is a massive spike
Outline when Dopamine spikes in cue and of reward
- When a reward is cued and delivered, Dopamine neurons only respond to the cue eventually (conditioning)
- When the cue occurs, dopamine peaks, and stays high until reward comes, but is no way near as big of a peak
- If no reward comes, dopamine drops - can impact mood
What is activated when DA Binds to receptor
When DA binds to receptor, it activates g-proteins
How does level of dopamine affect the amount of receptors?
- MORE DOPAMINE = LESS RECEPTORS
- If there is more dopamine, the brain doesnt need to work as hard to recapture it all - LESS DOPAMINE = MORE RECEPTORS
- needs to make sure it is all captured as there isnt very many
What does cocaine do to your receptors over time
Cocaine increases dopamine, but gives you too much
- as your brain is used to having loads, it doesnt need many receptors
- it knows cocaine will come later so dont need many receptors working hard to get as much DA back up
- therefore has less dopamine as default
What do Opiods, Amphetamines and Cocaine do to this system?
- Amphetamines do release and removal
- Opioids just do Release
- Cocaine just do removal
Outline receptor subtypes
there are receptor subtypes
- which are mainly targeted by Dopamine Antagonists
- when treating psychosis, Sz or delierium - you use dopamine antagonists here, like Anti-psychotics
What are the 2 enzymes that break down dopamine
- Once DA has done its job, brain breaks it down, loops it back around, metabolises it and reuses it
- COMT
- MAO
- Breaks it down into its metabolites - dopamines byproducts that can be used for other things
Outline the process of Dopamine crossing the synapse
- Sodium comes down, merges with vesicle, pushes dopamine down
- Depending on the message, is where it goes
3a. If it goes to: D1 Family of receptors - excitatory, stimulates cAMP, stimulates
3b. If it goes to: D2 family of receptors - inhibitory, deactivates cAMP, message doesnt continue
- this is the second messenger process - Can then be: reuptaken if theres too much left, or get broken down by MAO/ COMT
What is the receptor that reuptakes dopamine
DAT-1 receptor
When DA is broken down, by MAO & COMT, what does it get turned into?
Homovanillic Acid (HVA)
Where do most addictive drugs act on in this system?
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- Most addictive drugs cause an increase of DA release from the VTA (Start of the pathway)
- VTA is the start of both the mesolimbic and mesocortical pathways, so drugs target here
- Opiods, heroin
- Amphetamines (ritalin, speed)
- Benzos
- Cannabinoids
- Nicotine, alcohol etc
Whats the difference between Chemical and psychological addiction?
- Chemical Addiction
- long term impact as brain chemically adjusts, e.g. amount of receptors - Psychological addiction
- might relieve stress so you want to keep doing it
How do amphetamines, cocaine, Nicotine and morphine effect DA levels?
- Amphetamine
- Massive hugh spike of dopamine, food was 500, this is like over 1000
- just doesnt last too long - Cocaine
- high lasts much longer, but its not as high - Morphine
- Doesnt have a single spike, but does increase DA over time
- effects lots of other NT’s so the effects on DA arent as drastic as other drugs - Nicotine
- does spike, but not as high as others
What is the difference between endogenous endorphins and exogenous
- Endogenous Endorphines - natural endorphines
- e.g. Dynoprhine - Exogenous
- what your putting in
- morphine, heroin, opium etc
How do Opiods effect Dopamine
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- Opiods impact the G-protein coupled receptors which have inhibitory and excitatory subtypes
- Opiods sit in the receptor and inhibits GABA release
- As GABA inhibits dopamine, when you inhibit GABA, much more dopamine is released
How do Benzodiazepines effect Dopamine
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- Similarly to Opiods
- They dont directly impact the DA neurons
- But they effeect the GABA receptor, stops GABA from inhibiting DA release
- GABA communicates to DA neuron with how much DA to fire, when GABA Cant communicate this message, DA doesnt know how much to release, so just releases loads
- Interact strongly with a1 GABA-A receptors, in GABA interneurons in VTA
How does Nicotine effect Dopamine
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- Indirectly impacts on dopamine
- Nicotine activates reward pathways - has its own effects, but does impact on DA
- the VTA projects to the Tegmental Pedunculopontine Nucleus (TPP) - this is a region to do with non-DA-mediated reward
- In the standard system, GABA goes to TPP to tell it to regulate dopamine. Nicotine slows down GABA, so the TPP doesnt inhibit dopamine as much
- Nicotines impact on reward can be blocked by lesion/ GABA inhibition of TPP
Which pathway will Antagonists have a stronger effect on?
Antagonists, like anti-psychotics will have a stronger effect on the D2 pathway (inhibitory), compared to the D1 pathway (excitatory)
Outline DA reuptake inhibitors
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- Can use L-dopa to treat PD, but another treatment is to stop reuptake, we can use a few of these drugs:
- They inhibit DAT from removing DA from synapse, increasing the amount of DA transmission
•NDRI’s (Norepinephrine & Dopamine)
• SDRI’s (Serotonin & Dopamine)
•SNDRI (Serotonin, Nore, DA)
•TRI = triple reuptake inhibitor, does all 3
•DRI (Dopamine) - not used that much as it only targets DAT 1 receptor, but other receptors clean up in synapse
What is NDRI used for?
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Depression, ADHD, Narcolepsy, Parkinsons Disease
What are examples of SNDRI’s?
Cocaine and Amphetamines are both SNDRI’s - inhibit the reuptake of all of these
- leads to euphoria, motor activity, appetite, psychosis
How does Cocaine effect Dopamine
Cocaine sits right on the reuptake transporter, so none of the dopamine is being cleaned up
- Cocaine has a massive impact, on the reuptake phase, not release phase
- Different drugs have different effects depending on at which point they impact dopamine
What are the 2 variants of COMT breaking down Dopamine
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After stressor, lots of DA released, COMT has 2 ways of breaking down DA:
- Slow form
- Lots of DA hanging around, clean it slower
- leads to better concentration, cognitions - perhaps because brain stays more alert for longer - Fast form
- With less DA
- Brain goes mental when there is a stressful event, and afterwards brain can settle down quickly
Individual differences in how our brain calms down after a stress
