Dopamine Flashcards
Outline the differences between neurotransmission and neuromodulation, with reference to biogenic amines and cell population numbers
• Classically NT = GABA, Glutamate, ACh; transmits an AP between 2 neurons but can involve glia
Neuromodulators act on a longer timescale and distance to regulate these processes; dopamine is the archetype. DA is one of a family of biogenic amines which can do this.
• DA acts as an NT and an NM depending on context
• DA neuron has many synapses along its length
• Only around 100,000 neurons of the brain are dopaminergic
o NA = 10,000
• DA modulates neural activity via GPCRs; many intracellular pathways ‘myriad effects’
• DA neurons have many varicosities; bulges from which the NT is released. Around 250,000 varicosities per 100,000 DA neurons
Making use of a diagram, outline the dopamine synthesis pathway and describe how dopamine is removed from the synapse
Dopaminergic neurons stop synthesis at dopamine – DA cells DO NOT produce adrenaline/noradrenaline enzymes
Release of DA is activity-dependent, as with other enzymes
More activity –> more release
- Tyrosine is converted to DOPA by tyrosine hydroxylase – this is the rate limiting step of the pathway
- DOPA is converted to dopamine by DOPA decarboxylase – this is FAST; DOPA is normally immeasurable
- Dopamine is converted to NA by Dopamine β-hydroxylase
- NA is converted to NA by phenylethanolamine N-methyltransferase
Dopamine is removed from the synapse via the DOPA-transporter using a Na+-K+ ATPase, dependent on the K+ gradient
DOPA transporter is found peripherally from the release site – reuptake is diffusion-dependent; enables dopamine to have its wide-ranging effects
It is then metabolised to homovanillic acid (Parkinson’s biomarker)
diagram: https://www.researchgate.net/figure/Metabolic-pathway-of-dopamine-synthesis-in-the-brain-19_fig1_8250286
Outline the 5 main dopaminergic pathways within the brain AND their projections
- Nigrostriatal
a. Begins in the substantia nigra pars compacta, projecting to the striatum (RIGHT)
b. Responsible for motor function – damaged during Parkinson’s disease - Mesolimbic
a. Ventral tegmental area to the nucleus accumbens
b. Associated with reward learning - Mesocortical
a. VTA to dorsolateral and ventromedial prefrontal cortext
b. Implicated in reward anticipation and consumption - Tuberoinfundibular
a. Hypothalamus to the anterior pituitary –> inhibited prolactin secretion - Unnamed pathway
a. Periaqueductal grey and an unknown region for an unknown function
Outline the differences between the D1 and D2 families of dopamine receptors, and the receptors which comprise these families as well as the intracellular signalling pathways to which they are coupled.
D1-like receptors:
D1
D5
Gαs-linked; activate adenylyl cyclase when stimulated –> increased [cAMP]
D2-like receptors: D2 D3 D4 Gαi-linked; inhibit adenylyl cyclase when stimulated --> decreased [cAMP]
D1-like receptors increase firing (of the postsynaptic neuron)
D2-like receptors decrease firing (of the presynaptic neuron – these are autoreceptors)
Compare and contrast the mechanisms of action of cocaine and amphetamine
Cocaine:
Increase the spatial and temporal distribution of DA by antagonising:
o Dopamine transporters (DATs)
o Norepinephrine transporters (NETs)
o Serotonin-reuptake transporters (SERTs)
Due to similarity of molecules
o These are neuronal co-transporters; they couple amine reuptake to Na+ entry
Na+ provides an electrochemical gradient
Cl- exits; gives a neutral charge overall
Amphetamine:
Alternative substrate to amines, so act as competitive antagonists on:
o `DAT + NET (uptake)
o Vesicular monoamine pump (VMAT-2)
Cocaine and amphetamine cause DA to accumulate; they DO NOT trigger DA release (instead they work like SSRIs)
Outline 3 routes to elevated dopamine levels
- Affect transporters: e.g. Cocaine, amphetamine, MDMA
- Affect ionotropic receptors: nicotine, alcohol
- Affect GPCRs: opioids, cannabinoids, γ-hydroxybutyrate
Compare and contrast the pharmacokinetics of cocaine and amphetamine
- Cocaine:
• Est. £50-150/g
• Typically a hydrochloride salt taken nasally or via injection (water soluble), –>
o Vasoconstriction: atrophy, necrosis
o Within 30 minutes it’s metabolised rapidly in the liver
o Interactions with alcohol –> cocaethylene
o Enters hair follicles
• When un-neutralised, sublimates
• Crack = cocaine + sodium bicarbonate + heat
• Base = cocaine + base (e.g. ammonia) + ether evaporation
o Fastest-acting - Amphetamine:
• £5/g
• Taken orally/nasally; effects prominent within 1-2 hours
• Smoked as methamphetamine; alveolar surface area > nasal; doesn’t get into hair follicles; lowering pH of urine increases excretion
Briefly describe 2 dopamine pathologies
- Parkinson’s disease:
• Movement + psychiatric disorder – affects 1% of over 55s
• Progressive degeneration of the basal ganglia – symptoms prominent when 80-90% of neurons have been destroyed - Schizophrenia:
• Heterogeneous – disordered thought and belief; social withdrawal
Compare and contrast primary reinforcers and secondary reinforcers in the context of reward
Primary reinforcer: direct benefit to survival (food, water, sex)
o No training required
o The reward is viewed independently to the experience
Secondary reinforcer: no initial intrinsic value AND enables access to the primary reinforcer
o UCS + NS CS + CR
o Lecture doesn’t focus on punishment (adverse outcome) as this occupies a different neuronal circuit
Briefly outline an experimental design to investigate reward prediction and the neurological effects you’d expect, then apply this to a real-world scenario
Studying monkeys with electrophysiology; taking field recordings of many neurons
o Diameter is 10x greater than that of a patch clamp
o Only measures what goes on
o Awake + secured monkeys receive sweet juice after being given a diuretic (ensuring thirst). Monkeys prefer juice over food.
o Dopaminergic neurons of the VTA fire Aps – 100ms after receiving juice. Firing lasts 200ms. With repetition, these neurons stop responding to juice
o A light was then flashed before the administration of juice – the monkeys responded to the light, not the juice; this was mimicked in neuronal firing
o AKA – Pavlovian conditioning – DA firing is occurring for the conditioned stimulus
If no reward is provided, firing drops BELOW baseline
o Activation of VTA neurons increased as the magnitude of the reward increases
VTA activation is greatest with the lowest-probability reward (reward is ‘worth’ more)
• Applies to gambling – optimum reward ratio is 0.4
• Probability is more important than the amount of reward received
Explain reward prediction errors
Occur when there is a difference between the reward expected and the reward received
o Accurate expectations = little error, so no firing change
o Inaccurate expectations = reward is small/absent; high error, so firing decreases
• This can be applied to guide learning about outcomes
• This applies to primary and secondary reinforcers
How does unexpected reward work in humans?
thirst study (like the monkey one - outline the steps) in humans –> activity in nucleus accumbens. Greatest activity occurred when the stimuli were unpredictable.
Why is reproducibility an issue with human studies?
• Lack of multiple studies
• Single studies are curiosities
• Often seen in imaging but applies to all science
o Can be fixed with an activation likelihood estimation
Using the example of B-19, explain the difference between liking and wanting
B-19; human test subject in 1970s. Voracious self-stimulation of deep-brain structures, including the VTA
Would protest when prevented from stimulating
Yet had no exclamations of delight or reports of pleasure; simply a desire to repeatedly stimulate, and an overwhelming sexual drive
“edge of orgasm but unable to achieve” – intense frustration; NOT pleasure.
Link to DA receptors:
- DA release links cues and outcomes
- Drug-induced increased in [DA] are supra-normal, enhancing cue-outcome associations
There is considerable inter-individual variation in D2-receptor populations; a constitutively low level of activation will reduce normal reward-based conditioning
Exceptional drug-induced elevation – is there increased drug-dependence vulnerability?
In the long term, there is a drug-induced homeostatic reduction in receptor population –> diminished capacity for new associations (learning)
Basically:
DA links cues and outcomes
Drug-induced [DA] are above normal ∴ enhances cue-outcome association, –> long-term homeostatic reduction in the receptor population –> diminished capacity for future learning
