Dopamine and reward pathways

Dopamine

what it is, where it’s produced, type of neurotransmitter and roles

• A monoamine (catecholamine) neurotransmitter derived from tyrosine.

• Mainly in the substantia nigra (SN) and ventral tegmental area (VTA).

• can be excitatory or inhibitory depending on the cell

• Motor control, reward, motivation, cognition, arousal

What is the dopamine synthesis pathway and how is it released?

• Tyrosine to levodopa (L-DOPA) by tyrosine hydroxylase

• L-DOPA to dopamine by aromatic l-amino acid decarboxylase (DOPA decarboxylase)

• dopamine stores in synaptic vesicles in dopaminergic neurons, in noradrenergic or adrenergic cells can be converted into norepinephrine and epinephrine

• released from cells by exocytosis

How is dopamine removed from the synaptic cleft? what 2 enzymes break it down?

• Taken up by DAT dopamine transporter and monoamine transporters MATs on presynaptic terminal, DAT common drug target eg cocaine blocks it preventing dopamine breakdown

• Broken down by MOA monoamine oxidase and COMT Catechol O-methyltransferase

How many dopamine receptors

subgroups and how they work

• 5 receptors

• d1 like (D1 subtypes and D5): activates cAMP increasing glutamate receptor trafficking, Excitatory

• D2 like (D2, 3,4): reduces cAMP activation, modulates voltage sensitive calsium and potassium channels, Inhibitory

• D1 most common then D2

name the 4 dopamine pathways

• Nigrostriatal

• Mesolimbic

• Mesocortical

• Tuberoinfundibula

Nigrostriatal dopamine pathway

role, dysfunction leads to, theory with regards to dopamine

• Dopamine neurons in substantia nigra project to striatum and effects on nuclei of the basal ganglia

• Role: motor function and learning

• Dysfunction leads to Parkinsons

• Theory: Dopamine in nigrostriatal pathways facilitates selection of optimal response from competing motor/cognitive programs

Direct and indirect pathway of nigrostriatal dopamine pathway

Direct:

• Promotes direct pathway

• Activates D1 receptor on striatal neurons initiating movement

• Substantia nigra SN communicates with subthalamic nucleus STN in feedback loop preventing permanent activation of the pathway

Indirect:

• Suppress indirection pathway

• Inhibits D2 receptors on striatal neurons

Mesocorticolimbic dopamine pathway

name the 2 pathways, dysfunction causes what, theory

• 2 pathways: mesocortical and mesolimbic

• Relates to reward behaviour

• Dysfunction causes neuropsychiatric disorders eg depression, schizophrenia

• theory: dopamine facilitates and balanced goal directed and habitual behavior

Mesocortical pathway

pathways and role

• Midbrain dopaminergic neurons from ventral tegmental area VTA project to prefrontal cortex

• Cognitive control (attention, working memory, decision-making), motivation, emotional regulation, learning

Mesolimbic pathway

pathway and role

• Midbrain dopaminergic neurons from ventral tegmental area VTA project to ventral striatum mainly to nucleus accumbens NAc

• also projects to amygdala, hippocampus etc

• Reward, pleasure, motivation (“wanting”), fear, maternal behaviour

Tuberoinfundibular pathway

Pathways and role/what it does

• Projection from arcuate nucleus and periventricular nucleus of hypothalamus to pituitary gland

• Maternal behaviour function: regulation prolactin secretion promoting lactation

Goal directed behaviour vs habitual behaviour

type of action, cognitive load, after what kind of reward, role of dopamine in each and response to change

• control over actions vs automatic actions

• high vs low cognitive load

• reward directed/seeking vs learnt/reinforced rewards

• dopamine signals action outcome associations leading to learning vs involved in formation and maintenance of habitual behaviors

• Sensitive to rapid changes in outcome vs can become maladaptive

What is a reward?

2 types of reward, their definition and whether they are conditioned or unconditioned

what do reward systems determine

• Any stimulus that promotes approach behaviour

• Natural: activity that promotes survival and reproduction eg sex, eating, drinking. unconditioned- behaviour motivated because reward in inherently pleasurable

• Learned: rewards that derive value through conditioning eg drugs, hobbies, conditioned- behaviour motivated because rewards has learnt or associated pleasure

• reward system determines value of stimulus and signals to avoid or approach and assign priority

4 brain regions involved in reward pathway and what they do

NPHA

From VTA to these areas:

NAc motor function- actions to continue/repeat

PFC attention and planning- diverts attention to reward and increase

Hippocampus memory- remember how reward was got

Amydala emotion- positive emotions

2 pathways involved in reward

Cortico-basal ganglia-thalamo-cortical loop

Mesocorticolimbic dopamine system

Tonic vs phasic dopamine release

Tonic:

• dopamine neurons maintain steady baseline level of dopamine (normal functioning)

Phasic:

• dopamine neurons sharply increase or decrease dopamine in response to rewards or cues

What does dopamine encode in reward learning?

Reward > expected?

Reward < expected?

Reward = expected?

Prediction error (expected vs actual reward).

↑ Dopamine

↓ Dopamine

No change

Low vs high dopamine symptoms

Fatigue, low motivation, poor focus.

Euphoria, impulsivity, poor control.

Substance abuse disorders

how they work in terms of dopamine

• Compulsive drug seeking and use despite consequences

• Most drugs hijack brain reward system to stimulate dopamine release

• synaptic alterations in mesolimbic pathways are related to drug and food addiction

Parkinsons disease

caused by what

• Caused by loss of dopamine producing neurons in substantia nigra pars compacta (start of nigrostriatal dopamine pathway- basal ganglia dysfunction)

• motor symptoms (parkinsonism) and depression and cognitive impairment

Ways dopamine is used in pharmacology

LAAR

• Levodopa: dopamine precursor crossing blood brain barrier increasing dopamine

• Dopamine agonists: bind and activate dopamine receptors mimicking dopamine, good for parkinsons, depression ADHD

• Dopamine antagonists: bind and block dopamine receptors preventing dopamine action, used in antipsychotic drugs

• Dopamine reuptake inhibitors: prevent dopamine reabsorption by releasing pre synaptic neurons, used in depression and addiction and narcolepsy