Riley Dopamine 2

Question 1

What is reward associated with?

Answer 1

Increased dopamine concentration in the NAc

Question 2

What is intracranial self-stimulation?

Answer 2

Increasing activity in a particular area
A technique extremely sensitive to electrode location
Can identify effective targets for research

Question 3

How is electrical self-stimulation used in this context?

Answer 3

Midbrain dopaminergic neurons project from the VTA to the NAc
The medial forebrain bundle (MFB) contains axons of VTA neurons
This proves a very effective target for investigating reward
Anywhere you stimulate along here will cause dopamine release at the level of the NAc

Question 4

What does activation of the NAc do?

Answer 4

Electrical and pharmacological manipulation of the NAc alters responses to both rewarding and aversive stimuli
Hedonic (pleasure) responses activate more rostral areas of the NAc
Aversive responses activate more caudal regions (spatial sensitivity)

Question 5

What are the afferent projections to the NAc?

Answer 5

Amygdala, Hippocampus and PFC - tells us what the stimulus is
VTA - tells us that the stimulus is rewarding

Question 6

What do we need in order to work of whether something is rewarding?

Answer 6

Need to know the value of something every time you get it, and just generally know about it

Question 7

How would the reward system methodologically get that reward again?

Answer 7

There are 2 functionally distinct output pathways from the NAc:

1. Pre-motor related output
2. Reward/Emotion related output

Question 8

What does the pre-motor related output include?

Answer 8

1. dorsolateral ventral pallidium
2. entopeduncular nucleus
3. substantia nigra pars reticulata

The NAc biases the pre-motor output for learning reward

Question 9

What does the basal ganglia do?

Answer 9

It is believed to be one of the primary action selection centres and receives all the pre-motor related output
It works through inhibition
If chosen, the action will be expressed by the BG
A strong input from the NAc could maybe cause motor expression towards particular stimuli

Question 10

What does the basal ganglia do all this via?

Answer 10

Does it all via the substantia nigra

Question 11

What are the 3 major dopaminergic pathways?

Answer 11

1. the mesolimbic pathway
2. the mesocortical pathway
3. the nigrostriatal pathway

Question 12

Outline the mesolimbic pathway

Answer 12

Originates in the VTA and innervates the NAc (and other limbic structures)
Dopamine transmission is coincident with rewarding stimuli and thus facilitates reinforcement and reward-related motor learning
Will be focusing on this one as evidence points towards a crucial role of this pathway in reward processing

Question 13

Outline the mesocortical pathway

Answer 13

Also originates in the VTA but projects to the frontal cortex and surrounding structures
Thought to modulate activity in the dorsolateral PFC, which is linked to schizophrenia and psychosis

Question 14

Outline the nigrostriatal pathway

Answer 14

Projects from the substantia nigra to the striatum and is involved in motor control
Degeneration of this pathway causes Parkinson’s disease

Question 15

What does dopamine do in terminal areas?

Answer 15

Dopamine is a neuro-modulator so different pathways will do different things

Question 16

Where are dopaminergic cell bodies mainly found?

Answer 16

In the VTA and substantia nigra pars compacta. They have wide terminal regions including the NAc and PFC

Question 17

What receptors does dopamine act through?

Answer 17

G-protein coupled receptors (D1-like and D2-like)
D1-like activates adenylyl cyclase which increases the intracellular concentration of CAMP
Dopamine isn’t like glutamate or GABA where they directly open ion channels, they alter things inside cells like secondary messengers

Question 18

When do rat NAc DA levels increase?

Answer 18

Operant responses to obtain reward
Classically conditioned sensory stimuli
Primary rewards e.g. food, water
Exposure to receptive females
Goal-directed behaviours

Question 19

Do rats self-administer drugs and how?

Answer 19

Rats will self-administer certain drugs into certain areas using an anatomy very similar to that of electrical stimulation
Positioning the injecting cannula in the VTA and NAc is particularly effective in engaging rats in self-administration
They will inject cocaine and amphetamine into the NAc
And morphine, heroin, GABA antagonists and nicotine into the VTA

Question 20

What is cocaine’s effect on DA transmission?

Answer 20

Acts to block the binding site of Na+ on the dopamine transporter
Therefore re-uptake of DA to presynaptic neurons is blocked so DA stays in the synaptic cleft
The DA continues to agonise the post-synaptic neuron

Question 21

What is amphetamine’s action in the NAc?

Answer 21

Amphetamine is a substrate of DAT and therefore competitively inhibits DA re-uptake
Amphetamine is then transported into the presynaptic neuron so once it is in the cell it interferes with the vesicular monoamine transporter (VMAT2) and impedes the filling of synaptic vesicles
Vesicles are depleted so cytoplasmic DA increases
Promoting DAT-mediated reverse transport of DA into the synaptic cleft independent of action potential-induced vesicular release

• This is independent of any kind of stimulus and releases dopamine regardless

Question 22

What is opioid’s action on the VTA?

Answer 22

They target μ-opioid receptors (MORs) that are located exclusively on GABA neurons in the VTA
MORs are expressed on the presynaptic terminal of these cells and the somatodendritic compartment of the post synaptic cells
Activation of MORs inhibits GABA release

Question 23

Why does the inhibition of GABA release in the VTA cause an increase in NAc DA levels?

Answer 23

Increases firing to the NAc and therefore dopamine release

Question 24

How does cannabis mediate DA release?

Answer 24

Does this at the level of the VTA
Anandamide (AEA) and 2-AG are synthesised and released by DA cell bodies
It acts retrospectively on endocannabinoid type 1 receptors on nearby GABAergic interneurons
And mediates robust inhibition of GABA input to DA cells

Question 25

What action does cannabis have at VTA interneurons?

Answer 25

THC, an active component in cannabis, also acts to inhibit CB1 receptors which inhibits the release of GABA
This disinhibits VTA DA neurons and increases firing to the NAc - leading to reward

Question 26

How does nicotine affect dopamine?

Answer 26

Much simpler

Causes direct excitation of dopaminergic neurons in the VTA by activating ionotropic ACh nicotinic receptors