The Reward Pathway

Question 1

what is the reward pathway?

Answer 1

• can reinforce behaviours that are important for the survival of our species
• made up of VTA neurons in the midbrain
• the synapse is whats altered

Question 2

how can pharmalogical compounds effect the reward pathway?

Answer 2

• pharmalogical compounds can exhibit rewarding properties as they can activate the same system
• drugs of dependence can reinforce
• cause homeostatic changes
• need more of the drug to get the same reward

Question 3

where does the VTA send dopaminergic projections>

Answer 3

to the NuccAcc as well as the amygdala and the pre-frontal cortex

Question 4

how does the amygdala impact the reward pathway?

Answer 4

• learn and associate a memory of the reword

Question 5

how does the pre-frontal cortex impact the reward pathway?

Answer 5

• govern the behavior for the planning action of getting the reward

Question 6

where is dopamine synthesised?

Answer 6

locally at the presynaptic terminal

- lots of small NTs are made locally then packaged into vesicles

Question 7

how is dopamine synthesized?

Answer 7

• synthesized by tyrosine hydoxylase, converts L tyrosine to L dopa
• L dopa made into dopamine by dopadecarboxylase
• dopamine packaged into vesicles by the action of VMAT

Question 8

how is dopamine released?

Answer 8

• the arrival of an action potential will cause the release of dopamine

Question 9

where does dopamine interact?

Answer 9

interacts with postsynaptic dopamine receptors

- 3 types: D1, D2 and D5

Question 10

what are the features of the dopamine receptors?

Answer 10

• all are GPCRs
• D1 and D5 are coupled to an alpha subunit: you get an increase in cAMP
• D2 is coupled to a G10 subunit

Question 11

how is synpatic transmission at dopaminergic synpases terminated?

Answer 11

re-uptake of dopamine through a dopamine transporter

- packaged back into vesicles or is degraded by MAO

Question 12

what is DAT?

Answer 12

dopamine transporter on plasma membrane, dopamine re-uptake

Question 13

what is VMAT?

Answer 13

vesicular monoamine transporter, dopamine loading into vesicles firing

Question 14

what is MAO?

Answer 14

monoamine oxidase, dopamine degradation

Question 15

how does cocaine interact with dopamine transporters in the reward pathway?

Answer 15

cocaine inhibits monoamine uptake, blocks dopamine transporter, acutely increasing dopamine

Question 16

how do amphetamines interact with dopamine transporters in the reward pathway?

Answer 16

increases synpatic dopamin

• causes monoamine release
• enter cells via DAT
• vesicles via VMAT forcing dopamine into postsynaptic terminal
• makes DAT work in reverse
• high concentration of amphetamines can inhibit MAO

Question 17

what do DAT knockout mice show?

Answer 17

1. no behavioral activation after cocaine or amphetamine

2. no release of striatal dopamine by amphetamine

Question 18

what traits does cocaine induce?

Answer 18

• stereotypical locomotor activity
• sniffing, grooming and rearing
• side effects are attributed to their action on other dopaminergic synapses

Question 19

where do VTA and NuccAcc receive glutamatergic inputs?

Answer 19

from amygdala and prefrontal cortex (targets of other drugs)

Question 20

what inhibits VTA?

Answer 20

local GABAergic interneurons and NAc projections inhibit VTA (also a target)

Question 21

how is there indirect modulation of the reward pathway?

Answer 21

• targets GABAergic neuron
• glutamatergic inuputs from the amygdala and PC
• extra inputs, indirect modulation
• opiates inhibit GABAergic neurons causing them to release more dopamine

Question 22

what do opiates act via?

Answer 22

• via a GPCR

- inhibits NT release (GABA) by reducing the excitability of the presynaptic membrane

Question 23

how do opiates act on the u opioid receptor?

Answer 23

• G/O coupled
  1. response to activation, causes a signalling cascade downstream
  2. G beta gamma subunits act directly to open G protein gated inwardly rectifying K+ channels (hyperpolarise neurons)

Question 24

what is the signalling cascade of opiates acting on the u opioid receptor?

Answer 24

• decrease in cAMP levels due to inhibition of adenylyl cyclase
• AC regulated by G alpha subunit
• reduces activity of VGCC, less Ca2+ levels = less release of GABA

Question 25

what do the two effectors together do?

Answer 25

• reduce the excitability of the presynaptic neuron and reduce the amount of Ca2+ in the neuron
• less GABA, relieves the break on the VTA neuron

Question 26

how do you assess addictive behaviour?

Answer 26

• use a behavioral paradigm
• conditioned place preference
• development of preference for an environment
• need visible cues to make a memory
• associated with repeated administration of a drug abuse
• score: difference in time spent in each compartment after conditions

Question 27

what are the effects of a D2 receptor knockout on the reward pathway?

Answer 27

• conditioning with morphine

- dopamine D2 receptor KO mice show no morphine induced place preference

Question 28

how does nicotine work?

Answer 28

• acts on the acetylcholine receptor (AGONIST)
• nicotine acts on VTA nAchRs causing depolarisation and dopamine release by the VTA neurons
• also acts on presynaptic channels on glutamatergic axons from cortex and amygdala that project to VTA and NAc neurons

Question 29

what is the mechanism of addiction?

Answer 29

• drugs interact with defferent neuronal proteins to activate the reward pathway
• toleration
• dependence

Question 30

what is toleration in addiction?

Answer 30

• homeostatic adaptations/changes in cells and circuits
• lowered sensitivity
• to get the same feeling you need more
• can find other naturally occurring rewards less rewarding
• happens due to prolonged use

Question 31

what is dependence in addiction?

Answer 31

• drug induced changes that when unmasked by stopping lead to withdrawal
• eg prolongoed signalling can lead to changed connections
• plasticitiy