The Reward Pathway Flashcards
what is the reward pathway?
- 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
how can pharmalogical compounds effect the reward pathway?
- 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
where does the VTA send dopaminergic projections>
to the NuccAcc as well as the amygdala and the pre-frontal cortex
how does the amygdala impact the reward pathway?
- learn and associate a memory of the reword
how does the pre-frontal cortex impact the reward pathway?
- govern the behavior for the planning action of getting the reward
where is dopamine synthesised?
locally at the presynaptic terminal
- lots of small NTs are made locally then packaged into vesicles
how is dopamine synthesized?
- 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
how is dopamine released?
- the arrival of an action potential will cause the release of dopamine
where does dopamine interact?
interacts with postsynaptic dopamine receptors
- 3 types: D1, D2 and D5
what are the features of the dopamine receptors?
- 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
how is synpatic transmission at dopaminergic synpases terminated?
re-uptake of dopamine through a dopamine transporter
- packaged back into vesicles or is degraded by MAO
what is DAT?
dopamine transporter on plasma membrane, dopamine re-uptake
what is VMAT?
vesicular monoamine transporter, dopamine loading into vesicles firing
what is MAO?
monoamine oxidase, dopamine degradation
how does cocaine interact with dopamine transporters in the reward pathway?
cocaine inhibits monoamine uptake, blocks dopamine transporter, acutely increasing dopamine
how do amphetamines interact with dopamine transporters in the reward pathway?
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
what do DAT knockout mice show?
- no behavioral activation after cocaine or amphetamine
2. no release of striatal dopamine by amphetamine
what traits does cocaine induce?
- stereotypical locomotor activity
- sniffing, grooming and rearing
- side effects are attributed to their action on other dopaminergic synapses
where do VTA and NuccAcc receive glutamatergic inputs?
from amygdala and prefrontal cortex (targets of other drugs)
what inhibits VTA?
local GABAergic interneurons and NAc projections inhibit VTA (also a target)
how is there indirect modulation of the reward pathway?
- targets GABAergic neuron
- glutamatergic inuputs from the amygdala and PC
- extra inputs, indirect modulation
- opiates inhibit GABAergic neurons causing them to release more dopamine
what do opiates act via?
- via a GPCR
- inhibits NT release (GABA) by reducing the excitability of the presynaptic membrane
how do opiates act on the u opioid receptor?
- 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)
what is the signalling cascade of opiates acting on the u opioid receptor?
- 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
what do the two effectors together do?
- 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
how do you assess addictive behaviour?
- 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
what are the effects of a D2 receptor knockout on the reward pathway?
- conditioning with morphine
- dopamine D2 receptor KO mice show no morphine induced place preference
how does nicotine work?
- 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
what is the mechanism of addiction?
- drugs interact with defferent neuronal proteins to activate the reward pathway
- toleration
- dependence
what is toleration in addiction?
- 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
what is dependence in addiction?
- drug induced changes that when unmasked by stopping lead to withdrawal
- eg prolongoed signalling can lead to changed connections
- plasticitiy
