Dopamine Theory

Question 1

Studies on electrical self-stimulation by who were the foundation of reward neuroscience?

Answer 1

Olds

Question 2

In Olds’s studies of electrical self-stimulation, what was the rodents’ behavior regarding a corner where it had received a shock?

Answer 2

Rodent would return to that corner repeatedly

Question 3

The areas of the brain enriched in which neurotransmitter are most sensitive to effects of reward?

Answer 3

Dopamine

Question 4

Describe the principle of optogenetic studies with rodents and an apparatus with different corners:

1. How is the reward circuit activated?
2. What happens when the rodent steps into the corner of interest?
3. Where does the rodent go when given the choice to freely roam around the apparatus?

Answer 4

1. Reward circuit is activated by shining light of a certain wavelength that matches the genetically-implanted receptor
2. Rodent’s circuit is activated by light activating the receptor
3. Rodent returns to corner repeatedly to receive stimulation of reward circuit

Question 5

Frequency of stimulation necessary for reward:

1. How does amphetamine affect the dopamine system?
2. How does amphetamine affect the frequency of stimulation necessary for reinforcement?
3. How does pimozide affect the dopamine system?
4. How does pimozide affect the frequency of stimulation necessary for reinforcement?
5. What does this study show about the role of dopamine in brain stimulation reward?

Answer 5

1. Amphetamine stimulates the dopamine system
2. Amphetamine lowers the frequency necessary for reinforcement
3. Pimozide antagonizes dopamine receptors
4. Pimozide increases the frequency necessary for reinforcement
5. Dopamine has a role in brain stimulation reward

Question 6

Measuring firing of dopamine neurons in ventral tegmental area:

1. What happened to the rate of firing when monkeys randomly received a squirt of juice?
2. Does this result support or contradict the dopamine theory of reward?

Answer 6

1. Rate of dopamine neuron firing increased

2. Supports dopamine theory of reward

Question 7

Facial expressions when tasting something sweet:

1. What was administered to the rodents, and what was the effect on their dopamine systems?
2. How did this affect the rodents’ facial expressions when receiving a sweet tastant?
3. Did this result support or challenge the dopamine theory of reward?
4. What was the result on facial expressions when targeting the endogenous opioid system?

Answer 7

1. 6-hydroxydopamine
   Damaged dopamine system
2. No effect on rodents’ facial expressions
3. Challenged dopamine theory of reward
4. Manipulating opioid system changed facial expressions

Question 8

Measuring firing of dopamine neurons in ventral tegmental area:

1. In the cue-evoked delivery paradigm, did the cue itself raise dopamine firing rates? The reward itself?
2. If the cue was uncoupled from the reward (cue presented, but no reward), what happened to the level of dopamine neuron firing?
3. Explain the concept of dopamine as a “reward error signal.”

Answer 8

1. Cue raised dopamine neuron firing rates, but reward itself didn’t
2. Dopamine neuron firing decreased
3. Unexpected/better than expected rewards lead to increases in dopamine firing, but expected rewards or cue without reward don’t

Question 9

Dopamine synthesis steps:

1. __-____ converted to __-____ by ____ _____
2. ____-______ converted to _____ by ______ ______
3. Where in the neuron do these synthesis steps occur?

Answer 9

1. L-tyrosine 
L- DOPA
Tyrosine hydroxylase
2. L-DOPA 
Dopamine
DOPA decarboxylase
3. Nerve terminal

Question 10

Cytoplasmic dopamine in the nerve terminal can be packaged for ____ or ____-____ ____.

Answer 10

Release

Long-term storage

Question 11

What happens to dopamine once it is released from the pre-synaptic cell?

Answer 11

Bind to post-synaptic receptors and initiates signaling in post-synaptic cell

Question 12

What is the role of the dopamine transporter in the pre-synaptic neuron and signaling process?

Answer 12

Terminates signaling by taking dopamine back into pre-synaptic cell

Question 13

Dopamine synapses are on what kind of neurons in the nucleus accumbens?

Answer 13

Medium spiny neurons

Question 14

On medium spiny neurons in the nucleus accumbens, are dopamine synapses on the heads or shafts of the spines? What type of synapses exist in the other location?

Answer 14

Shafts

Glutamate

Question 15

For dopamine transport across the plasma membrane of the pre-synaptic cell to occur, what other ions must be exchanged?

Answer 15

Na+ and Cl-

Question 16

What does cocaine do to the dopamine transporter? What effect does this have on the extracellular dopamine concentration? Is this action potential dependent?

Answer 16

Cocaine binds the dopamine transporter
Increases extracellular dopamine concentration
Yes

Question 17

1. Microdialysis can be used to measure the presence of dopamine where?
2. How does microdialysis work (brain to liquid chromatography)?
3. Microdialysis can be combined with what other kinds of experiments? What does this enable?

Answer 17

1. Extracellular space
2. Tube implanted into brain region (usually nucleus accumbens) -> semi-permeable membrane enables neurotransmitter to cross -> neurotransmitters travel through tube to liquid chromatography instrument, which enables detection of neurotransmitter
3. Behavioral experiments
   Correlation of animal activity with dopamine release

Question 18

Microdialysis studies of nucleus accumbens:

1. What is the effect of cocaine on extracellular dopamine? How is this affected by the amount of cocaine?
2. What is the effect of amphetamine on extracellular dopamine? Which causes more dopamine release, cocaine or amphetamine?
3. What 4 other drugs/active ingredients increase extracellular dopamine? Do these drugs directly act on the dopamine system?

Answer 18

1. Cocaine increases extracellular dopamine
   More cocaine -> more dopamine released
2. Amphetamine increases extracellular dopamine
   Amphetamine
3. Morphine, THC, alcohol, nicotine
   No

Question 19

What does amphetamine do to the dopamine transporter? What effect does this have on the extracellular dopamine concentration? Is this action potential dependent? Which is more potent, amphetamine or cocaine?

Answer 19

Amphetamine reverses the dopamine transporter, so dopamine can exit the pre-synaptic cell rather than being taken back up
Increases extracellular dopamine concentration
No
Amphetamine

Question 20

1. Morphine acts on what type of receptors?
2. THC acts on what type of receptors?
3. Nicotine acts on what type of receptors?
4. Alcohol acts on what type of receptors?

Answer 20

1. Opioid
2. Cannabinoid
3. Nicotinic acetylcholine
4. GABA A receptors

Question 21

Drugs acting on dopamine system:

1) What class of drugs directly act on dopamine? What are two examples of these drugs?
2) Nicotine binds to ____ ____ receptors on ____ neurons in the _____ (area), causing what overall effect on dopamine neuron firing?

Answer 21

1) Stimulants
Cocaine, amphetamine
2) Nicotinic acetylcholine
Dopamine 
Ventral tegmental area
Increasing dopamine neuron firing

Question 22

Drugs acting on dopamine system:
Opioids have a(n) (excitatory/inhibitory) effect on ____ (neurotransmitter) (excitatory/inhibitory) interneurons in the _____ (area). Since these interneurons act directly on dopamine neurons, what is the overall effect on dopamine neuron firing?

Answer 22

Inhibitory
GABA inhibitory interneurons
Ventral tegmental area
Increases dopamine neuron firing

Question 23

Drugs acting on dopamine system:
Alcohol (excites/inhibits) (excitatory/inhibitory) interneurons in the ____ (area). Since these interneurons act directly on dopamine neurons, what is the overall effect on dopamine neuron firing?

Answer 23

Inhibits
Inhibitory
Ventral tegmental area
Increase dopamine neuron firing

Question 24

Between a natural reward of food and a drug reward of amphetamine, which causes the greater increase in dopamine?

Answer 24

Amphetamine

Question 25

Dopamine transporter inhibition/cocaine self-administration correlation study: 1) Describe what was being measured in the dopamine transporter inhibition portion of the experiment. 2) Did a correlation exist between dopamine transporter inhibition and cocaine self-stimulation? 3) Correlation for transporters of what two other neurotransmitters was assessed? Were the correlations for inhibition of these transporters and cocaine self-administration smaller or larger than for dopamine?

Answer 25

1) Amount of cocaine needed to inhibit dopamine binding to dopamine transporter 2) Yes 3) Norepinephrine and serotonin Smaller

Question 26

Repeated amphetamine/cocaine administration experiments (measuring over days): 1) What two treatment groups were assessed? 2) What was the effect of repeated amphetamine exposure on locomotor sensitization? 3) What was the effect of repeated amphetamine exposure on dopamine release? 4) In similar studies using cocaine, were the results for locomotor sensitization and dopamine release the same or different? If different, how so? 5) Waiting a month or so after repeated drug treatment: did the results for locomotor sensitization and dopamine release change? If so, how?

Answer 26

1) Repeated exposure to amphetamine (experimental) Pre-treatment with saline, one exposure to amphetamine (control) 2) Repeated exposure to amphetamine increased locomotor activation over control group 3) Repeated exposure to amphetamine increased dopamine release over control group 4) Same 5) Locomotor sensitization was still elevated, but dopamine release decreased

Question 27

1) How does D2 dopamine receptor activation affect further dopamine release? 2) How does quinpirole affect D2 receptors?

Answer 27

1) Reduces further dopamine release | 2) Agonist (activates D2 receptors)

Question 28

1) In an experiment with repeated cocaine administration with quinpirole treatment, which showed greater decreases in dopamine, the experimental group or saline pre-treated control group? 2) Was this effect more pronounced in the early or late stages of the experiment? 3) What does this experiment reveal about D2 receptors in the early phases of repeated drug use?

Answer 28

1) Control group 2) Early 3) D2 receptors are reduced in early phases of repeated drug administration

Question 29

D2 receptor knockout experiment: 1) Between knockout and control mice, which showed the greater increase in dopamine upon cocaine treatment? 2) What does this experiment reveal about D2 receptors and sensitized dopamine release in the early phases of repeated drug use? 3) According to this model, why does sensitized dopamine release stop occurring in the late phases of repeated drug use? 4) According to this model, is it likely that dopamine mediates behavioral sensitization in the late phases of repeated drug use? Why or why not?

Answer 29

1) Knockout mice 2) Sensitized dopamine release may occur as a result of D2 receptor downregulation 3) D2 receptor levels may be restored with time, so sensitized dopamine release no longer occurs 4) No- sensitized dopamine release doesn't occur in late stages of repeated drug use

Question 30

Dopamine-deficient mice and morphine reward: 1) How was dopamine depleted in these mice? 2) When treated with morphine, how did these mice behave in the conditioned place preference test? 3) What does this suggest about the role of dopamine in reward?

Answer 30

1) Tyrosine hydroxylase gene deleted- no synthesis of dopamine 2) Showed preference for morphine-paired chamber 3) Dopamine isn't the only mediator of reward

Question 31

Dopamine transporter deficient mice and cocaine: 1) What happens to extracellular dopamine in dopamine transporter-deficient mice? 2) What happens to dopamine levels following cocaine treatment in dopamine transporter deficient mice? 3) Do dopamine transporter deficient mice self-administer cocaine? 4) What does the result of this experiment suggest about the effects of cocaine on dopamine transport (specific to these mice)?

Answer 31

1) Dopamine builds up in extracellular space (no transporter to take it up) 2) No increase in dopamine (cocaine acts on dopamine transporter) 3) Yes 4) Cocaine may be acting on more than just dopamine transporter in dopamine transporter deficient mice

Question 32

Dopamine transporter mutant mice and cocaine: 1) How was the dopamine transporter damaged in these mice? How did that effect cocaine's mechanism of action? 2) In the dopamine transporter mutant mice, how did cocaine treatment affect dopamine levels? Amphetamine treatment? 3) Did the mutant mice show conditioned place preference for cocaine? Amphetamine? 4) Did the mutant mice show locomotor sensitization to cocaine? Amphetamine? Morphine? 5) Did the results of this experiment strengthen or weaken the understanding of cocaine's mechanism of action? How?

Answer 32

1) Binding pocket was damaged Cocaine could no longer bind to dopamine transporter 2) Cocaine- no increase in dopamine Amphetamine- increase in dopamine 3) No CPP for cocaine, but CPP for amphetamine 4) No locomotor sensitization for cocaine, but did occur with amphetamine and morphine 5) Strengthened- showed that dopamine transporter binding pocket was site of action for cocaine

Question 33

Dopamine and serotonin transporter mutant mice and cocaine: 1) Mutating which of the following transporters had the greatest effect on conditioned place preference for cocaine: dopamine, serotonin, or both? What was the effect? 2) What does the result of this experiment reveal about the role of serotonin transporter in reward?

Answer 33

1) Both Decrease in conditioned place preference 2) Serotonin transporter could act in absence of dopamine transporter to produce reward

Question 34

Optogenetics: 1) What type of protein is channel rhodopsin? How is it activated? 2) How is channel rhodopsin expressed/implanted in neurons of interest? 3) Once channel rhodopsin is expressed in the neurons of interest, how can those neurons be activated?

Answer 34

1) Ion channel Activated by light of a specific wavelength 2) Viral vector expressing gene for channel rhodopsin as well as promotor for gene of interest (ex- tyrosine hydroxylase for dopamine neurons)-> inject into part of animal's brain to be studied 3) Shining light of specific wavelength into animal's brain (through fiber optic cable implanted into brain region of interest)

Question 35

Optogenetics and dopamine neurons: 1) What specific group of neurons were targeted for this study? 2) What happened to the rate of bar pressing when the animals were rewarded with stimulation of these neurons? 3) When the mice were given cocaine prior to the self-administration paradigm, did the rate of bar pressing increase or decrease? 4) What did this result reveal about cocaine and dopamine?

Answer 35

1) Tyrosine hydroxylase containing neurons 2) Bar pressing rate increased 3) Decrease 4) Cocaine activates dopamine system: animals feel less need to bar press to activate tyrosine hydroxylase containing neurons because they are experiencing an increase in dopamine through cocaine administration