Riley Dopamine 3

Question 1

Why is it difficult to disentangle a dopaminergic input from a non-dopaminergic input?

Answer 1

Because there are so many converging inputs on the NAc

Question 2

How can we measure DA activity in the NAc?

Answer 2

Electrophysiology allows us to record from populations of brain cells in deep structures
It has excellent spatial and temporal resolution
It can also assess both the synaptic activity (input) and action potentials (output) of neurons

BUT the connectivity of the NAc makes things tricky

Question 3

Why can’t you use EEG as a DA activity measure?

Answer 3

Is a scalp measure so the NAc is too deep

Question 4

Why can’t you use fMRI to measure DA activity in the NAc?

Answer 4

It is a slow haemodynamic measure, and the rat is small so the fMRI’s limited spatial resolution would get in the way.
Rats also need to be anaesthetised for fMRI and they need to be awake to study reward
Need something more precise

Question 5

Why does the connectivity of the NAc make things tricky?

Answer 5

The immunocytochemistry in conjunction with electron microscopy has shown that hippocampal and dopaminergic (VTA) inputs make synaptic connections with the same NAc neuron
Therefore this increases the noise and makes it difficult to differentiate

Question 6

What can we do instead to avoid this complication of hippocampal neurons and VTA neurons making connections with the same neuron?

Answer 6

Directly assess the secretion of NTs. Only the VTA input to the NAc is dopaminergic as other projections rely on glutamate

Question 7

How can you directly assess secretions of NTs?

Answer 7

Through microdialysis
Enables sampling and collecting of small-molecular weight substances from the interstitial space
One of few techniques available that permits direct quantification of NT levels in behaving animals
Requires chronic implantation of a dialysis probe

Question 8

How does microdialysis work?

Answer 8

Through the chronic implantation of a probe, artificial CSF is constantly perfused. It is semi-permeable to DA and other small molecules
The DA on the outside of the dialysis membrane diffuses into the probe along the conc. gradient
The perfusate is infused slowly and continuously through the length of the dialysis probe.
It can then be collected for subsequent analyte quantification

Question 9

Evaluate microdialysis

Answer 9

It doesn’t quite have the desired temporal specificity as it is a relatively slow process
But it does have excellent biochemical specificity

Question 10

What are the effects of cocaine at the level of the NAc using microdialysis?

Answer 10

Early evidence (Hernandez and Hoebel, 1988) showed that local injections of cocaine increase DA concentration in the NAc
It also showed that the DA metabolite DOPAC decreased in concentration because dopamine isn't being broken down
The findings do show that drugs of abuse target mesolimbic DA but the methodology is a bit basic

Question 11

What did Ranaldi et al. (1999) find?

Answer 11

Lab animals learn lever pressing when intravenous amphetamine or cocaine injections are contingent on such responses
Within a few weeks of regular testing, the behaviour becomes regulated by the systematic drug level:
- an initial loading phase
- a maintenance phase

Question 12

What happens when there’s decreases in doses?

Answer 12

It is met with compensatory increases in lever pressing, therefore maintaining the drug level
Is this due to DA concentration in the NAc?

Question 13

What methods did Ranaldi et al. (1999) use?

Answer 13

Rats implanted with chronic microdialysis probes in the NAc and chronic intravenous catheters for later injections of amphetamine
Trained rats to press lever to administer i.v. amphetamine
DA levels in the NAc were measured during maintenance, extinction and reinstatement of amphetamine levels

Question 14

What was seen in the initial loading phase?

Answer 14

Intense lever pressing accompanied by a sharp rise in DA concentrations in the NAc

Question 15

What was seen in the maintenance phase?

Answer 15

Lever is pressed when there is a dip in DA levels to maintain the increased DA levels - a clear self maintenance effect is seen as it is almost exclusively when NAc DA levels drop

Question 16

How do we know these lever presses are not out of habit?

Answer 16

They are not time contingent and not equally spaced

Question 17

What happened during the extinction phase?

Answer 17

A lot of lever presses, with decreases in DA concentration, with the presses attempting to increase DA concentration
The greatest decline in DA coincides with the period of highest lever pressing

Question 18

What happened during the reinstatement phase?

Answer 18

There is an observed loading phase which then settles into the previously seen maintenance phase and normal lever pressing

Question 19

What are some additional behavioural observations made during the experiment?

Answer 19

During the final ~30 mins of extinction, the rats had ceased the stereotyped sniffing or locomotion and were lying down
A single non-contingent infusion of D-amphetamine caused rats to reinitiate the exploratory locomotion and sniffing typically seen under the influence of this drug

Question 20

What conclusions were made from Ranaldi et al.’s (1999) study?

Answer 20

The rate of amphetamine self-administration is under the control of NAc DA concentration - NOT a timed response habit
Additional amphetamine has little rewarding efficacy when the DA levels are already elevated - some form of saturation in the reward system?
Strongly supports notion that dopamine in the NAc acts as a primary reward

Question 21

What did Xi et al. (1998) in regards to heroin and DA levels?

Answer 21

Made 3 main observations:

1. There are dose-dependent increases of DA in the NAc during heroin self-administration
2. The frequency of self-administration declines as a function of dose (less SA for higher doses and more for lower doses)
3. Heroin co-administered with naloxone (an opioid receptor antagonist) reduced the amount of DA released in the NAc

Question 22

What did Lecca et al. (2007) find in relation to heroin and DA in rats?

Answer 22

Either self-administer heroin or have experimenter controlled (yoked) heroin administration and used microdialysis over 4 weeks
Heroin increases DA concentration in NAc, but this is more pronounced in SA conditions

Question 23

What was the difference between SA and yoked rats?

Answer 23

In SA rats there is a distinction seen between the NAc shell and core which is not seen in yoked rats
Potentially due to SA rats having some awareness of the motor programme that initiated that so its the hedonic aspect that is more reinforced

Question 24

What was seen after 4 weeks of injections?

Answer 24

The yoked rats now also show comparable increase of DA in NAc following the heroin injection with a reversal of shell/core dichotomy seen in SA rats
Could potentially be because the yoked rats reinforce their motor programmes - but the author didn’t address this particularly well

Question 25

What did Hernandez and Hoebel (1988) find in relation to natural rewards?

Answer 25

They measured DA levels in the NAc following natural rewards, electrical stimulation and drugs
Extracellular DA concentrations increased when food was made available
This increase is relatively long-lasting - for the learning signal as it takes a relatively long time to process
It remained high for over an hour after feeding stopped

Question 26

Can electrical stimulation of the food centres produce similar effects to the presentation of food?

Answer 26

When the lateral hypothalamus was stimulated:

1. DA concentration increased in the NAc
2. If food was available animals would seek it out and eat

This happened because descending neurons from the LH project to midbrain DA neurons, and the VTA projects to the NAc

Question 27

What is the one thing that rats like more than food and drugs?

Answer 27

Sex,
If you have a sexually naive rat and sexually experienced rat, the sexually experienced rat will have a dopamine hit with bedding a female and female odour
Whereas the naive rat doesn’t experience such DA increases, but then becomes conditioned to this and associated bedding and odour with primary reward