Glutamate Theory

Question 1

What is the chief excitatory neurotransmitter in the brain? From what type of molecule is it derived?

Answer 1

Glutamate

Amino acid

Question 2

From what 3 areas of the brain does the nucleus accumbens receive glutamatergic inputs?

Answer 2

Prefrontal cortex
Hippocampus
Amygdala

Question 3

In the medium spiny neurons of the nucleus accumbens, where are the glutamate synapses? The dopamine synapses?

Answer 3

Glutamate synapses- spine heads

Dopamine synapses- shafts

Question 4

1) What is the difference between volume and point-to-point neurotransmission?
2) Which neurotransmitter is involved in volume neurotransmission? Point-to-point neurotransmission?

Answer 4

1) Point-to-point involves controlled, short-distance release acting at one site, whereas volume involves long-distance release with many sites of action
2) Volume: dopamine
Point-to-point: glutamate

Question 5

Drug context/associative learning experiment with amphetamine:

1) Explain the difference between the 3 groups (control, paired, 3rd world)
2) How did the 3 groups compare on test day in locomotor sensitization?
3) What did this experiment reveal about the context of drug administration? Associative learning?

Answer 5

1) Control received saline until test day and in same environment each time
Paired received amphetamine (including test day) and in same environment each time
3rd world received amphetamine (including test day), but in different environment on test day
2) Paired group showed greatest locomotor sensitization
No difference between 3rd world and control mice
3) Context has an impact on behavior
Associative learning occurs in drug addiction

Question 6

Nucleus accumbens glutamate and amphetamine experiments:

1) Explain the difference between the 3 groups (control, sensitized, nonsensitized)
2) How did the experimenters measure glutamate?
3) How did the 3 groups compare in terms of glutamate release upon saline injection? Amphetamine injection?
4) What does this reveal about the role of glutamate in repeated amphetamine use?

Answer 6

1) Control had previously received saline
Sensitized had previously received amphetamine and showed locomotor sensitization
Nonsensitized had previously received amphetamine and didn’t show locomotor sensitization
2) Microdialysis
3) No increase in glutamate for any group with saline
Increase in glutamate for sensitized group with amphetamine
Saline and nonsensitized about the same
4) Glutamate is increased in repeated amphetamine use with sensitization

Question 7

Locomotor sensitization and AMPA agonist experiments:

1) Explain the difference between the 3 groups (control, sensitized, nonsensitized)
2) What type of receptor is AMPA? What type of transmission (speed, excitatory/inhibitory) is it involved in?
3) How did the 3 groups compare in terms of locomotor activity upon AMPA agonist injection?
4) What does this reveal about glutamate signaling in repeated amphetamine use?

Answer 7

1) Control had previously received saline
Sensitized had previously received amphetamine and showed locomotor sensitization
Nonsensitized had previously received amphetamine and didn’t show locomotor sensitization
2) Glutamate receptor
Fast, excitatory
3) Sensitized group showed greatest increase in locomotor sensitization
Saline and nonsensitized about the same
4) Glutamate signaling increases with repeated amphetamine use

Question 8

Describe the self-administration, extinction and reinstatement paradigm. What aspect of drug addiction is this a model for?

Answer 8

Animal self-administers drug consistently ->
Uncouple lever press from drug infusion ->
Animal decreases lever pressing (extinction) ->
Stimulus (ex- drug injection) is presented ->
Animal’s lever pressing increases (reinstatement)
Relapse

Question 9

Self-administration, extinction, reinstatement and glutamate experiment:

1) Experimental manipulation #1: antagonist for dopamine or AMPA was injected where?
2) Experimental manipulation #2: cocaine was injected locally or systemically?
3) When was the antagonist delivered?
4) On the reinstatement test, how was lever pressing affected with dopamine antagonist vs control treatment?
5) On the reinstatement test, how was lever pressing affected with AMPA antagonist vs control treatment?

Answer 9

1) Nucleus accumbens
2) Systemically
3) Just before reinstatement test
4) Similar levels of lever pressing for dopamine antagonist and saline: both showed reinstatement
5) Lever pressing was decreased for AMPA antagonist group: decreased reinstatement

Question 10

Amphetamine sensitization, self-administration, and resinstatement experiment:

1) What was the difference in cocaine self-administration on an FR1 (1 lever press, 1 cocaine infusion) or FR2 (2 lever presses, 1 cocaine infusion) schedule between mice that had previously received amphetamine and those that had previously received saline?
2) What was the difference between the previous amphetamine and previous saline groups in terms of number of times they would be willing to lever press for cocaine?
3) What was used for reinstatement? Where was it injected?
4) What was the difference in terms of lever presses upon reinstatement for previous amphetamine and previous saline treated mice?
5) What does this experiment reveal about the role of previous exposure in relapse and willingness to work for drug?
6) What does this experiment reveal about the role of AMPA receptors in relapse?

Answer 10

1) No difference in self-administration for previous amphetamine and previous saline
2) Previous amphetamine would press lever more times for cocaine before giving up
3) AMPA agonist
Nucleus accumbens
4) Previous amphetamine had more lever presses upon reinstatement than previous saline
5) Previous exposure increases relapse and willingness to work for drug
6) AMPA receptors mediate susceptibility to relapse in previously exposed animals

Question 11

Glutamate and dopamine reinstatement experiment:

1) Explain the difference between the 3 groups (self-administer, yoked cocaine, yoked saline)
2) How were glutamate and dopamine levels measured?
3) How did the 3 groups compare in terms of glutamate levels upon cocaine treatment?
4) How did the 3 groups compare in terms of dopamine levels upon cocaine treatment?
5) How did the 3 groups compare in terms of lever presses upon cocaine treatment? Why was this?
6) What does this experiment reveal about the role of glutamate vs dopamine in self-administration learning?

Answer 11

1) Self-administer group gets to freely self-administer cocaine
Yoked cocaine receives a cocaine infusion every time paired self-adminster animal self-administers cocaine
Yoked saline receives a saline infusion every time paired self-administer animal self-administers cocaine
2) Microdialysis
3) Only self-administration group showed increase in glutamate
4) All 3 groups showed increase in dopamine
5) Only self-administration group showed increase in lever presses (yoked animals weren’t trained to lever press)
6) Glutamate, but not dopamine, underlies learning effect with self-administration

Question 12

What are the 2 different types of glutamate receptors?

Answer 12

Ionotropic

Metabotropic

Question 13

What are the 3 different types of ionotropic glutamate receptors? What is their speed of action? Why?

Answer 13

AMPA, NMDA, kainate

Fast- ions flow through and directly lead to action potentials

Question 14

Metabotropic glutamate receptors work through what 2 types of molecules? Do they play a direct or modulatory role in drug effects?

Answer 14

G proteins and 2nd messengers

Modulatory

Question 15

Glutamate receptors and repeated cocaine:

1) What 2 AMPA subunits were measured in this experiment? What NMDA subunit was measured in this experiment?
2) How did the 3 subunits differ across cocaine pre-treated and saline pre-treated animals?
3) How did the 3 subunits differ across cocaine/sensitized, cocaine/non-sensitized, saline/sensitized, and saline/non-sensitized animals?
4) What does this reveal about how glutamate receptors change with repeated cocaine usage?

Answer 15

1) GluR1, GluR2/3
NMDAR1
2) Cocaine pre-treated showed slightly higher levels of GluR1 and NMDAR1 than saline pre-treated; same for GluR2/3
3) Cocaine/sensitized showed much higher levels of GluR1 than others; about the same for other 2 receptors
4) Glutamate receptors increase upon repeated cocaine usage

Question 16

Glutamate receptors and repeated cocaine (2nd experiment):

1) How were cell surface receptors differentiated from internal receptors in this experiment? How did this affect how they were seen on Western blots?
2) What 2 AMPA subunits were measured in this experiment?
3) How did the 2 subunits differ across cocaine/sensitized, cocaine/non-sensitized, and saline animals? Were the changes seen in cell surface receptors or internal receptors?
4) What does this reveal about how glutamate receptors change with repeated cocaine usage?

Answer 16

1) Drug was given to cross-link cell surface receptors together- cross-linked proteins showed up on Western blot as smears
2) GluR1, GluR2/3
3) GluR1 and GluR2/3 were increased for cocaine/sensitized animals; about the same for other 2 groups
Cell surface receptors
4) Surface AMPA receptors increase with repeated cocaine usage with sensitization

Question 17

1) On medium spiny neurons, are branched spines considered to represent new or established growth?
2) Medium spiny neuron heads are the sites of what type of synapses?
3) How does repeated amphetamine exposure affect number of spines per dendrite and number of branched spines?
4) What does this reveal about repeated amphetamine usage and number of sites for AMPA receptors?

Answer 17

1) New
2) Glutamate
3) Increases both number of spines per dendrite and number of branched spines
4) Repeated amphetamine usage raises number of sites for AMPA receptors by increasing numbers of dendritic spines on MSNs

Question 18

What two forms of synaptic plasticity underlie learning and memory?

Answer 18

Long term potentiation (LTP) and long term depression (LTD)

Question 19

1) Long term potentiation (LTP): an (increase/decrease) in synaptic strength following (low/high) frequency stimulation of neuron for a (short/long) period of time
2) Long term depression (LTD): an (increase/decrease) in synaptic strength following (low/high) frequency stimulation of neuron for a (short/long) period of time

Answer 19

1) Increase
High
Short
2) Decrease
Low
Long

Question 20

LTP and LTD are mediated by movement of what type of receptor in and out of the neuronal membrane? LTP is mediated by a(n) (decrease/increase) in this receptor in the neuronal membrane, whereas LTD is mediated by a(n) (decrease/increase) in this receptor in the neuronal membrane.

Answer 20

AMPA
LTP- increase
LTD- decrease

Question 21

Synaptic plasticity and AMPA and NMDA receptors:

1) AMPA and NMDA receptors: which is able to move in and out of neuronal membrane freely? Which does this less frequently?
2) Between AMPA and NMDA receptors, which has the faster speed of transmission?
3) Is the rate of AMPA/NMDA receptors relatively stable for a neuron?
4) After LTP is induced at a synapse, how does the number of AMPA receptors at the post synaptic membrane change? NMDA receptors?
5) What type of change in AMPA/NMDA ratio indicate synaptic strengthening?

Answer 21

1) AMPA
NMDA
2) AMPA
3) Yes
4) AMPA increases, NMDA doesn't change
5) Increase in AMPA/NMDA ratio

Question 22

Synaptic plasticity and repeated cocaine/amphetamine :

1) How is the AMPA/NMDA ratio measured experimentally?
2) How did the AMPA/NMDA ratio change with repeated saline administration? Repeated cocaine?
3) How long did this effect last?
4) Were the results of this experiment repeated with amphetamine? If not, how were they different?
5) What does this reveal about synaptic plasticity as a result of repeated cocaine or amphetamine usage?

Answer 22

1) Responses for each receptor are measured individually by blocking other receptor
2) Saline- little to no change
Cocaine- large change
3) Weeks after drug exposure
4) Results were the same
5) LTP occurs after repeated cocaine and amphetamine usage

Question 23

Synaptic plasticity and cocaine re-exposure:

1) For about how long were animals abstinent after taking cocaine for several days?
2) How did AMPA/NMDA ratio change with: repeated cocaine/no injection following abstinence, repeated cocaine/saline injection following abstinence, and repeated cocaine/cocaine injection following abstinence?
3) What does this reveal about synaptic plasticity following reinstatement?

Answer 23

1) 10-14 days
2) Repeated cocaine/no injection and repeated cocaine/saline reinstatement showed increase in AMPA/NMDA ratio, but repeated cocaine/cocaine reinstatement had baseline AMPA/NMDA ratio
3) LTD occurs after reinstatement

Question 24

Synaptic plasticity and stress exposure (repeated cocaine):

1) How were rodents stressed in this paradigm? When was stress induced in the experiment? What was stress being used to trigger?
2) How did the following groups of animals compare in AMPA/NMDA ratio in this experiment:
a) saline/no stress, saline/stress
b) cocaine/sensitized/no stress, cocaine/sensitized/stress
c) cocaine/non-sensitized/no stress, cocaine/non-sensitized/stress
3) What does this reveal about synaptic plasticity in relapse?

Answer 24

1) Making them swim
Following period of abstinence
Relapse
2a) AMPA/NMDA ratio increased with stress in saline-treated animals
2b) AMPA/NMDA ratio decreased with stress in repeated cocaine/sensitized animals
2c) Little to no change in AMPA/NMDA ratio with stress in repeated cocaine/non-sensitized animals
3) LTD occurs after relapse

Question 25

Synaptic plasticity and cocaine conditioned place preference reinstatement:

1) What were the 3 phases of this experiment?
2) How was reinstatement triggered in this experiment?
3) How did the AMPA/NMDA ratio of repeated cocaine treated animals change with conditioning? Reinstatement?
4) What does this reveal about synaptic plasticity in repeated cocaine use?

Answer 25

1) Conditioning, extinction, reinstatement
2) Injection of cocaine
3) AMPA/NMDA ratio increased in conditioning, but decreased in reinstatement
4) LTP initially occurs in repeated cocaine use, but LTD occurs upon reinstatement

Question 26

Synaptic plasticity and cocaine self-administration reinstatement:

1) What were the 3 phases of this experiment?
2) What 4 possible conditions were used for reinstatement? What is yohimbine?
3) Which of the 4 reinstatement conditions increased cocaine self-administration in repeated cocaine-treated animals?
4) How did each of the 4 reinstatement conditions affect AMPA/NMDA ratio in repeated cocaine treated animals?
5) What does this reveal about synaptic plasticity in cocaine relapse?

Answer 26

1) Conditioning, extinction, reinstatement
2) Saline, drug-associated cue, cocaine, or yohimbine
Yohimbine is a chemical stressor
3) Drug-associated cue, cocaine, yohimbine
4) Saline: increased AMPA/NMDA ratio
Drug-associated cue, cocaine, yohimbine: decreased AMPA/NMDA ratio
5) LTD occurs in cocaine relapse

Question 27

LTD prevention and cocaine conditioned place preference reinstatement:

1) How can LTD be blocked with a specific peptide treatment?
2) When did treatment with this peptide occur in the experiment?
3) How was conditioned place preference reinstatement affected with peptide treatment for repeated cocaine treated animals?
4) What does this reveal about synaptic plasticity in cocaine relapse?

Answer 27

1) AMPA endocytosis is prevented
2) Just before reinstatement
3) Preference was decreased in reinstatement for peptide/cocaine treated animals
4) LTD underlies cocaine relapse

Question 28

LTD activation and cocaine conditioned place preference reinstatement:

1) Optogenetic stimulation was used for projections from what region to what region? What type of inputs were these?
2) How was LTD triggered by optogenetics?
3) What was used to trigger reinstatement in this experiment?
4) How was preference affected by the reinstatement trigger?
5) What does this reveal about synaptic plasticity in cocaine relapse?

Answer 28

1) Infralimbic cortex (part of prefrontal cortex) to nucleus accumbens
Glutamate
2) Frequency of light stimulation triggers LTD in these neurons
3) LTD optical stimulation
4) Preference was restored (present in conditioning, absent in extinction)
5) LTD underlies cocaine relapse

Question 29

AMPA-induced LTD in nucleus accumbens:

1) How does treatment with an AMPA agonist in the nucleus accumbens affect synaptic plasticity?
2) Treatment with a peptide with what effect blocks this effect of AMPA agonist treatment?
3) Are these effects seen in drug treated or drug naive animals?

Answer 29

1) AMPA agonist in NAc causes LTD
2) Blocks endocytosis of AMPA receptors
3) Drug naive animals

Question 30

In people with a cocaine use disorder, decrease in connectivity between what two areas is linked to an increased likelihood of relapse?

Answer 30

Prefrontal cortex

Nucleus accumbens