learning and memory

Question 1

What is overall paragraph structure

Answer 1

1. Intro
2. Synaptic plasticity and LTP
3. Positioning of glutamatergic synapses
4. Impact of drug of abuse on LTP
5. Effect of disrupting synaptic plasticity on drug conditioned learning
6. Reconsolidation therapy
7. Extinction training

Question 2

Points in intro

Answer 2

1. Memory involved in the learning and maintenance of drug-related behaviours.
2. Drug-related memories are formed through a process called associative learning, in which drug-related cues become associated with the pleasurable effects of the drug.
3. memories trigger strong cravings and lead to relapse, even after extended periods of abstinence.
4. There are 3 major stimuli for drug relapse;
5. Addiction and relapse big problem

Question 3

Points in synaptic plasticity and LTP

Answer 3

1. Synaptic plasticity mainly occurs at glutamatergic receptors which release glutamate and activate post synaptic NMDA and AMPA receptors.
2. LTP), is a form of synaptic plasticity and is believed to underlie the formation of memories,when there is a burst of high frequency action potentials.
3. cellular mechanisms underlie long term potentiation, increase in the number of AMPA receptors in the post-synaptic side of the glutamatergic synapse.
4. This increases the synaptic strength.
5. This LTP can persist for a very long time and different patterns of LTP across engrams encode memories.
6. fear memories were encoded in the amygdala pathway, hypothesis that reward memories may be encoded in the meso-limbic dopamine pathway.

Question 4

Points in positioning of gabaergic

Answer 4

1. The cell bodies and dendrites of the dopaminergic meso-limbic neurones are found in VTA and project into the NAC where they release dopamine.
2. glutamatergic input from other brain regions to the VTA, particularly from the pre-frontal cortex and hippocampus.
3. glutamatergic synapses on the GABAergic interneurons and on dopaminergic neurons capable of exhibiting LTP which could underlie reward related memories.

Question 5

Impact of drug of abuse on LTP

Answer 5

1. Ungless et al, 2001,
2. The mechanism which leads to LTP is not fully known, known that Ca2+ entry through NMDA receptors which somehow activates PKA which in turn causes protein synthesis.
3. Ungless study the effect lasted for 5 days which was not long enough to explain the persistence in drug-seeking behaviour.
4. Saal et al 2003,
5. However, both these studies involved experimenter administered drug injections which may not reveal the full picture of drug addiction in humans.
6. Chen et al 2008.

Question 6

Ungless et al

Answer 6

1. 2001
2. injected mice with cocaine and then took brain slices to measure the synaptic strength at glutamatergic synapses in dopaminergic neurons in the VTA.
3. They separated the AMPA and NMDA receptor mediated components and measured the ratio of the AMPA receptor-mediated current to the NMDA receptor-mediated current.
4. This ratio was significantly increased in the cocaine injected animals for a period of 5 days, so was present after the initial euphoric effects had worn off.
5. This increase in AMPA receptor expression and synaptic strength that persists after the acute effect of a drug has worn off is an LTP-like effect.

Question 7

Saal et al

Answer 7

1. 2003
2. carried out a further study using different drugs of abuse including ethanol and morphine which showed similar results.
3. They also tested psychoactive drugs such as fluoxetine which show no addictive liability and these had no effect on the AMPA/NMDA ratio,
4. providing further evidence that these changes to the synapses are related to the addictive properties.

Question 8

Chen et al

Answer 8

1. 2008
2. therefore carried out a similar study but where the rats self-administered the cocaine,
3. this resulted in elevated levels of synaptic potentiation after 90 days (a much longer time than observed for involuntary injections in previous studies).
4. These results suggested that the pharmacological effect of the drug itself is not enough to potentiate glutamate transmission in the VTA
5. and that a strong association with a cue is necessary to induce this form of synaptic plasticity.

Question 9

Effect of disrupting synaptic plasticity

Answer 9

1. Harris et al 2004
2. This study indicated that the VTA is a critical site for synaptic modifications involved in the learning and memory of environmental cues predicting reward
3. and therefore targeting this mechanism may help to prevent addiction.
4. However, drug addicts already have those associative memories, so to treat drug addiction a way to inhibit or erase memories which have already formed is needed.
5. Research has focused on two main ways this could be done: reconsolidation therapy and extinction therapy.

Question 10

Harris et al 2004

Answer 10

1. To determine the effect of disrupting synaptic plasticity in the VTA on drug conditioned learning
2. Harris et al 2004, carried out a conditioned place preference study on rats with morphine.
3. They disrupted synaptic plasticity by injecting a glutamate receptor antagonist into the VTA which resulted in a failure of the rat to develop a morphine-conditioned place preference.
4. They made a similar observation when they injected a PKA inhibitor in the VTA but not when they injected either inhibitor into the dorsal area.

Question 11

Reconsolidation pt 1

Answer 11

1. when a memory is reactivated it becomes labile and undergoes a process called reconsolidation which makes the memory stronger.
2. interfering with reconsolidation by inhibiting synaptic plasticity (e.g. by a protein synthesis inhibitor) could be a way to weaken long-lasting memories that can trigger relapse.
3. Milekic et al 2006
4. However, studies by Lee et al. (2005) and Miller and Marshall 2005, suggest that it may be possible to disrupt drug induced associative memories using the conditioned stimulus alone.

Question 12

Milekic et al

Answer 12

1. This was investigated by Milekic et al 2006, who found that administration of a protein synthesis inhibitor during a reactivation session led to absences of previously established morphine conditioned place preference.
2. This was found for injections into the hippocampus, basolateral amygdala and nucleus accumbens but not in the VTA.
3. Furthermore, they found that this preference did not return after further conditioning, suggesting the disruption is persistent.
4. This study found that the reactivation session did not occur on drug or contextual exposure alone but required both.

Question 13

Reconsolidation part 2

Answer 13

1. Therefore, re-exposure training of a drug addict alongside a specific inhibitor which can disrupt the drug-related memories may be an effective treatment to reduce the risk of relapse.
2. Soeter and Kindt 2015
3. However, fear-related memories only involve the glutamatergic synapses in the amygdala, so are easier to manipulate as there is only one type of synapse involved whereas, addiction memories are very complex and involve a number of brain regions.
4. There have been a number of studies on the idea that there is a hierarchical structure of the brain regions involved, starting with the VTA and nucleus accumbens and then as the drug use becomes more prolonged and the compulsivity and addiction becomes more extreme, the prefrontal cortex and amygdala are involved Koob 1992.
5. This means that a protein synthesis inhibitor can’t be used for drug addiction treatment as this would inhibit synaptic plasticity in all these regions and so would erase all other memories that are reactivated at the same time.
6. Therefore, further research to find a specific inhibitor for the brain regions involved is needed before reconsolidation therapy can be used for drug addiction.

Question 14

Soeter and Kindt

Answer 14

1. 2015
2. This approach has been successful for some fear related memories, for example, exposed participants with a fear of spiders to a live tarantula followed by treatment with propranolol (a beta blocker which blocks adrenal receptors in the amygdala required for synaptic plasticity in fear-related memories).
3. These participants showed a dramatic reduction in fear of spiders even up to a year after exposure.

Question 15

Extinction

Answer 15

1. enhance extinction
2. Extinction training is where individuals are repeatedly exposed to drug-related cues without the administration of the drug,
3. this builds up a new memory which doesn’t associate the drug related cue with the pleasurable effects leading to the weakening of the association between the cue and the drug’s pleasurable effects.
4. Extinction is not replacing the old memory as seen in a study where when a rat is given a single priming dose (stress or cue) the drug-seeking behaviour will reinstate.
5. It is thought to be overlaying a novel inhibitory memory on top of the original memory.
6. Therefore, if this memory can be enhanced it could reduce reinstatement in test animals in response to a trigger and therefore reduce relapse in humans.
7. This could be achieved using cognitive enhancers which increase memory formation however at present there are not many effective cognitive enhancers.
8. Nic Dhonnchada et al 2010
9. Although this study demonstrated some promising results the lack of a more effective cognitive enhancer currently provides limitations to this treatment idea.

Question 16

Nic Dhonnchada et al 2010

Answer 16

2. found that when DCS (a cognitive enhancer which targets the glycine-binding site of NMDA receptors) was injected into rats and squirrel monkeys before or straight after extinction training along with handling (a stress induction),
3. subsequent reacquisition of cocaine self-administration was decreased.
4. However, these results only saw significant reductions compared to when vehicle was injected after 0 hours with stress induction and not after 6 hours or 0 hours without handling.