CB L3 - Role of learning and memory in drug addiction

Question 1

Why is learing and memory a big area of interest?

Answer 1

Opens potential new treatments ideas - can we tweak the existing memories?

Question 2

Memory formation occurs through

Answer 2

synaptic plasticity

Question 3

2 forms of synaptic plasticity

Answer 3

Long term potentiation (LTP) - most

Long term depression (LTD)

Question 4

LTP occurs mainly in what type of synapse

what two types of receptors are found here

Answer 4

glutamatergic.

glutamate activates
NMDA +
AMPA
ligand gated ionotropic receptors

Question 5

After LTP what is the prominant effect on the neurone?

Answer 5

Delivery of AMPA receptors - physically have more active receptors for the glu to bind to

Question 6

when you stimulate a synapse you get a ….

Answer 6

Excitatory post synaptic potential
EPSP

(essentially it’s a depolarising current)

Question 7

What would happen if you only activated the afferent fiber once in a while?

Answer 7

It would produce the same EPSP always

Question 8

If you produce a high frequency stimulation of the afferent fibre you get….

Answer 8

Theta burst - bust of high frequency stimulation which induces LTP (insertion of posysynaptic AMPA receptors)

Question 9

How long does LTP last

Answer 9

as long as we’ve ever been able to measure

Question 10

e.g. of memories/brain location we understand quite well

Answer 10

Amygdala - fear

Maybe the reward pathway is responsible for reward memory?

Question 11

e.g. of memories/brain location we understand quite well

Answer 11

Amygdala - fear

Maybe the reward pathway is responsible for reward memory?

Question 12

Glutamatergic afferens are found where?

coming from where?

Answer 12

in all brain regions, coming from the pre-frontal cortex, hippocampus and other regions

Question 13

What is the affect of drugs of abuse on LTP?

ref

Answer 13

Single dose of cocaine in mice induces LTP in the VTA
(shown by increase in AMPA:NMDA ratio. So there is a bigger AMPA component)

Ungless et al. (2001)

Question 14

Does LTP occur in vitro?

Answer 14

no - you need the whole working network.

Doesn’t work on a slice of brain

Question 15

What is the affect of drugs of abuse on LTP?

ref

Answer 15

Single dose of cocaine in mice induces LTP in the VTA
(shown by increase in AMPA:NMDA ratio. So there is a bigger AMPA component)
[at least 5 days for single cocaine injection]

Ungless et al. (2001)

Question 16

Does LTP occur in vitro?

Answer 16

no - you need the whole working network.

Doesn’t wash cocaine onto a slice of brain

Question 17

Every drug of abuse requires ….. in vivo injection to cause LTP

Psychoactive substances?

Answer 17

just one

doesn’t work for other psychoactive drugs (so it’s just things that are addicting)

Question 18

Molecular mechanism underlying LTP?

Answer 18

We don’t know much.

Ca comes in through NMDA
activates PKA
somehow causes protein synth causing more AMPA receptors on the membrane

Question 19

What can we put into the………………… to prevent drug conditioned learning?

ref

Answer 19

Conditioned place preferenace with morhpine doesn’t work if you infuse glutamate antagonist into the VTA.

(only works in the VTA!)

Also works with a PKA inhibitor (remeber PKA was part of the pathway too)

harris et al 2004

Question 20

2 processes of inhibiting synnpatic plasticity

Answer 20

PKA inhibitors

Glutamate antagonists

straight into the VTA

(it’s kind of hard to apply because treatment is sort once you are already an addict)

Question 21

2 methods that could be used to treat drug addicts (in animal models)

Answer 21

• interferring with reconsolidation

- enhance extiction

Question 22

If you inhibit the development of synaptic plasticity in brain areas related to addiction, do you prevent addiction?

Answer 22

yes probs

Question 23

Extiction is thought to be…

Answer 23

the process of overlaying a novel INHIBITORY memory on top of the original memory

Question 24

If the inhibitory memory is stronger than ……………. is reduced

So the approach to treating drug addiction is……. with a …..

Answer 24

reinstatement

extinction training with a cognitive enhancer

Question 25

If the inhibitory memory is stronger than ……………. is reduced

So the approach to treating drug addiction is……. with a …..

Answer 25

reinstatement

extinction training with a cognitive enhancer

Question 26

Enhancing Extinction to decrease relapse rates

Answer 26

so they press the lever but don’t get any drug so they start to learn a new rule (but the original memory is still there as you can reinstate the behaviour)

Question 27

e.g. of a cognitive enhancer

Answer 27

we don’t really have one. Maybe in the furutre

Question 28

What is consolidation

Answer 28

the first time a memory appears in the brain - then it gets reactivated (you experience it again)

Question 29

the more you reactivate the memory the more reconsolidation you get and the ….. the memory trace

Answer 29

stronger

Question 30

if you reactivate a memory and inhbit synaptic plasticity what happens?

Answer 30

you would think it stays where it is but

it actually gets weaker (it becomes labile)

Question 31

Where as interferring with extinction overlaying a new memory when you interfer with reconsolidation what happens?

Answer 31

you are removing the memory completely

Question 32

Where as interfering with extinction overlaying a new memory

when you interfere with re consolidation what happens?

Answer 32

you are removing the memory completely

Question 33

How do we interfere with reconsolidation

Answer 33

re exposure training.
(reactivate the memory also
using an amnesic agent)

Question 34

How do we interfere with reconsolidation

Answer 34

re exposure training.
(reactivate the memory also
using an amnesic agent)

Question 35

what is the purpose of the amnestic agent

Answer 35

inhibits synaptic plasticity

Question 36

Does the rexeposure training approach work in animal models

ref

Answer 36

yes probably because the queues they experience are very symplistic

so reconsolidation with cyclohexamide rerases the memory

Milekic MH et al (2006)

Question 37

what is cyclohexamide?

Answer 37

protein synthesis inhbitor (one way of inhibiting synaptic plasticity)

Question 38

If you inhibit the development of synaptic plasticity in brain areas related to addiction, do you prevent addiction?

How can this be used to treat people who are already addicts?

Answer 38

probably

interfering with reconsolidation

Question 39

In what localised areas do you need the drug to access on reactivation?

Answer 39

VTA is important for inhibition during the LEARNING
but the memory is already there in now so higher brain regions become involved

amygdala
hip
NAcc
prefrontal cortex

(this is backed up by mri scans of addicts, higher regions light that don’t light in non-addicts)

Question 40

In what localised areas do you need the drug to access on reactivation?

Answer 40

VTA is important for inhibition during the LEARNING
but the memory is already there in now so higher brain regions become involved

amygdala
hip
NAcc
prefrontal cortex

(this is backed up by mri scans of addicts, higher regions light that don’t light in non-addicts)

Question 41

Fear related memories are basic and only involve the …….

and unlike any other memory it requires activation of…

Answer 41

amygdala

activation of beta adrenergic receptors

Question 42

how can we interfere with fear based memories

ref?

Answer 42

Rat is fear condition with electric shot linked with a light/sound queue. Rat freezes on presentation of the stimulus.

In a reactivation session compared saline and propanolol. They freeze less with propanolol and after a month the memory is gone

debiec & ledoux

Question 43

application of propanolol fear conditioned memory in humans

Answer 43

PTSD

using talking therapy to trigger panic attack. Given propanolol after panic attack.

They had less evodence of panic attack when they reactovated the memory a week later (HR and sweating)

Question 44

So the missing pharmacological agent is …

Answer 44

the addiction version of propanolol. But its such a complex process its hard to find addiction specific synaptic plasticity.

Question 45

So the missing pharmacological agent is …

Answer 45

the addiction version of propanolol. But its such a complex process its hard to find addiction specific synaptic plasticity.

Question 46

So the missing pharmacological agent is …

Answer 46

the addiction version of propanolol. But its such a complex process its hard to find addiction specific synaptic plasticity.

Question 47

Look at the final three slides of the lecture

Answer 47

….