Addiction lecture 3

Question 1

List the 3 major stimuli for relapse in humans

Answer 1

1) Priming dose of drug (small dose of drug)
2) Drug related cues - has to be learned
3) Stress

Question 2

Psychological dependence (addiction and craving) must have a learned component to it. Memory formation is thought to occur due to _____ _____ (LTP). Therefore inhibiting ____ _____ and hence inhibiting ____ ____ inhibits the conditioned response.

Answer 2

Synaptic plasticity
Synaptic plasticity
Memory formation

Question 3

Dopamine release becomes a predictor of reward. Explain the study by Volkow et al 2011.

Answer 3

This study assessed whether drug conditioned cues increased dopamine in cocaine addicted subjects.

1) Tested active cocaine addicted subjects when watched a neutral video (nature scene) VS when they watched a cocaine cue video (procuring and smoking cocaine)
2) Cocaine cues significantly increased dopamine levels in the dorsal striatum and the magnitude of increase correlated with subjective experience of craving
3) Similar findings were reported by another lab and non addicts did not experience this same increase in dopamine levels when watching the cocaine cue video

Dopamine release was measured using PET scans. There was a decreased signal in addicts as there was more dopamine related so less radioligand binding.

Question 4

The study by Willuhn L et al in 2010 showed what in relation to dopamine release and predicting reward?

Answer 4

• The study looked at phasic signalling in NAcc associated with drug seeking and taking in rats
• The phasic DA signalling consist of multiple phasic events
• The 1st event was the approach of the rat towards to operant lever which controlled the infusion of a euphoric substance which resulted in a release of dopamine
• The second event was an audiovisual cue associated with the drug taking - this resulted in a bigger release of dopamine
• When the lever was pressed, the 3rd event was the beginning of drug infusion which results in a direct pharmacological drug effect in the rats - dopamine release
• The releases of dopamine when approaching the lever and seeing audiovisual cue were due to the predictive effect of getting the euphoric drug soon!

During extinction the rat did not receive the drug when it pressed the lever. Initially the rat still had a dopamine release when it saw the cue and pressed the lever but it did not get the pharmacological effect of the drug after this

• This resulted in the predictive release of dopamine reducing over time as the rat - it was not getting reinforced to carry out the behaviour
• The rat started to learn that pressing the lever would not release the drug

This showed that cues related to taking drugs are motivating and that these are LEARNED responses. Hence environmental stimuli can affect brain wiring!

Question 5

Synaptic plasticity:

- Memory consolidation is thought to occur by…

Answer 5

Synaptic long term potentiation (LTP) or long term depression (LDP)

Question 6

What does synaptic LTP cause?

Answer 6

LTP is induced by a burst of neuronal activation (theta burst) which causes an increase in AMPA receptor recruitment to the membrane due to calcium levels increasing (Roland Jones) therefore the synapse becomes stronger so glutamate release has action at more AMPA receptors resulting in a bigger effect!

Question 7

Synaptic plasticity e.g. due to LTP increasing synaptic strength is responsible for _____ ______.

The hippocampus is responsible for ____ memories
The amygdala is responsible for ____ memories

Are the reward pathways responsible for reward memories? Do they have a role in addiction and relapse?

Answer 7

Encoding memories

Place
Fear

Question 8

Glutamatergic synapses on DA neurones exhibit ___.

Answer 8

LTP

Question 9

____ et al 2001 showed that changes in synaptic strength following cocaine administration occurs. Explain this study.

Answer 9

1) A single dose of cocaine induced increase in AMPAR/NMDAR ratio in VTA dopamine cells compared to saline injected animals
2) This increase in AMPARs was due to AMPAR recruitment to the post synaptic membrane
3) This induces LTP in the VTA
4) This LTP is still observed 5 days after cocaine exposure (increased synaptic strength)

SO this LTP of AMPAR mediated currents occurs at excitatory synapses onto DA cells in VTA.

Question 10

Saal et al 2003 looked at the effects of a variety of drugs of abuse on LTP. It was found that all drugs of abuse that cause an increase in __ in the ___ cause LTP of ____ mediated currents in the VTA. They all caused strengthening of synapses!

Answer 10

DA
NAcc
AMPAR

Question 11

Molecular mechanisms underlying synaptic plasticity:

1) Presynaptic ____ release and depolarisation of post synaptic neurones leads to ___ elevation in postsynaptic cells
2) ____ activates PKA
3) PKA phosphorylates _____ and AMPARs insert into the membrane
4) Activation of protein synthesis also occurs which underlies persistent forms of synaptic plasticity

Answer 11

Glutamate
Ca2+
CAMP
AMPARs

Question 12

_____ et al 2004 looked at how disrupting ____ _____ in the VTA prevents drug conditioning learning.

They tested whether the activation of _____ receptors and PKA was needed for acquisition and expression of _____ conditioned ____ preference.

Rats had an injection of an ____ antagonist or AMPAR antagonist or vehicle into their VTA before each of 3 ____ conditioning sessions

BOTH AMPAR and NMDAR antagonists blocked the development of ____ conditioned ___ response when injected into their VTA but not when outside the VTA.

SO they didn’t learn to associate the environment (cue) with the drug effects when given these agents that disturbed _____ _____.

Answer 12

Harris et al 2004
Synaptic plasticity

Glutamate
Morphine conditioned place preference

NMDAR
Morphine

Morphine conditioned place preference

Synaptic Plasticity

Question 13

PKA inhibitors block morphine ____ when administered into the ___. This indicates that the ___ is an important site for synaptic modifications involved in learning and memory of environmental cues predicting reward. _____ and __ input is also critical in this process.

Thus you need _____ _____ in the ____ for drug related memories to form!

Answer 13

CPP
VTA
VTA
Glutamate and PKA 
Synaptic plasticity 
VTA

Question 14

If you were to try and inhibit the development of _____ _____ in the brain areas related to addiction, then addiction could possibly be prevented.

To treat those who are already addicted you would need to interfere with ______ or enhance _______.

Answer 14

Synaptic plasticity

Reconsolidation or enhance extinction

Question 15

Enhancing extinction is an approach that can be taken to try and reduce relapse rates.

Extinction is not WHAT?

Answer 15

Forgetting about the drug

Question 16

Reinstatement of drug taking can occur due to three things. What are they?

Extinction is thought to be ‘overlaying’ a novel inhibitory memory on top of an _____ memory. If the inhibitory memory is ____ then reinstatement is reduced.

Thus enhancing extinction memory could be an approach to reducing relapse. What is this approach?

Answer 16

Priming dose, cues, stress

Original
Stronger

Conducting extinction therapy training with a cognitive enhancer should allow extinction memory to ‘cover up’ the initial memory

Question 17

Nic Dhonnnchadha and Kantack KM 2011 looked at enhancing extinction to reduce relapse rates:

What happened?

Answer 17

• Looked at cocaine cue extinction and reacquisition of cocaine self administration after treatment with CDPPB - cognitive enhancer
• Extinction therapy was quicker and better with rats who ere given the cognitive enhancer and stopped pressing the lever quicker (extinction) when it was not linked to cocaine
• During reacquisition, the lever was linked to cocaine again. Rats who were extinction trained with the cognitive enhance took longer to reacquire cocaine self administration (longer resistance to the behaviour)

SO an enhanced extinction memory sat on top of the initial memory!

Question 18

Disrupting memory ______ extinguishes memory:

Forming memory from initial training involves _____.
_____ of the memory occurs every time the drug is taken.
______ requires _____ ____ to occur.

Inhibiting this ____ _____ and then reactivating the memory makes the memory grow ______.

Answer 18

Reconsolidation

Consolidation
Reactivation
Re-consolidation requires synaptic plasticity

Synaptic plasticity

Question 19

Synaptic plasticity, dependence and relapse:

Inhibiting ____ _____ during _____ appears to extinguish drug seeking behaviour BUT you would need to be specific so addicts only forget drug seeking behaviour.

Approach: re-exposure training with _____ agent
SO take drug surrounded by ___ with ____ agent, to inhibit synaptic plasticity and should decrease memory over time.

Answer 19

synaptic plasticity
reactivation 
amnestic 
cues 
amnestic

Question 20

Disrupting memory reconsolidation extinguishes memory:

• Memories can be reduced if recalled and then disrupted by inhibiting _____ _____/
• Established morphine ___ disrupted if _____ _____ blocked by inhibitor after representation of conditioning session
• This worked as it inhibited _____ _____ which prevented memory reconsolidating.
• This caused disruption of the morphine ____.

This disruption seemed to be permanent as preference didn’t return after further conditioning.

SO established memories induced by drug of abuse can be permanently disrupted after reactivation of conditioning experience.

Answer 20

Protein synthesis 
CPP (conditioned place preference) 
Protein synthesis 
Synaptic plasticity 
CPP

Question 21

The study by Milekic MH et al 2006 found that morphine ___ was disrupted after a conditioning session took place with protein synthesis blocked in the hippocampus, amygdala, NAcc but NOT in the VTA.

Answer 21

CPP

Question 22

LTP is seen at ______ synapses. The challenge is to find one molecule that inhibits ____ ____ at ALL these synapses but ONLY these synapses.

Answer 22

Glutamatergic

Protein synthesis

Question 23

Important synaptic plasticity events identified by Koob GF and Volkow MD in 2010:

Synaptic plasticity seen after just 1 day of a single injection of ____

Increased excitability of mesolimbic DA system reflected in LTP dependent on changes in glutamate activity

Activation of DA increases excitability of ventral striatum with decreased glutamatergic activity during withdrawal and increased activity during drug ____ and ___ induced drug seeking

Compulsivity occurs and evolves into full addiction and loss of function occurs in frontal cortex systems that control executive function so poor decision making

Finally gain of function in brain stress systems results in incentive silence for drugs over natural reinforcers

SO inhibiting development of synaptic plasticity in brain areas related to memory addiction = probably prevent addiction.
In those who already addicts = need to interfere with _______.

Answer 23

Cocaine
Primed and Cue
Reconsolidation

Question 24

Study by ____ A et al 2008.
Proof of disrupting memory reconsolidating concept has been seen in those with ___.

The brain area associated with fear = ____ which has lots of B adrenergic receptors. So target fear memories using B blockers to block these beta receptors

Patients with PTSD were made to talk about their traumatic event which induced ___ ___ like symptoms e.g. increased HR.Half the patients were given a placebo and the others ______ when they reactivated this memory.
When they returned a week later they had to talk about the event again
Those who were given the _____ before didn’t have a ____ ____ this time (they had reduced HR and skin conductance)
Those with a placebo had a ____ ____.

The beta blocker prevented memory reconsolidating so the synaptic plasticity was prevented and extinction of the memory occurred. This specifically wiped out the fear memory as B receptors are abundant in the amygdala.

Answer 24

Brunet 
PTSD
Amygdala 
Panic attack
Propranolol 
Propranolol

Question 25

List two memory approaches to treat drug addicts:

Answer 25

1) extinction therapy with cognitive enhancer

2) Reconsolidating therapy (cue and drug) with amnestic agent