How do we know this pathway is involved?

Question 1

How do we know this pathway is involved in reward?

Answer 1

Animal studies
Damage to the nucleus accumbens decreases self-administration of heroin
Rat kept coming back and wanted more stimulation, when hoocked with electrodes to stimulated NA, they stimulate themselves so much - willing to get a shock
Mesocorticolimbic pathway needed for drug to have a rewarding effect

Question 2

What do psychomotor stimulants do?

Answer 2

Potentiate monoaminergic transmission by inhibition of domaine, serotonin and norepinephrine transporters

Question 3

What does cocaine and amphetamine do?

Answer 3

Cocaine - blocks and inhibits transporter to prolong pool of extracellular DA
Amphetamine - reverses transpoter to increase extracellular DA levels

Question 4

What is directly related to the reinforcing effects?

Answer 4

The action of dopamine transporter - increasing DA in NA

Question 5

What else is affected other than dopamine?

Answer 5

Serotonin and norepineephine - subjective effects are mediated by actions of rugs at other sites

Question 6

How do we know other sites are effected by dopamine?

Answer 6

In animal transporters:
DAT transporter knockouts still want cocaine and drugs - without the dopamine
Only triple knockout (DAT, SERT and NET) show no drug action - need all of this to get rid of rewards

Question 7

What do opiates do?

Answer 7

Morphine and heroin

act an endogenous opioid receptors: inhibitory, decrease AC, lead to opening K channels and close Na channels

Question 8

What are endogenous opioid peptides?

Answer 8

Endorphins
Enkephalins
Dynorphins
three families of opioid receptors, with lots of subtypes in brain regions

Question 9

How is morphine rewarding?

Answer 9

Through actions at mu receptors

Question 10

What are the side effects of morphine?

Answer 10

Addictive and suppresses breathing if take too much, so came up with heroin but these are worse

Question 11

Why does our brain have its own opioids?

Answer 11

Because we need them for painfull events - they bind to morphine and heroin

Question 12

What is the difference between heroin and morphine?

Answer 12

Euphoria and intense rush with heroin compared to morphine due to route of administration and entry to brain (seconds vs minutes)

Question 13

How do opioids impact the dopamine system?

Answer 13

The opioids inhibit the GABAinterneurons (which usually inhibits dopamine) so disinhibiting DA neurons in VTA (the neurons fire tonically) so have increase dopamine
Action at opiate receptors in the Na - independent of DA release
DA has an independent action at the NAcc

Question 14

What is the difference between the normal reward system and opiat action?

Answer 14

Normal - glutamate releases to GABA, regulating dopamine in the NA

Opiate action - more DA released because disinhibition of DA neurons in the VTA through inhibition of GABAinterneuron - leads to pleasure and reward

Question 15

What does inhibition of GABAinterneuron mean?

Answer 15

The GABAinterneuron isn’t working - so things aren’t being inhibited

Question 16

What does alcohol do?

Answer 16

GABAa agonist (inhibitory) and NMDA atnagonist (blocks excitation) also affects glycogen, nicotine and serotonin
Large doses inhibit functioning of most voltage gated channels - sedation

Question 17

What are the subjective effects of alcohol?

Answer 17

Low doses of alcohol = mild euphoria and anxiolytic effects, takes anxiety away
Higher doses = poor coordination, amnesia, sedation, coma
Chronic alcoholism = Korsakoff’s Amnesia (thiamine deficiency) - can’t form new memories because ion deficiency

Question 18

Why does alcohol effect memory?

Answer 18

Introduces Korsakoff’s amnesia - not due to alcohol specifically but due to malnutrition, empty calories when drinking, so not eating properly

Question 19

Why does alcohol effect people differently?

Answer 19

Depends on our bodies and how much we have on board

women metabolise it a lot slower, so that is why they have to have less

Question 20

What is alcohols effect on the reward circuit?

Answer 20

Alcohol leads to increase DA - NMDA antagonist of VTA leads to increased DA
suppression of corticol ouput
no activation of GABAinterneuron
DA neurons disinhibited in VTA so able to fire
Rewarding effects blocked by DA receptor antagonists in NA

Question 21

How are alcohols rewarding effects blocked?

Answer 21

By a DA receptor antagonist in the NAcc

Question 22

How does alcohol affect the opiate system?

Answer 22

Naltrexone - opiate antagonist
This reduces alcohol self administration in animals
Used as a treatment to reduce ethanal consumption, relapse and craving

Question 23

What does nicotine do?

Answer 23

Acts at nicotinic acetylcholine receptors - ligand gated ion channels located pre or post synaptically
Pre synaptic receptors - influx of Ca+ - transmitter release

Question 24

What is the difference between nicotine and cocaine/opiats?

Answer 24

Nicotine is powerfully reinforcing in the absence of euphoria

Question 25

What does prolonged activation of nicotine lead to?

Answer 25

Desensitization
first cigarette of day - subjective response (rapid densensitization of receptors)
subsequent cigarettes - less obvious reported effects (overnight - normalisation)

Question 26

What happens when you smoke?

Answer 26

Stimulate the release of acetylcholine and domaine

Question 27

What is nicotine’s effects on the reward circuitry?

Answer 27

Nicotine Treatment increases DA release in the NA
Release of DA due to:
activation of nACh receptors on the cell body in the VTA
facilitation of DA release by presynaptic receptors in the NAc
More presynaptic activity of DA released and more and more postsynaptic activity of DA

Question 28

What is the opiate systems involvement in nicotine?

Answer 28

Both opiate and DA antagonists can block nicotine induced behaviours and selfadministeration - naltrexone - can aid smoking cessation - decrease the reinforcing effects of smoking

Question 29

What are the natural reward system vs when on drugs?

Answer 29

Natural rewards - DA release, behaviours associated with stimuli are reinforced, we repeat these behaviours

Drugs - more DA release - drug taking is reinforced

Question 30

How do we become addicted?

Answer 30

Impaired response inhibition and salience attribution (R-RISA) model - Volkow

Question 31

What is the impaired response inhibition and salience attribution (R-RISA) model - Volkow?

Answer 31

Non addicted brain - drugs are there but not salient, we don’t go into the effort to remember what they are, have the pleasure system on board but got a frontal lobe saying stop - can control self and inhibit tendency
Control - drive (stop) - memory
Addiction brain - stimulus is becoming important because of changes in our brain (new synapses. LTP - remember who we were with, so powerful drive system telling us to go seek the substance and have it again, limbic system telling us to get it, inactive control system so can’t stop the behaviour
No control - drive (go) - memory

Question 32

Who is Volkow?

Answer 32

The main person for addiction

Question 33

In the impaired response inhibition and salience attribution model, what is the difference in an addiction brain?

Answer 33

Weakening of top-down inhibitory control functions and strengthening of bottom up functions

Question 34

Who actually becomes dependent?

Answer 34

Only a small population who use drugs, 15% become addicted

Question 35

What causes addiction?

Answer 35

Volkow - heredity (40-60%) change in receptors, age (adolescence more vulnerable) and environment (access to drug)

Question 36

When does addiction begin?

Answer 36

Begins in adolescence, 50% of addiction cases begin between the ages of 15-18 and very few begin after the age of 20