Neurobiology and neurochemistry of reward and addictive behaviours

Question 1

Addiction/ substance dependence

Answer 1

A persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual

Both physical and psychological

Question 2

Withdrawal symptoms

Answer 2

Negative physiological and emotional features that occur when the drug is not taken

Different for each drug of abuse, but generally opposite to positive experience induced by the drug

Question 3

Tolerance

Answer 3

Diminished response to the effects of a given amount of drug following repeated exposures to the drug

Implies increasingly larger doses of the drug are required to induce the same behavioural effect

Question 4

Where do drugs act in the brain?

Answer 4

Drugs hijack reward system

• mesolimbic system
• mesocortical system

Also involves

• PFC
• amygdala
• hippocampus

Question 5

Dopamine

- error or learning signal

Answer 5

Primary activating neurotransmitter for the reward pathway

Animal has to change behaviour in order to get reward

Reinforcement system is activated by unexpected reinforcing stimuli, and by presence of reward relative to its prediction

Question 6

Unexpected reward

Answer 6

Activity in the nucleus accumbens

Response that tells our brain there is something we should be learning

Question 7

Pretictable response

Answer 7

Disappears from NAcc ad response is seen in temporal lobes

Indicates learning has taken place

Question 8

Functions of the reinforcement system

Answer 8

Detect reinforcing stimulus

Recognise something good has just happened

Time to learn

Strengthen neural connections

Between neurones that detect the stimulus and neurones that produce instrumental response

Long term potentiation

Question 9

The mesocorticolimbic dopamine system

Answer 9

Drug induced synaptic plasticity in the

• NAcc
• dorsal striatum

Contribute to addiction by consolidating

• drug wanting
• drug seeking
• drug taking

Question 10

Mesocorticolimbic dopamine system

Answer 10

Behaviours activating system are reinforced
- more likely to be repeated

Addictive drugs cause more powerful and reliable activation than natural
- they hijack the system

Blockade of DA in the region
- attenuates most measurable reinforcing and rewarding effects of addictive drugs

Question 11

Action of psychostimulants

Answer 11

Direct action on DAergic neurones in NAcc

Question 12

Action of opitates

Answer 12

Indirectly inhibit GABAergic interneurones in VTA

Disinhibition of VTA DA nruones

Question 13

Action of alcohol

Answer 13

Disinhibition of VTA DA neurone

Question 14

Action of nicotine

Answer 14

Increases NAcc DA directly and indirectly

Stimulates nicotinic cholinergic receptors on mesocorticolimbic DA neurones

Question 15

Cocaine and amphetamine

DA agonists

Answer 15

Potentiate monoaminergic transmission by inhibition of dopamine, serotonin and norepinephrine reuptake transporters

Action at dopamine transporter most directly related to reinforcing effects

Feelings of euphoria

Question 16

Cocaine action

Answer 16

Blocks and inhibits transporter to prolong pool of extracellular DA

Question 17

Amphetamine action

Answer 17

Reverses transporter to increase extracellular DA

Question 18

Effects of cocaine and amphetamine

Answer 18

Psychotic behaviour

Adverse long term effects on the brain
- reduced DA transporters/ terminals

Cellular and molecular changes the promote dysregulation
- increased activity of VTA tyrosine hydroxylase

Hypofrontality

Question 19

Increased excitatory strength

Answer 19

All drugs of abuse - significant increase in AMPA/ NMDA ratio

Increase in basal excitatory synaptic strength

Question 20

Fewer D2 receptors in addiction

Answer 20

Decreased D2 receptors in cocaine addict

Dopamine system central to conditioning and motivation

Changes likely responsible for reduced sensitivity to natural rewards that develops with addiction

Question 21

Emotional dependence

Answer 21

Compensatory changes in VTA/ NAcc to lower A transmission

Increased activity at D1 receptors in NAcc

Adenylyl cyclase- cAMP- PKA - downstream eventes increased DYN synthesis

DYN released in VTA acts as K opioid receptor

Inhibits VTA neurone firing and NAcc DA release

Less DA release in NAcc

Question 22

Associative learning

Answer 22

Potential sites for LTP
- glutamatergic synpases on reciprocal connections between NAcc, VTA, cortex, hippocampus and amygdala

Sensory information, people, places, emotions etc at time of drug taking associated with taking the drug

Question 23

Dopamine enhances long term potentiation

Answer 23

Dopamine at D1 receptors

Adenylyl cyclase- cAMP- PKA

Modifies glutamatergic transmission allowing LTP

CREB mediated gene transcription and new protein synthesis

Synaptic remodelling- increased spines and dendritic branches

Long term molecular and cellular changes remain months after abstinence

Memories in these pathways may trigger relapse years later

Question 24

Opiates action

e.g. morphine and heroin

Answer 24

Endogenous opioid receptors

Inhibitory

• decrease adenylyl cyclase activity
• lead to open K+ channels, close Ca2+ channels

Different receptor subtypes
- on different cells in different brain regions

Question 25

Opiates reward and reinforcement

Answer 25

Disinhibition of DA neurones in VTA

Action at opiate receptors in NAcc- independent of DA release

Question 26

Alcohol

Answer 26

GABA agonist (inhibitory)

NDMA antagonist (blocks excitation)

Large doses inhibit funcitoning of most voltage gate channels

EtOH leads to increased DA release in NAcc

Question 27

Nicotine

Answer 27

Acts at nicotinic acetylcholine receptors

• ligand gated ion channels
• presynaptic receptors- influx of Ca2+- transmitter release

Question 28

Nicotine treatment increases DA release in NAcc

Answer 28

Activation of receptors on cell body in VTA

Facilitation of DA release by pre-synaptic receptors in NAcc