Neurobiology and neurochemistry of reward and addictive behaviours

Question 1

What is addiction/substance dependance?

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

What are 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

What is tolerance?

Answer 3

Diminished response to the effects of a given amount of drug following repeated exposures to the drug.
This implies that increasingly larger dosed of the drug are required to induce the same behavioural effect.

Question 4

Where do drugs act in the brain?

Answer 4

Mesolimbic system
Mesocortical system

Mesocorticolimbic system
Addiction also involves PFC (impulsiveness, decision making, self monitoring) , Amygdala and hippocampus

Question 5

What does anticipation of the reward do?

Answer 5

Recruits nucleus accumbens

Question 6

How does dopamine aid learning?

Answer 6

Instrumental conditioning
Error signal
Anticipation of the reward is more enjoyable than the reward itself

Question 7

Which part of the brain is engaged when unpredictable-predictable?

Answer 7

Nucleus accumbens

Question 8

Which part of the brain is engaged when predictable-unpredictable?

Answer 8

Temporal lobe

Question 9

Describe the functions of reinforcement system

Answer 9

Detect reinforcing stimulus
-Recognise something good has just happened
-Time to learn
Strengthen neural connections
-Between neurons that detect the stimulus and the neurons that produce the instrumental response
-Long term potentiation

Question 10

What is the mesocorticolimbic dopamine system used for?

Answer 10

Pathway for reward and reinforcement
Natural reinforcers - food, drink, sex etc - extracellular DA released in NAcc

Behaviours activating system are reinforced
More likely to be repeated
Addictive drugs causes more powerful and reliable activation than natural
they hijack the system
Blockade of DA in this region
attenuates most measurable reinforcing and rewarding effects of addictive drugs

Question 11

Describe the action of psychostimulants on the DA system

Answer 11

Direct action on Daergic neurons in NAcc

Question 12

Describe the action of opiates on the DA system

Answer 12

Indirectly – inhibit GABAergic interneurons in VTA = disinhibition of VTA DA neurons

Question 13

Describe the action of alcohol on the DA system

Answer 13

Disinhibition of VTA DA neurons

Question 14

Describe the action of nicotine on the DA system

Answer 14

Increases Nacc DA directly and indirectly, stimulates nicotinic cholinergic receptors on mesocortiolimbic DA neurons

Question 15

Name some DA antagonists

Answer 15

Cocaine and amphetamine

Question 16

How do cocaine and amphetamine work?

Answer 16

Potentiate monoaminergic transmission by inhibition of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) reuptake transporters
Cocaine blocks and inhibits transporter to prolong pool of extracellular DA
Amphetamine reverses transporter to increase extracellular DA levels

Action at dopamine transporter (DAT)
most directly related to reinforcing effects

Feelings of euphoria etc. through activation of this pathway or actions at transporters located elsewhere

Increases extracellular DA in NAcc

Question 17

List some effects of cocaine and amphetamine

Answer 17

Psychotic behaviour

(Evidence DA involvement in the positive symptoms of schizophrenia)

Adverse long-term effects on the brain, e.g. DA transporters / terminals

Cellular and molecular changes that promote dysregulation, e.g. increased
activity of VTA tyrosine hydroxylase, CREB, GluR1 (AMPA)

Hypofrontality

Question 18

Describe D2 receptors in addiction

Answer 18

Decreased dopamine (D2) receptors in cocaine addict

The dopamine system central to conditioning and motivation

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

Question 19

Describe associative learning in terms of drug addiction

Answer 19

“cells that fire together wire together”

Coincident firing between sensory pathways and the mesocorticolimbic pathway will induce LTP and strengthen synaptic connections

Reminder – LTP = Long Term Potentiation
A persistent strengthening of synapses based on recent patterns of activity
Used to explain memory

Potential sites for LTP
Glutamatergic synapses on reciprocal connections between
NAcc, VTA, cortex, hippocampus and amygdala

Thus sensory information, people, places, emotions etc. present at the time when drug induced DA release occurs will become associated with taking the drug

Question 20

How does dopamine enhance long term potentiation?

Answer 20

Dopamine at D1 receptor (Gs coupled)

adenylyl cyclase - cAMP - PKA

• modifies glutamatergic transmission allowing LTP
  CREB mediated gene transcription and new protein synthesis (steps in late phase LTP)
• 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 21

Describe the action of opiates

Answer 21

Action:
endogenous opioid receptors (Gi coupled)
Inhibitory - decrease adenylyl cyclase activity
- lead to open K+ channels, close Ca2+ channels

Different receptor subtypes
on different cells in different brain regions (m, k, d)

Most of morphine’s analgesic and rewarding properties are through actions at m (mu) receptors

Question 22

Describe reward and reinforcement of opiates

Answer 22

a) Disinhibition of DA neurons in VTA (DA neurons fire tonically but are inhibited by GABA interneurons - m receptor activation on GABA neurons inhibits them from firing - relieving inhibition on DA neurons)
b) Action at opiate receptors in the NAcc - independent of DA release (m or d)

Question 23

Describe alcohol in terms of addiction

Answer 23

GABAA agonist (inhibitory)

NMDA antagonist (blocks excitation)

• Large doses inhibit functioning of most
  voltage gated channels

EtOH leads to increased DA release in NAcc
NMDA antagonism of cortical inputs to VTA disinhibits VTA DA neurons - resulting in increased DA release in NAcc.

Ethanol rewarding effects blocked by DA receptor antagonists in NAcc

Opiate system involvement
Naltrexone (an opiate antagonist)
- reduces EtOH self administration in animals
- used as a treatment to reduce EtOH consumption, relapse and craving in alcoholics

Question 24

Describe nicotine addiction

Answer 24

Acts at nicotinic acetylcholine receptors (nAChRs)

-Ligand gated ion channels located pre or post-synaptically
			(present throughout brain, excitatory or modulatory)
-Presynaptic receptors - influx of Ca2+ - transmitter release

Nicotine treatment increases DA release in the NAcc

Release of DA likely due to:

a) activation of receptors on cell body in the VTA (increasing cell firing)
b) facilitation of DA release by pre-synaptic receptors in NAcc

Opiate system involvement
Both opiate and DA antagonists can block nicotine induced behaviours and self administration
(Naltrexone as a drug to aid smoking cessation and associated weight gain, encouraging preliminary results)