Neurobiology and neurochemistry or reward based behaviours

Question 1

Addiction

Answer 1

Persistent disorder of brain function where compulsive drug use occurs despite serious negative consequences in afflicted individual
- Due to changes in synaptic plasticity

Question 2

Withdrawal symptoms

Answer 2

Negative physiological and emotional features that occurs when a drug is not taken.

Usually opposite to positive experience induced by the drug

Question 3

Tolerance

Answer 3

Diminished response to the effects of a given amount of drug
- Due to repeated exposure to the drug

Increasing larger dosage is required to have the same effect

Question 4

Regions in the brain for the natural reward system/ addicition

Answer 4

Mesocorticolimbic system

Prefrontal cortex

Amygdala

Hippocampus

Question 5

Dopamine error / learning signal

Answer 5

When given a reward with no stimulus
- There is a spike in activity after the reward

When given a stimulus prior to the reward

• Spike in activity before reward
• Anticipation of the reward is more pleasurable than receiving the reward

When reward does not come

• Anticipation still spikes
• Fall in dopaminergic effect

Question 6

Predicted vs unpredicted stimulus and learning

Answer 6

Unpredicted reward = increased activity in nucleus accumbens
- Tells the brain they should be something being learned

Predictable = response in temporal lobe
- Indicates learning has taken place

Question 7

Functions of the Reinforcement System

Answer 7

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 8

Natural reinforcers for reward

Answer 8

Food
Sex

Causes extracellular dopamine release in nucleus accumbens

Question 9

Psychostimulants

- Effects on dopaminergic system

Answer 9

Directly affects dopaminergic neurones in the nucleus accumbens

Question 10

Opiates

- Effects on dopaminergic system

Answer 10

Indirectly – inhibit GABAergic interneurons in VTA

- Disinhibition of VTA DA neurons

Question 11

Alcohol

- Effects on dopaminergic system

Answer 11

Disinhibition of dopamine neurones

Question 12

Nicotine

- Action

Answer 12

Increases Nacc DA directly and indirectly

Stimulates nicotinic cholinergic receptors on mesocortiolimbic DA neurons

Question 13

Dependance

Answer 13

Homeostatic response to repeated drug administration

Unmasked by withdrawal

Question 14

Sensitisation

Answer 14

Repeated administrating of drug = escalating effects

Question 15

Cocaine and amphetamine

• Mechanism
• Role in reinforcement

Answer 15

Inhibits dopamine, serotonin and noradrenaline reuptake transporters

• Cocaine inhibits
• Amphetamine reverses transporters

= Increased synaptic DA

Reinforcement
- Action on dopamine transporter on plasma membrane

Question 16

Cocaine and amphetamine

- Effects

Answer 16

Psychosis

Long term

• Decreases dopamine transporters and terminals
• Increased cellular and molecular changes that promote dysregulation

Hypofrontality [decreased blood flow to prefrontal cortex]

Question 17

Increased excitatory strength and drug abuse

Answer 17

Drug abuse shows significant increase in AMPA/NMDA ratio

= Increased basal excitatory synaptic strength

Question 18

Dopamine receptors in addiction

Answer 18

Fewer D2 receptors

- Reduces sensitivity to natural rewards that develops with addicition

Question 19

Molecular activity of emotional dependence

Answer 19

Compensatory changes in the VTA or Nucleus accumbens = lower DA transmission

At first;
- Increased D1 receptor activity in NAcc sets off Gs protein signalling

PKA and cAMP release =

VTA

• dynorphin synthesis and release is inhibited
• Acts on K opiod receptor

Nucleus accumbens
- Less DA release

Question 20

Associative learning and addiction

Answer 20

Coincident firing in sensory and mesocorticolimbic pathways
= LTP induction = strengthened synaptic connections

Glutaminergic synapses form on reciprocal connections in:
- NAcc
- VTA
- Cortex
- Hippocampus
- Amygdala
= Potential sites for LTP

Information present at the time of drug induced DA release —–> associated with drug taking

Question 21

Dopamine and LTP

Answer 21

DA acts on D1 receptor [Gs protein]
- Increase in PKA = gulatamatergic transmssion = LTP

Late phase LTP
- CREB protein mediation and protein synthesis

Synaptic remodelling
- Increased spines and dendrite branches
- long term molecular and 
cellular changes remain
months after abstinence
- Memories in these 
pathways may trigger 
relapse years later

Question 22

Opiates

• Action
• Reward and reinforcement

Answer 22

Acts on endogenous opioid receptors (Gi coupled)

Morphine mainly acts on gamma receptors

Reward and reinforcement
- Disinhibition of DA neurons in VTA

• Action at opiate receptors in the NAcc - independent of DA release (μ or δ)

Question 23

Alcohol

- Mechanisms

Answer 23

1. GABA-alpha agonist
2. NMDA antagonist
   - In the VTA cortical inputs = disinhibits VTA DA neurones
   - Increases Dopamine release in the nucleus accumbens

Rewarding effects blocked by DA receptor antagonists in NAcc

Question 24

Naltrexone and alcohol

Answer 24

Opiate antagonist
- Reduces alcohol self administration in animals

• Used to reduce alcohol consumption, relapse and craving

Question 25

Nicotine | - Mechanism

Answer 25

Acts on nicotinic Ach receptors Nicotine = release of dopamine in nucleus accumbens due to: - Activation of receptors on cell body in the VTA - Facilitated DA release by pre-synaptic receptors in NAcc

Question 26

Opiates and nicotine

Answer 26

Opiates block nicotine induced behaviours and self administration - I.e Naltrexone used to add smoking cessation

Question 27

Physical dependancy on opiates

Answer 27

Locus coeruleus - Contains opiate receptors - Nucleus involved in attention, arousal and vigilance [NADR] Chronic activation of opiate receptors = homeostatic compensation = tolerance and physical dependance

Question 28

Morphine and locus coeruleus

Answer 28

Acute morphine = inhibits LC neurones Chronic morphine = LC neurones return to firing state Withdrawal = Dramatic increase in LC neurones firing - Over activation of ANS

Question 29

Clonidine

Answer 29

Alpha-2 agonist that blocks the over activation of ANS seen in physical withdrawal of opiates

Question 30

Physical dependance to alcohol

Answer 30

Acute effects - GABA-alpha agonist - NMDA antagonist = Cell firing inhibited Chronic - Downregulation of GABA-alpha - Upregulation of NMDA - Firing rates normal in presence of alcohol Withdrawal - In alcohol absence= excitation - Physical symptoms

Question 31

Reward pathway in the brain

Answer 31

Release of dopamine in mesocorticolimbic system. DA released from the VTA to multiple areas when a rewarding stimulus is experienced: - Prefrontal cortex - Nucleus Accumbens - VTA - Amygdala - Hippocampus Release of DA stimulates the desire for the stimulus again

Question 32

Mechanism of emotional dependance

Answer 32

Due to compensatory control to decrease Dopamine release in the VTA and NAcc 1. Drugs act on D1 receptors [Gs] in NAcc - Triggers downstream events [cAMP, PKA] 2. Downstream events trigger release of Dynorphin from NAcc to VTA - Dynorphin acts on Kappa receptors on VTA DA neurones. 3. Activation of K receptors reduces VTA DA neuronal firing= less release of DA into NAcc As a result--> Less DA is released in the event of the drug not being there - Naturally rewarding stimuli cannot produce enough DA