Dopamine, Schizophrenia and Reward

Question 1

Familial histories

Answer 1

good for single gene diseases

Question 2

Genome wide association studies (GWAS)

Answer 2

uses larger populations but isn’t hypothesis driven

Question 3

Copy number variations (CNVs)

Answer 3

Examines genomes for deletions or duplications of regions (few kilo-bases to mega-bases)

Question 4

Familiar histories in schizophrenia

Answer 4

Disrupted in schizophrenia 1 (DISC1) translocation between chromosomes 1 and 11, which has also been implicated in depression, bipolar, autism and other mental disorders ( not found in GWAS)

Question 5

How does a GWAS work?

Answer 5

If one type of the variant (one allele) is more frequent in people with the disease, the SNP is said to be “associated” with the disease (Initially exons only because of cost, more disease than seeing links to regulation, whole genomes too)

Question 6

Copy number variations and schizophrenia

Answer 6

Deletions, translocations and duplications of regions are sporadic (as 2/3 schizophrenia cases)

Question 7

which genes have familial studies indicated in schizophrenia?

Answer 7

DISC1 (synapse function) NRG1 (synapses) RELN (synapses) COMT DRD2 PDE4B PRODH (Glu synthesis) AKT-1 (IC signalling)

Question 8

which genes have GWAS indicated in schizophrenia?

Answer 8

NRG1 RELN ZNF804A HIST genes Notch4 VMAT2 CACNA1C

Question 9

which genes have CNV studies indicated in schizophrenia

Answer 9

GLUR7 ERB4 (TKR for NRG1) NRXN1 SLC1A3

Question 10

Of the genes implicated in schizophrenia which are developmental?

Answer 10

NRG1 RELN Notch4

Question 11

which features schizophrenia does not yet have a genetic link established?

Answer 11

Changes in brain region size

Question 12

Schizophrenia associated genes (and the pathways, in relation to drug treatments)

Answer 12

Question 13

DISC1

Answer 13

Expressed in all brain regions at birth but high in: olfactory bulb, cortex, hippocampus, hypothalamus, cerebellum In adult: highest in hippocampus (present in neurons AND glia) Scaffold Protein linked to neurodevelopment and synaptic function

Question 14

DISC1 interactions

Answer 14

Diagram

Question 15

DISC1 function in the synapse

Answer 15

Spine number Spine size AMPA receptor expression Frequency of spontaneous release

Question 16

DISC1 in the synapse

Answer 16

Diagram

Question 17

In relation to reward, what does dopamine signal?

Answer 17

Dopamine is now thought of as a reward prediction signal

Question 18

which natural activities are a pleasure pathways involved?

Answer 18

Food, water, sexual activity (expand)

Question 19

Reward inducing drugs

Answer 19

Ethanol; opiates (reduce inhibition to dopamine neurons); cocaine (monoamine reuptake inhibitor); amphetamine (stimulates monoamine release); nicotine and cannabinoids (increase dopamine release)

Question 20

Mesolimbic system

Answer 20

emotion, memory, thoughts and perception conserved throughout the animal kingdom

Question 21

Reward pathways

Answer 21

Amygdala and frontal association cortex feed into nucleus accumbens

Question 22

What happens when something is as expected?

Answer 22

expected = tonic (D2R)

Question 23

What happens when something is better-than-expected?

Answer 23

better than expected = phasic (D1R)

Question 24

What happens when something is worse than expected?

Answer 24

pause in activity

Question 25

What might explain why roots of drug administration that achieve fast/high DA concentrations are more rewarding?

Answer 25

high DA release cause D2R → D1R stimulation = reward

Question 26

Which methods of drug administration almost addictive?

Answer 26

Fastest methods for high onset of the most addictive

Question 27

Ventral palladium and reward

Answer 27

Morgane (1961): lesions of VP lead to aphagia (reduced eating) and adipsia( reduced drinking) in rats 1990’s: lesions of VP reduce ‘liking’ for sucrose -> effect can be mimicked by infusion of GABA agonists (eg muscimol) into VP Humans with VP partial lesions report decreased ‘cravings’ and ‘pleasure’ from: food, recreational drugs

Question 28

Components of reward

Answer 28

Liking, wanting and learning

Question 29

Liking

Answer 29

Hedonic impact

Question 30

Wanting

Answer 30

Incentive salience

Question 31

Learning

Answer 31

Predictive associations and cognitions

Question 32

Experiment: electrodes placed in VP under control of a lever push by rat

Answer 32

Result: rat presses the lever more times when the stimulus is applied than. when it is not

Question 33

Experiment: Optogenetic activation of DA-containing neurons

Answer 33

Result: monkey prefers choice associated with optogenetic activation

Question 34

Pair bonding

Answer 34

Activity in the VP increases during sexual arousal (higher in males!): → sex / pornography can be addictive

Question 35

prairie voles and pair bonding

Answer 35

Bonds for life Males have high levels of vasopressin 1 receptors in VP

Question 36

A link between schizophrenia and reward?

Answer 36

Increased DA release may lead to aberrant assignment of ‘salience’ to otherwise innocuous stimuli. aka – over-reaction (+ ve symptoms) Heightened dopamine signalling may also elevate ‘noise’ in the reward system which ‘drowns-out’ normal reward. aka – reward is not perceived (-ve symptoms)