Dopamine

Question 1

Dopamine synthesis

Answer 1

Tyrosine converted to L-DOPA by tyrosine hydroxylase.
Then L-DOPA converted to dopamine by DOPA decarboxylase.
Packaged into vesicles by VMAT2 (inhibited by reserpine).

Question 2

Carlsson 1960s

Answer 2

Dopamine hypothesis I.
Chlorpromazine and other typical APS relieve positive Sz symptoms by blocking D2Rs.
So hypothesised there must be increased DA at synaptic terminals.
Also: anti-Parkinsonian drugs can induce psychosis.
But atypical APS e.g. clozapine? Control -ve symptoms better. And PCP can induce psychosis (NMDAR antagonist).

APS take weeks to work.
So D2R antagonists not working on primary mechanism?

Question 3

Howes & Kapur 2009

Answer 3

Dopamine hypothesis III: many changes in neurotransmitter/neural systems along with environmental, genetic factors etc converge to produce elevated presynaptic DA in striatal neurons = final common pathway.

Elevated presynaptic striatal DA consistently found by imaging studies using radiolabelled L-DOPA and PET scans etc; amount of DA directly correlated to severity of psychotic symptoms.

Also hypofunction of DA in PFC.

Argued EPSD is marker of psychosis, not specifically Sz (can be seen in other psychotic disorders too e.g. bipolar).

Question 4

Howes 2008

Answer 4

Studied patients w/ prodromal symptoms but not full blown Sz.
Already had elevated presynaptic striatal DA, and this was correlated w/ symptom severity.

Consistent with role of DA in pathogenesis of Sz.

Also found level of DA in associative striatum negatively correlated with verbal fluency, which is carried out by PFC.
Suggests direct link between striatal DA dysfunction and dysfunction in PFC and executive functions so could explain neurocognitive deficits, e.g. poor working memory.

Question 5

Bowers 2007

Answer 5

Increased DA metabolites in cannabis-associated psychosis.

Question 6

Kegeles 2007

Answer 6

Ketamine (NMDA antagonist) given to healthy subjects. Raised amphetamine-induced striatal DA levels to levels seen in Sz.
So supports hypothesis that may factors can contibute to elevated PSD and potentially cause psychosis and Sz. May explain why drug use in Sz patients can make symptoms a lot worse.

PCP also blocks NMDARs and can induce psychosis. Due to indirect effects on DA system?

Question 7

Vernaleken 2006

Answer 7

Healthy participants: typical APS that block D2Rs increase DA synthesis in striatal neurons by blocking presynaptic autoreceptors.

Question 8

McGowan 2004

Answer 8

Sz patients who have been on APS for many years show increased striatal DA synthesis (due to blockade of presynaptic autoreceptors).

Question 9

Autopsy studies

Answer 9

Reduced size of NAc (major subcortical DA area) and reduced blood flow from basal ganglia to frontal lobes.
Supports theory of elevated subcortical DA but hypofunction in PFC.
Reduced prefrontal DA could mean DA is less able to modulate NMDAR Glu transmission so poorer cognitive ability/learning/working memory etc?

Question 10

Mesolimbic system

Answer 10

Dopaminergic VTA neurons synapse on NAc which contains D1Rs and D2Rs and ends GABAergic projections to VP. VP is major output of reward pathway.

Lesion VP in rats = reduced motivational drive for rewarding behaviours e.g. eating, drugs.

Monkey optogenetic study.

Question 11

Hubner 1990

Answer 11

Rats with VP lesions no longer self-administer cocaine/heroin.

Question 12

VP

Answer 12

VP necessary for normal reward and motivation, and stimulation is sufficient to cause reward.
Activation patterns specifically encode signals to rewarding stimuli via phasic bursts of activation.

Question 13

Volkow 2015

Answer 13

D2Rs in NAc = tonic firing (indirect pathway). Have higher affinity for DA than D1Rs.
If DA increases enough then D1Rs start becoming activated too = phasic firing (direct pathway).
D1Rs encode reward prediction signal.

Explains why drugs of abuse have more pleasurable effects depending on route of administration e.g. IV raises DA levels more quickly.

Results in associative learning and motivational drive to seek out rewarding behaviour.

Question 14

Caine 2007

Answer 14

In lab, stimulation of D1Rs only is sufficient to cause reward.

Question 15

Steinberg 2014

Answer 15

Reward signal stronger when both D1Rs and D2Rs activated.

Question 16

Kapur 2003

Answer 16

Aberrant salience hypothesis.

Increased/dysregulated DA release causes dopaminergic reward pathways to assign salience to irrelevant stimuli; exaggerrated salience placed on certain percepts/ideas. Heightened awareness etc.

Delusions are top-down cognitive explanations that eventually form as way to make sense of situation (explains cultural differences) = “psychotic insight”.

Hallucinations occur as aberrant salience is placed upon internal representations and experiences, e.g. inner voice.

APs work by “dampening salience”. Could explain why they normally work better for +ve symptoms?

Could also explain why APs don’t work immediately; not simply faulty DA signalling itself causing symptoms, instead it is facilitating the formation of beliefs and delusions etc to form. Explains why APs don’t get rid of beliefs, just become less of an issue, and why same delusions often return if meds stopped (salience is attributed to existing beliefs again). Drugs just make it less likely new aberrant saliences will form, while old ones get less important. Emphasises role for things like cognitive behavioural therapy too.

Question 17

Roiser 2009

Answer 17

Salience Attribution Test.

In line with Kapur’s hypothesis, Sz w/ +ve symptoms showed sig more aberrant salience. More “false positives”.

Medicated Sz (no +ve symptoms) showed reduced adaptive salience compared to controls (dampening down of drugs).

Controls w/ schizotypal traits e.g. anhedonia = also reduced adaptive salience i.e. more “false negatives”.

Question 18

Krabbe 2015

Answer 18

Rats that overexpress D2Rs in striatum showed changes in VTA firing pattern, so affected mesolimbic reward pathway.

Question 19

Knutson 2004

Answer 19

fMRI using healthy subjects, monetary gains vs loss task.

Amphetamines reduced VTA response to gains but increased VTA activity for losses.

Dampening down of signal:noise ratio in DA reward system, so aberrant salience model could explain both +ve and -ve symptoms of Sz?

Question 20

Lopez 2001

Answer 20

APs reduce motivational drive even towards previously conditioned rewarding stimuli.

Explained by aberrant salience model and dampening down action of APs?

Question 21

Taylor 2005

Answer 21

Medicated Sz patients = lower VTA fMRI activation in response to positive emotional pictures.

Question 22

Stauffer 2016

Answer 22

Optogenetics: monkeys expressed channelrhodopsin in VP.

Consistently chose drink which was associated with VP stimulation i.e. reward.

Question 23

Kellendonk 2006

Answer 23

Sz linked to hypofunction of DA in PFC which can lead to neurocognitive deficits e.g. poor working memory and attention.

Due to reduced DA modulation of NMDARs causing altered prefrontal connectivity?