Flashcards in Dopamine Deck (23):
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).
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?
Howes & Kapur 2009
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).
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.
Increased DA metabolites in cannabis-associated psychosis.
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?
Healthy participants: typical APS that block D2Rs increase DA synthesis in striatal neurons by blocking presynaptic autoreceptors.
Sz patients who have been on APS for many years show increased striatal DA synthesis (due to blockade of presynaptic autoreceptors).
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?
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.
Rats with VP lesions no longer self-administer cocaine/heroin.
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.
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.
In lab, stimulation of D1Rs only is sufficient to cause reward.
Reward signal stronger when both D1Rs and D2Rs activated.
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.
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".
Rats that overexpress D2Rs in striatum showed changes in VTA firing pattern, so affected mesolimbic reward pathway.
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?
APs reduce motivational drive even towards previously conditioned rewarding stimuli.
Explained by aberrant salience model and dampening down action of APs?
Medicated Sz patients = lower VTA fMRI activation in response to positive emotional pictures.
Optogenetics: monkeys expressed channelrhodopsin in VP.
Consistently chose drink which was associated with VP stimulation i.e. reward.