Dopamine

Question 1

Nigrostriatal pathway

Answer 1

Dopaminergic neuron cells bodies are located in the substantia nigra - the axons then travel along the medial forebrain bundle where the synapse in the corpus striatium, more specifically the dorsal striatum comprising the caudate nucleus and the putamen which is part of the basal ganglia so therefore the nigrostriatal pathway is involved in motor control

Question 2

Tuberohypophyseal pathway

Answer 2

Dopaminergic cells bodies are located in the hypothalamus where the travel to the median eminence of the pituitary gland - in the pituitary the dopamine controls release of prolaction by supressing it - in some cases this can lead to hyperprolactemia which causes unusual menstruation and lacation in men and woman and is a side effect of some drugs that enhance dopamine levels

Question 3

Mesocortical/mesolimbic pathway

Answer 3

Both pathways begin with the dopameinergic neurons located in the ventral tegmentum - the axons then travek through the medial forebrain bundle where the mesocortical neurons synapse in the cerebral cortex (particullary in the frontal lobes) and the mesolimbic neurons synapse in the nucleus accumbens which is part of the limbic system, where it is thought to be involved in cognitive function and part of the reward pathway. Both of these pathways are hyperactive in schizophrenia

Question 4

Dopamine Receptor

Answer 4

D1 family (D1 and D5) are linked to the gs gprotein coupled receptor and the D2 family (d2 d3 and d4) are linked to the gi protein coupled receptor

Question 5

Risk factors of parkinsons

Answer 5

Age is the biggest risk but there has been also a genetic link found in some autosomal dominant and recessive mutations of genes such as Parkin and LRRK2

Question 6

Symptoms of parkinsons

Answer 6

Rigidity
Slowness of movement (bradykinesia)
Resting tremor
Non-motor symptoms such as deementia and depression

Question 7

Cause of parkinsons

Answer 7

Loss of dopaminergic neurons in the nigrostriatal pathway
Symptoms become clear after about 50% is lost
Lewy bodies in the neurons that are left intact are a hallmark of cancer

Question 8

Levodopa

Answer 8

Can be taken up by dopaminergic neruons where it replaces the lost dopamine in the nigrostrital pathway and reduces rigidity and bradykinesia but comes with side effects such as nausea, vomitting and postural hypotension - these can be helped by taking them with either carbidopa, which inhibit peripheral dopa dexcarboxylase and prevents levadopa being converted to dopamine in the periphery and reduces side effect, or with a COMT inhibiotr which inhibts peropheral comt ttod do the same thing (e.g. Entacapone)

Question 9

Selegiline

Answer 9

A selective MOAb inhibitor - MOA breaksdown dopamine so by inhibiting this is prolongs dopamines action

Question 10

Amantadine

Answer 10

A indirect DA agonsit which increases dopamine release from nerve endings and is also thought to be involved in slowing the reuptake of dopamine from the synaptic cleft

Question 11

Benztropine

Answer 11

A muscarnic antagonist - when the dopamine system is out of sync this correlates to changes in the cholinergic system so using a muscarnic antagonist can help bring back balance and reduce some symptoms, however it does lead to the usual symptoms seen with musacarnic blockers e.g. dry mouth, glaucoma, constipation etc

Question 12

What are the positive symptoms of schizophrenia?

Answer 12

Hallucinations and dellusions - these respond well to antipsychotics

Question 13

What are the negative symptoms of schizophrenia

Answer 13

Scoail withdrawl, flattened emotional response - these do not respond well to anti psychotics

Question 14

What is the evidence that dopamine is involved in the pathophysiology of schizophrenia?

Answer 14

1. All anti-psychotics are DA antagonists
2. Chronic amphetamine leads to psychosis - amphetamines get in via the uptake 1 where the usually displace NA which gives them their properties hwoeber due to the similar structure of DA to NA it can also displace DA leading to increased DA in the synaptic cleft
3. Chronic levodopa leads to psychosis
4. Left amygdala concentration of DA is increased in schizphrenics
5. There has been shown to be an increase in the number of dopamine receptors in the brains of schizophrenics (contradictory)

Question 15

What is the evidence that 5HT is involved in the pathophysiology of schizophrenia?

Answer 15

1. LSD is a 5HT analogue and causes hallucinations
2. Dimethyltryptamine is a metabolite of 5ht that causes hallucinations and delusions and is also found in high concentrations in the urine of schizophrenics

Question 16

Ziprasidone

Answer 16

A 5ht2a and d2 agonist that leads to psychosis and is part of the proof that both 5ht and dopamine as involved in the pathophysiology of shizphrenia

Question 17

Typical antipsychotics

Answer 17

The classical ones
based on the structure of phenothiazine - the first to be used was promethanzine which was used to relax patients before surgery - this lead to the development of chlopromazine which is a sedative used in schizophrenia. It is a d2 antagonist in the mesolimbic/mesocortical pathway but is not very specific and this leads to serious extrapyramidal side effects due to blocks dopamine receptors in the nigrostrial pathway. EPSs can be actue dystonias where muscle spasms occur ut get better after treatment is stopped or more seriously tardive dystonias which get worse even after treamtnet stops and of which there is no cure. The typical antipsychotics also tend to block h1 receptors leading to weight gain (patient compliace a probem), muscarnic receptor block (dry mouth, constipation) as well as blocking a1 receptors leading to postural hypotension.

Question 18

Clozapine

Answer 18

An atypical antipsychotic that is more speicific for the ventral tegmentum dopamine receptors so effects mostly the mesolimbic/mesocortical pathways but does still have some EPS effets - also blocks 5ht which leads to weight gain and can cause patient incompliance which is a problem

Question 19

Apriprazole

Answer 19

The future of antipsychotics - this is a partial agonist for d2 receptors so rather than blocking their activity it regulates it and has a low chance of EPS occuring