Antipsychotics and neuroleptics

Question 1

What is the principle neurotransmitter in the sympathetic nervous system?

Answer 1

Noradrenaline

Question 2

Name the 4 amine neurotransmitters in CNS

Answer 2

Noradrenaline, Dopamine, Serotonin (5-hydroxytryptamine), Acetylcholine

Question 3

Where are these amine transmitters used in the brain?

Answer 3

Localised to small populations of neurones in the brain stem and basal forebrain

Question 4

What is the main source of noradrenaline?

Answer 4

Locus coeruleus

Question 5

What increases the activity of Locus Coeruleus?

Answer 5

Behavioural arrousal
Controls wakefulness, alertness and mood

Question 6

How close are NA producing neurones and what does this effect?

Answer 6

Not closely associated therefore NA released can effect many other neurones and cells
Therefore drugs that effect noradrenergic transmission will affect other cells too

Question 7

What type of receptors are noradrenergic receptors?

Answer 7

ALL G-protein coupled receptors

Question 8

Name the receptors for noradrenaline

Answer 8

Alpha1, alpha2 and beta1

Question 9

What G-proteins are connected to each noradrenergic receptor?

Answer 9

Alpha1 –> Gq –> increases phospholipase C
Alpha2 –> Gi (inhibitory) –> inhibits production of cAMP
Beta1 –> Gs –> increases cAMP

Question 10

Name the 4 pathways of dopamine in the CNS

Answer 10

Nigrostriatal, Mesolimbic, Mesocortical and Tuberohypophyseal

Question 11

Describe the production of dopamine

Answer 11

Tyrosine –> DOPA –> Dopamine –> Noradrenaline –> Adrenaline

Question 12

Why is it difficult to find a drug that selectively targets dopamine receptors?

Answer 12

Dopaminergic and Noradrenergic receptors have very similar structures (dopamine and noradrenaline very similar)
So to find drug that selectively targets just one

Question 13

What leads to Parkinson’s disease?

Answer 13

Nigrostriatal pathway neurone loss (substantia nigra)

Question 14

What enzymes do dopaminergic cells express?

Answer 14

Tyrosine hydroxylase
DOPA decarboxylase

Question 15

What enzymes do noradrenergic cells express?

Answer 15

Tyrosine hydroxylase
DOPA decarboxylase
Dopamine beta-hydroxylase

Question 16

Which enzymes found extracellularly and intracellularly are responsible for dopamine break down?

Answer 16

MAO- monoamine oxidase
COMT- catechol - O - methyltransferase

Question 17

What type of molecules are dopamine, noradrenaline, and adrenaline?

Answer 17

Catecholamines (monoamine)

Question 18

What can terminate action of dopamine?

Answer 18

Catabolism by MAO and COMT
Re-uptake by transporters

Question 19

What type of receptor is a dopaminergic receptor?

Answer 19

G- protein coupled

Question 20

What families of dopaminergic receptors are there?

Answer 20

2 families based on whether receptor coupled to Gs or Gi protein

Question 21

Which receptors are coupled to Gs and what does this effect?

Answer 21

D1, D5 coupled to Gs
Stimulates adenylyl cyclase, increasing cAMP -> PKA -> protein phosphorylation

Question 22

Which receptors are coupled to Gi and what does this effect?

Answer 22

D2, D3 and D4
Inhibits adenylyl cyclase, activated K+ channels leading to hyperpolarisation and reduce action potentials
Also inhibit Voltage gated calcium channels -> reduce influx of Ca2+ in neurones
Oppose effects of D1 and D5 receptors

Question 23

What happens if a D2 receptor is activated on a pre-synaptic membrane?

Answer 23

D2 is auto-inhibitory receptor (Gi)
Inhibits VGCC so reduces Ca2+ influx into neuron
Therefore inhibits the fusion of vesicles containing dopamine to the post synaptic membrane and acting on other neurones
Auto-inhibitory meaning stops release of self (dopamine)

Question 24

Why is D2 important other than being cause/ target for anti-psychotics?

Answer 24

Found in the pituitary gland
Activation of D2 receptor reduces prolactin
Prolactin responsible for lactation

Question 25

What effect do amphetamines have on DA?

Answer 25

Amphetamines = false substrate
Displace DA (and NA) from transport vesicles
Increase concentration of DA in cytosol
Re-uptake transporters work in reverse and transport DA into synaptic cleft
Therefore increasing DA signaling -> increased motor activity

Question 26

What effect does cocaine have on DA?

Answer 26

Cocaine = DA transporter inhibitor
DA stays in synaptic cleft for longer
Increased DA signalling -> increased motor activity

Question 27

Name some positive and negative symptoms of schizophrenia

Answer 27

Positive - Hallucinations (voices), delusions, aggression, defects in selective attention, catatonia
Negative - Blunting of emotions, anhedonia, withdrawal from social contacts and self care
Also cognitive issues, anxiety, depression

Question 28

Physical difference between schizophrenic brain and healthy brain

Answer 28

Schizophrenic brains tend to have larger lateral ventricles and smaller volume of tissue in the left temporal lobe

Question 29

Which receptors targeted by antagonistic anti-psychotic drugs can reduce positive symptoms of schizophrenia?

Answer 29

D2 receptors

Question 30

Which dopamine brain pathways are thought to be responsible for schizophrenia?

Answer 30

Overactivation of mesolimbic pathway = +ve schizo symptoms, activation of D2 receptors
Decreased activation of mesocortical pathway = -ve schizo symptoms, D1 receptors implicated

Question 31

Why is treating schizophrenia pharmacologically difficult?

Answer 31

Need a D2 antagonist to reduce positive symptoms
D1 agonist to reduce negative symptoms