Lecture 14 (CNS Pharmacology III - Antipsychotic drugs)

Question 1

What are the main amine transmitters in the CNS? (4)

Answer 1

-Noradrenaline
-Dopamine
-5-Hydroxytryptamine (seratonin)
-Acetylcholine

Question 2

What are the 3 GPCRs that affect noradrenaline and what do they do? (6)

Answer 2

Alpha 1 = wide distributions, involved in motor control, cognition and fear
Alpha 2 =involved in central regulation of blood pressure, have sedative and analgesic effects
Beta 1 = Another GPCR, in striatum and hippocampus

Question 3

What are the 3 functional aspects of dopamine? (3)

Answer 3

Nigrostriatal pathway – fine motor control, degenerates in Parkinson’s disease

Mesorortical and mesolimbic pathway – cortex, behavioural effects in animals, disruption leads to stereotypical behaviors
Pathway also involved in pleasure, euphoria and reward, part that drive motivation and addiction, involved in compulsive behavior

Tuberohypophesical pathway – controls secretion of some hormones in the pituitary gland

Question 4

Which enzymes is dopamine release terminated by? (2)
and which enzyme blocks dopamine storage?

Answer 4

-COMT
-MAO

-Reserpine

Question 5

Which enzyme is dopamine made up of?
How do we make it into dopamine?

Answer 5

-Tyrosine hydrolase (forms DOPA)
-Dopa is converted into dopamine with DOPA decarboxylase

(If we increase function of this enzyme, increases dopamine in brain)

Question 6

What happens to dopamine in Parkinson’s?
how do we treat this?

Answer 6

-Dopamine is lost
-Patients given L-DOPA so neurones can make more dopamine

Question 7

What is dopamine the precursor for? (2)

Answer 7

-Adrenaline
-Normadrenaline

(Dopaminergic neurons express first 2 enzymes, noradrenergic express first 3)

Question 8

What are the two families of dopamine receptors? (2)
and which dopamine receptors are in them? (5)

Answer 8

Gs coupled receptors (stimulate adenyl cyclase)

D1 and D5

Gi coupled (inhibitory) receptors (inhibit adenyl cyclase)

D2, D3 and D4

Question 9

Which dopamine receptor from the 5 is the most pharmacologically important?
and why?

Answer 9

D2

D2 receptor are auto-inhibitory receptors, inhibit release of dopamine so have modulatory function

Question 10

What do the two classes of dopamine receptors do? (2)

Answer 10

Gs coupled receptors (D1 and D5)
-Stimulated adenyl cyclase
-Increased activity in -ve symptoms
-Increased activity in mesolimbic system

Gi coupled (inhibitory) receptors(D2, D3 andD4)
-Inhibit adenyl cyclase
-Increased activity in +ve symptoms
-Increased activity in mesocortical system

Question 11

What do amphetamines do in regards to DA and NA? (2)

Answer 11

-Stimulate secretion of DA and NA from vesicles
-causes re-uptake transporters to work in reverse

-Increases DA signalling leads to increased motor activity and activation of reward pathways

Question 12

Which dopamine receptors is impacted in reward pathway?

Answer 12

D1

Question 13

Which neural disease involving DA receptors are these symptoms of?

Positive : Hallucinations (voices), delusions (paranoid), thought disorders (irrational/wild, delusions of grandeur, garbled sentences) , defects in selective attention, bizarre behaviour, aggression, stereotyped movements, catatonia

Negative: blunting of emotions, withdrawal from social contacts, flattening of emotional responses, anhedonia, reluctance to perform everyday tasks.

May be accompanied by cognitive deficits (attention, memory), anxiety, depression, self punishment suicide attempts (50% cases)

Answer 13

Schizophrenia

Question 14

At what age are positive and negative symptoms prevalent in schizophrenia? (2)
and what DA receptors are impacted for each? (2)

Answer 14

Positive symptoms tend to be found in young
D2 receptors implicated

Negative symptoms tend to be found in elderly
D1 receptors implicated

Question 15

What are differences in schizophrenic brains compared to normal? (2)

Answer 15

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

Question 16

What kind of drugs increase positive-schizophrenia-like symptoms?

Answer 16

Drugs that enhance DA signalling

Question 17

Do environmental factors have an effect of presence of schizophrenia?
What other neurotransmitter other than dopamine is involved in it?

Answer 17

Yes (e.g consumption of cannabis in adolescence)

Serotonin

Question 18

What do ketamine and LSD do? (2)

Answer 18

Ketamine – NMDA receptor antagonist, ketamine can mimic positive symptoms in schizophrenia

LSD – Drug exerts action as agonist of particular serotonin receptor 5 HT2A, loss of cortical inhibition thought to underlie hallucinogenic effect

Question 19

What type of schizophrenic activity does overactivity in mesolimbic pathway and decreased activity in mesocortical pathway correlate to? (2)

Answer 19

-Overactivity of Mesolimbic pathway associated with +ve symptoms increased
D2 activity

-Decreased activity in Mesocortical pathway
Associated with –ve symptoms
D1 receptors implicated

Question 20

Which dopamine receptor antagonists can reduce schizophrenia symptoms?

Answer 20

D2

Question 21

What do DA antagonists do?
in terms of schizophrenia?

Answer 21

Block DA storage, control positive symptoms of schizophrenia

Question 22

What are the two generations of antipsychotic drugs? (2)

Answer 22

Antipsychotics
1st generation referred to as typical, severe side effects, motor disturbances and prolactin secretion

2nd generation refereed to as atypical, less motor disturbances

(want to target mesolyombic pathway and avoid nigrostriatal pathway)

Question 23

What are unwanted side-effects of antipsychotic drugs?

Answer 23

Some side effects build up over time such as dyskinesia
Uncontrolled movement of muscles, irreversible side-effect
Can also lead to sedation, hypertension and weight gain

Question 24

What areas of the brain are amine transmitters localised to? (2)

Answer 24

Localised to small populations in:
-Brain stem
-Basal forebrain

Question 25

What part of the brain neuronal activity is increased with behavioural arousal?

Answer 25

The locus coeruleus (LC)

Question 26

What amine transporter is involved in serval common disorders?
(Parkinson’s Disease, Schizophrenia, Attention Deficit disorder, Drug dependence and some endocrine disorders)

Answer 26

Dopamine

Question 27

Where is Dopamine high in the brain?
what does this form?

Answer 27

-Striatum

-Part of the ‘extrapyramidal motor system’ involved in coordination of movement

Question 28

Where is D1 found?
What condition is it a drug target for?

Answer 28

D1 receptor found a lot in cortex and is a drug target for schizophrenia

Question 29

Where is D2 found?

Answer 29

D2 receptors found in pituitary and on DA neurons (inhibitory auto receptors)

Question 30

What are the type of drugs used for schizophrenia called?

Answer 30

Antipsychotic drugs also referred to as Neuroleptic drugs

Question 31

What is a side effect of treating Parkinson’s patients with levodopa?

Answer 31

Hallucinations

Question 32

What does DA release in animals produce?
What does D2 receptor agonists induce in animals? (2)

Answer 32

-Stereotypical behaviour

-Stereotypical behaviour
-Exacerbate symptoms of schizophrenia patients

Question 33

What do amphetamines produce similar effects to?

Answer 33

Amphetamine produces behaviours similar to acute schizophrenic episode

Question 34

What controls positive symptoms of schizophrenia? (2)

Answer 34

-DA antagonists
-Drugs that block DA storage (reserpine)