Lecture 14 (CNS Pharmacology III - Antipsychotic drugs) Flashcards
What are the main amine transmitters in the CNS? (4)
-Noradrenaline
-Dopamine
-5-Hydroxytryptamine (seratonin)
-Acetylcholine
What are the 3 GPCRs that affect noradrenaline and what do they do? (6)
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
What are the 3 functional aspects of dopamine? (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
Which enzymes is dopamine release terminated by? (2)
and which enzyme blocks dopamine storage?
-COMT
-MAO
-Reserpine
Which enzyme is dopamine made up of?
How do we make it into dopamine?
-Tyrosine hydrolase (forms DOPA)
-Dopa is converted into dopamine with DOPA decarboxylase
(If we increase function of this enzyme, increases dopamine in brain)
What happens to dopamine in Parkinson’s?
how do we treat this?
-Dopamine is lost
-Patients given L-DOPA so neurones can make more dopamine
What is dopamine the precursor for? (2)
-Adrenaline
-Normadrenaline
(Dopaminergic neurons express first 2 enzymes, noradrenergic express first 3)
What are the two families of dopamine receptors? (2)
and which dopamine receptors are in them? (5)
Gs coupled receptors (stimulate adenyl cyclase)
D1 and D5
Gi coupled (inhibitory) receptors (inhibit adenyl cyclase)
D2, D3 and D4
Which dopamine receptor from the 5 is the most pharmacologically important?
and why?
D2
D2 receptor are auto-inhibitory receptors, inhibit release of dopamine so have modulatory function
What do the two classes of dopamine receptors do? (2)
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
What do amphetamines do in regards to DA and NA? (2)
-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
Which dopamine receptors is impacted in reward pathway?
D1
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)
Schizophrenia
At what age are positive and negative symptoms prevalent in schizophrenia? (2)
and what DA receptors are impacted for each? (2)
Positive symptoms tend to be found in young
D2 receptors implicated
Negative symptoms tend to be found in elderly
D1 receptors implicated
What are differences in schizophrenic brains compared to normal? (2)
Schizophrenic brains tend to have larger lateral ventricles and a smaller volume of tissue in the left temporal lobe.
What kind of drugs increase positive-schizophrenia-like symptoms?
Drugs that enhance DA signalling
Do environmental factors have an effect of presence of schizophrenia?
What other neurotransmitter other than dopamine is involved in it?
Yes (e.g consumption of cannabis in adolescence)
Serotonin
What do ketamine and LSD do? (2)
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
What type of schizophrenic activity does overactivity in mesolimbic pathway and decreased activity in mesocortical pathway correlate to? (2)
-Overactivity of Mesolimbic pathway associated with +ve symptoms increased
D2 activity
-Decreased activity in Mesocortical pathway
Associated with –ve symptoms
D1 receptors implicated
Which dopamine receptor antagonists can reduce schizophrenia symptoms?
D2
What do DA antagonists do?
in terms of schizophrenia?
Block DA storage, control positive symptoms of schizophrenia
What are the two generations of antipsychotic drugs? (2)
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)
What are unwanted side-effects of antipsychotic drugs?
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
What areas of the brain are amine transmitters localised to? (2)
Localised to small populations in:
-Brain stem
-Basal forebrain
What part of the brain neuronal activity is increased with behavioural arousal?
The locus coeruleus (LC)
What amine transporter is involved in serval common disorders?
(Parkinson’s Disease, Schizophrenia, Attention Deficit disorder, Drug dependence and some endocrine disorders)
Dopamine
Where is Dopamine high in the brain?
what does this form?
-Striatum
-Part of the ‘extrapyramidal motor system’ involved in coordination of movement
Where is D1 found?
What condition is it a drug target for?
D1 receptor found a lot in cortex and is a drug target for schizophrenia
Where is D2 found?
D2 receptors found in pituitary and on DA neurons (inhibitory auto receptors)
What are the type of drugs used for schizophrenia called?
Antipsychotic drugs also referred to as Neuroleptic drugs
What is a side effect of treating Parkinson’s patients with levodopa?
Hallucinations
What does DA release in animals produce?
What does D2 receptor agonists induce in animals? (2)
-Stereotypical behaviour
-Stereotypical behaviour
-Exacerbate symptoms of schizophrenia patients
What do amphetamines produce similar effects to?
Amphetamine produces behaviours similar to acute schizophrenic episode
What controls positive symptoms of schizophrenia? (2)
-DA antagonists
-Drugs that block DA storage (reserpine)
