Antipsychotics and neuroleptics Flashcards
What is the principle neurotransmitter in the sympathetic nervous system?
Noradrenaline
Name the 4 amine neurotransmitters in CNS
Noradrenaline, Dopamine, Serotonin (5-hydroxytryptamine), Acetylcholine
Where are these amine transmitters used in the brain?
Localised to small populations of neurones in the brain stem and basal forebrain
What is the main source of noradrenaline?
Locus coeruleus
What increases the activity of Locus Coeruleus?
Behavioural arrousal
Controls wakefulness, alertness and mood
How close are NA producing neurones and what does this effect?
Not closely associated therefore NA released can effect many other neurones and cells
Therefore drugs that effect noradrenergic transmission will affect other cells too
What type of receptors are noradrenergic receptors?
ALL G-protein coupled receptors
Name the receptors for noradrenaline
Alpha1, alpha2 and beta1
What G-proteins are connected to each noradrenergic receptor?
Alpha1 –> Gq –> increases phospholipase C
Alpha2 –> Gi (inhibitory) –> inhibits production of cAMP
Beta1 –> Gs –> increases cAMP
Name the 4 pathways of dopamine in the CNS
Nigrostriatal, Mesolimbic, Mesocortical and Tuberohypophyseal
Describe the production of dopamine
Tyrosine –> DOPA –> Dopamine –> Noradrenaline –> Adrenaline
Why is it difficult to find a drug that selectively targets dopamine receptors?
Dopaminergic and Noradrenergic receptors have very similar structures (dopamine and noradrenaline very similar)
So to find drug that selectively targets just one
What leads to Parkinson’s disease?
Nigrostriatal pathway neurone loss (substantia nigra)
What enzymes do dopaminergic cells express?
Tyrosine hydroxylase
DOPA decarboxylase
What enzymes do noradrenergic cells express?
Tyrosine hydroxylase
DOPA decarboxylase
Dopamine beta-hydroxylase
Which enzymes found extracellularly and intracellularly are responsible for dopamine break down?
MAO- monoamine oxidase
COMT- catechol - O - methyltransferase
What type of molecules are dopamine, noradrenaline, and adrenaline?
Catecholamines (monoamine)
What can terminate action of dopamine?
Catabolism by MAO and COMT
Re-uptake by transporters
What type of receptor is a dopaminergic receptor?
G- protein coupled
What families of dopaminergic receptors are there?
2 families based on whether receptor coupled to Gs or Gi protein
Which receptors are coupled to Gs and what does this effect?
D1, D5 coupled to Gs
Stimulates adenylyl cyclase, increasing cAMP -> PKA -> protein phosphorylation
Which receptors are coupled to Gi and what does this effect?
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
What happens if a D2 receptor is activated on a pre-synaptic membrane?
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)
Why is D2 important other than being cause/ target for anti-psychotics?
Found in the pituitary gland
Activation of D2 receptor reduces prolactin
Prolactin responsible for lactation
What effect do amphetamines have on DA?
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
What effect does cocaine have on DA?
Cocaine = DA transporter inhibitor
DA stays in synaptic cleft for longer
Increased DA signalling -> increased motor activity
Name some positive and negative symptoms of schizophrenia
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
Physical difference between schizophrenic brain and healthy brain
Schizophrenic brains tend to have larger lateral ventricles and smaller volume of tissue in the left temporal lobe
Which receptors targeted by antagonistic anti-psychotic drugs can reduce positive symptoms of schizophrenia?
D2 receptors
Which dopamine brain pathways are thought to be responsible for schizophrenia?
Overactivation of mesolimbic pathway = +ve schizo symptoms, activation of D2 receptors
Decreased activation of mesocortical pathway = -ve schizo symptoms, D1 receptors implicated
Why is treating schizophrenia pharmacologically difficult?
Need a D2 antagonist to reduce positive symptoms
D1 agonist to reduce negative symptoms
