what are the 4 amine transmitters in the CNS?
- noradrenaline
- dopamine
- serotonin
- acetylcholine
what are the properties of the amine transmitters in the CNS?
Where are they found in the brain
What behavior are amines responsible for
- localised to small populations of neurons with cell bodies in the brainstem and basal forebrain
- associated with high level behaviours e.g. emotion, cognition and awareness
antipsychotics and antidepressants exert their actions by interfering with amine transmission
what are the functional aspects of noradrenaline transmission?
- alpha1 receptors (Gq) widely distributed: involved in motor control, cognition and fear
- alpha2 receptors (Gi): involved in regylation of blood pressure, sedation and analgesia
- beta1 receptors (Gs) found in cortex, striatum and hippocampus: contribute to long-term effects of antidepressants
which brain area produces noradrenaline?
locus coeruleus
- linked with behavioural arousal, wakefulness and alertness
- deficiency of NA production is linked to depression
how is noradrealine metabolised?
- recycled by neuronal reuptake transporters
- broken down by MAO, aldehyde reductase or COMT
where is noradrenaline localised?
10000 cell bodies of noradrenergic neurons found in the locus coeruleus in the pons
- axons give millions of NA terminals to the cortex, hippocampus, hypothalamus, amygdala, thalamus and cerebellum
what are the receptors for noradrenaline?
What type of receptor is it
- all GPCRs the same in CNS and PNS
- widely distributed in the brain
- involved in motor control via cerebellum, cognition via cortex and fear responses via amygdala
what are the functional aspects of dopamine transmission?
- nigrostriatal pathway: fine motor control
- degenerates in Parkinson’s in the substantia nigra - mesocortical and mesolimbic pathways (cell bodies in VTA)
- behavioural effects, stereotypical, pleasure-euphoria-reward, motivation, compulsion - tuberohypophyseal pathway: pituitary hormone secretion e.g. prolactin
what disorders is dopamine involved in?
- Parkinson’s disease
- Schizophrenia
- Attention deficit disorder
- Drug dependence
- Endocrine disorders
what is the distribution of dopamine in the CNS?
- high levels of dopamine in striatum
- forms part of extrapyramidal motor system in cerebellum
- distribution is more restricted compared to NA
how is dopamine synthesised?
- tyrosine is converted into DOPA by tyrosine hydroxylase
- L-DOPA is converted into dopamine by DOPA decarboxylase
tyrosine hydroxylase is the rate limiting amount: if its function increases, amount of dopamine produced increases
leads to production of NA via dopamine beta-hydroxylase and then adrenaline
how is dopamine metabolised?
- COMT and MAO break down dopamine
- reuptake transporters can recycle it too
what is reserpine?
it blocks dopamine storage and leads to depletion of dopamine
used to control positive symptoms of schizophrenia
how can L-DOPA be used to treat Parkinson’s?
dopaminergic neurons do not express dopamine beta-hydroylase
- in parkinson’s, dopaminergic neurons are lost
- L-DOPA can be administered to increase dopamine synthesis, but can produce hallucinations
what are the 2 families of dopamine receptors?
- D1 and D5: Gs-coupled receptors
- stimulate adenylyl cyclase, increase cAMP, PKA and protein phosphorylation
- D1: decreased activity in mesocortical contributes to negative symptoms - D2, D3 and D4: Gi coupled receptors
- inhibit adenylyl cyclse, activate K+ channels, inhibit VGCC, inhibit AP firing and decrease Ca2+ influx into neurons by closing Ca2+ channels
- less dopamine is released from synapse due to less Ca2+ = autoinhibitory receptors
- opposite effects to D1
- D2: increased activity in mesolimbic system to cause positive symptoms
what are the agonists and antagonists of D2 receptors?
agonists = dopamine, apomorphine, bromocriptine, all produce stereotypic behaviour
antagonists = chloroproamzine, haloperidol, sulpiride, clozapine
- treat schizophrenia
where are D2 receptors found and what do they do?
found in pituitary gland and on dopaminergic neurons
- inhibitory autoreceptors
- dopamine inhibits/regulate prolactin release
inhibition of D2 receptors causes increased prolactin secretion
how do amphetamines effect dopamine (DA) and NA transmission?
- stimulate secretion of DA/NA
- they displace DA/NA from vesicles, causing reuptake transporters to work in reverse
- buildup of DA/NA in cytosol causes the transporters to expel the amines into the synaptic cleft, causing greater receptor signalling
amphetamine-like drugs treat narcolepsy and ADHD to stimulate wakefulness and increase concentration, respectively
how does cocaine affect DA and NA transmission?
- inhibits DA transporter so that DA remains in the cleft for longer and has more signalling
- increased signalling leads to increased motor activity
- in animals, there are stereotypic behaviours, activation of reward pathways and euphoric feelings
what is schizophrenia?
- caused by problems in the dopamine system
- symptoms characterised by disturbances in areas of the brain associated with thought, perception, attention, motor behaviour and emotion
what are the positive symptoms of schizophrenia?
D2 receptors implicated - increased activity in mesolimbic pathway:
- Hallucinations (voices) and delusions (paranoid)
- thought disorders (irrational/wild, delusions of grandeur, garbled
sentences)
- defects in selective attention
- bizarre behaviour: aggression, stereotyped movements, catatonia
what are the negative symptoms of schizophrenia?
D1 receptors implicated - decreased activity in mesocortical pathway
- blunting of emotions
- withdrawal from social contacts
- flattening of emotional responses
- anhedonia (cannot feel pleasure)
- reluctance to perform everyday tasks
what are the causes of schizophrenia?
- combination of environmental and genetic factors
- hereditary as a result of abnormalities arising early in life which disrupt brain development
- no single gene is responsible
- consumption of cannabis in adolescence is an environmental factor
what are the structural differences in a schizophrenic brain and a healthy brain?
- schizophrenic brains have larger ventricles and smaller volume of tissue in the left temporal lobe
