Neuro: Neurotransmitter Systems III: Monoamines Flashcards
Why is the monoamine system important?
- Involved in behavioural effects e.g. motivation, reward, pleasure, movement, learning, cognition, arousal, mood etc.
- Dysregulation or disruption of this monoamine system is well known to lead to various psychiatric conditions.
- Important to study the different disruptions that take place in these conditions so that you can develop appropriate pharmacotherapy to manage some of the symptoms.
What are the three CNS systems that control behaviour?
Autonomic nervous system - hypothalamus is responsible for the control of the automatic nervous system. The autonomic nervous system is not under voluntary control.
Hypothalamic-pituitary neurohormones - pituitary and hypothalamus release neurohormones which affect behaviour (e.g. HPA)
Diffuse monoamine system
What are the four main systems we talk about when discussing the diffuse monoamine system?
- Noradrenergic Locus Coeruleus
- Serotonergic Raphe Nuclei
- Dopaminergic Substantia Nigra and Ventral tegmental Area
- Cholinergic Basal Forebrain and Brain Stem Complexes
What are some principles that the 4 monoamine systems have in common?
- they have a small set of neurons at their core
- they arise from the brain stem
- one neuron influences many others
- synapses release transmitter molecules into the extracellular fluid
Signalling in the nervous system can be fast or slow.
Describe the fast and slow signalling.
FAST point-to-point signalling:
- neurotransmitters producing excitatory or inhibitory potentials
- ligand-gated ion channels
- glutamate, GABA, ACh
SLOW transmission:
- neurotransmitters and neuromodulators
- G-protein coupled receptors
- monoamines, peptides, ACh
Give some examples of metabotropic receptors and their consequent actions upon stimulation.
- 5-HT1: inhibits Adenylate Cyclase (AC)
- 5-HT2: stimulate Phospholipase C (PLC)
- Dopamine D1: stimulates AC
- Dopamine D2: inhibits AC
- Noradrenaline β: stimulates AC (Gs coupled, increase cAMP)
- Noradrenaline α1: stimulates PLC (Gq coupled, create IP3)
- Noradrenaline α2: inhibits AC (Gi coupled, decrease cAMP)
Describe the noradrenergic monoamine system.
It consists of noradrenergic neurons which project from the central core, the locus coeruleus (LC).
They project to several areas of the brain, including:
- the cortex
- the amygdala
- the hypothalamus
- the spinal cord
- the cerebellum
Briefly mention some actions of noradrenaline on the body.
Noradrenaline is very important in brain arousal enabling us to think and take action fast.
It also affects our cardiovascular system by increasing our heart rate and blood pressure, etc. It does this not only by acting on the heart muscle directly but also by acting on the cardiovascular systems in the brain.
When gambling/etc., we get a noradrenergic surge, which plays a role in addiction.
It is also involved in exploration and mood (low NA involved in depression)
How is noradrenaline synthesised?
- Tyrosine is acted upon by the enzyme tyrosine hydroxylase, making DOPA
- DOPA is then acted upon by DOPA decarboxylase, making dopamine
- Dopamine is metabolised into noradrenaline via the enzyme Dopamine beta-hydroxylase
How is noradrenaline regulated?
If there is an excess of release of NA, it get re-uptaken back inside the neurone via the noradrenaline transporter. Once NA is inside the neurone it gets broken down and metabolised by an enzyme called monoamine oxidase. This allows the termination of NA action.
List some drugs and their effect on noradrenaline levels.
- Reserpine: depleted NA stores by inhibiting vesicular uptake
- Amphetamine (indirect sympathomimetic): enters vesicles, displacing NA into the cytoplasm, increasing NA leakage out of the neuron
- Cocaine: blocks NA reuptake
How can you increase levels of noradrenaline inside the synaptic media?
- Low NA associated with depression
- Can block the noradrenaline transporter - NA wont be able to get back inside the neurone
- Inhibit the monoamine oxidase, increasing NA levels in the synaptic cleft, causing it to leak out
List the different dopaminergic pathways.
- Dopaminergic neurones which project from the Substantia nigra (SN) go to the striatum where dopamine gets released. Involved in movement. Parkinson’s disease is due to neurodegeneration of the striatum neurones.
- Mesolimbic pathway. Dopaminergic neurones project from ventral tegmental area (VTA) to various regions. The nucleus accumbens (Ac) - region involved in reward, pleasure. The amygdala (Am) - region of the brain involved in emotionality. The hippocampus - involved in memory and learning. Hyperactivity of the mesolimbic dopaminergic system associated with schizophrenia.
- Mesocortical dopaminergic system. Dopaminergic neurones which project from the VTA directly to the frontal cortex. This is involved in executive function.
- Tubero-hypophyseal pathway. Dopamine released by the hypothalamus in portal system and is transported via blood circulation to the pituitary. Causes activation of the dopamine D2 receptor in pituitary - inhibits release of hormone prolactin. Regulates prolactin function.
- Dopamine receptors in chemoreceptor trigger zone (CTZ) have an important function in inducing emesis. So activation of the D2 receptor by dopamine induces vomiting.
How is dopamine synthesised?
- Tyrosine is acted upon by the enzyme tyrosine hydroxylase, making DOPA
- DOPA is then acted upon by DOPA decarboxylase, making dopamine
What are some ways in which we could increase the amount of dopamine in the synaptic cleft?
- Inhibit the dopamine reuptake transporter on the pre-synaptic neurone, meaning there is more dopamine available
- Inhibit monoamine oxidase B activity, reducing the breakdown of dopamine e.g. selegiline.
- Introduce a dopamine precursor e.g. L-dopa to increase the production of dopamine.
