Neurotransmitters II: Monoamines Flashcards
What are the CNS systems that control behaviour?
Autonomic nervous system
Hypothalamic pituitary neurohormones
Diffuse monoamine system
What is the Diffuse Modulatory System?
The Diffuse Modulatory System of the Brain (monoamines)
Four systems with common principles:
Small set of neurons at core
Arise from brain stem
One neuron influences many others
Synapses release transmitter molecules into extracellular fluid
Four main systems:
Noradrenergic Locus Coeruleus- so project from the locus coeruleus
Serotonergic Raphe Nuclei
Dopaminergic Substantia Nigra and Ventral tegmental Area
Cholinergic Basal Forebrain and Brain Stem Complexes
How does communication in the diffuse modulatory systems differ from point to point communication?
A- point to point communication as seen in GABA and glutamate communication:
- Fast
- Restricted
B- diffuse modulatory systems seen for our monoamines:
- Neuron communicates with many neurons
- Slower
- Widespread
- Exerts a modulatory effect instead of inhibitory or excitatory
Behavioural effects; mood, memory, rewards, movement, motivation
What effect does noradrenaline have and what parts of the brain does it affect?
Monoamines: Noradrenaline (NA)
- Arousal
- Wakefulness
- Exploration and mood (low NA in depressed)
- Blood pressure, higher levels increase blood pressure
- Addiction/gambling, the rush you get form gambling is from a surge in NA
Cell bodies for NAergic neurons, main one in locus coeruleus (LC),gives rise to millions of NAergic nerve terminals throughout the cortex, hippocampus, amygdala and cerebellum.
Release transmitter diffusely (i.e. like an aerosol)
Hypothalamus- hormones, sleep, body temperature, endocrine and autonomic controller)
Thalamus- main relay station for most information going into the brain
Locus coeruleus- known as ‘blue spot’ because of pigmentation.
NA in this region makes brain more responsive, increases information processing – LC involved in attention, arousal, anxiety, sleep/wake. Neurons most active when novel stimuli presented (when animal is vigilant). Low arousal associated with low NA e.g. depressed patients.
Temporal lobe = deep within the temporal lobe = amygdala
How are catecholamines synthesised?
The precursor molecule for dopamine is tyrosine
Tyrosine gets metabolised to DOPA through an enzyme called tyrosine hydroxylase
DOPA gets metabolised to dopamine through DOPA decarboxylase
Dopamine gets metabolised to noradrenaline via the enzyme called dopamine beta-hydroxylase
How is NA regulated?
NA in vesicles gets released when needed through exocytosis and activated NA receptors
Post-synaptic:
- Carry on the message
Pre-synaptic:
- Usually inhibitory (So a2 receptor is there)
- Negative feedback mechanism
If you get an excess of NA the NA will get re-uptaken back inside the neuron via the NA transporter
Once it is inside the neuron it gets metabolised by an enzyme called monoamine oxidase (MAO)
What are noradrenergic receptors like?
All are G-protein coupled receptors
Alpha1, Alpha2 and Beta
A1 activation will activate phospholipase C which will induce the conversion of PIP to IP3 and DAG
IP3 releases Ca2+ inner storage
Activation of a2 receptors will inhibit adenyl cyclase and as a result decreases cAMP, also inhibits the release of noradrenaline because it decreases intracellular calcium
Activation of the beta receptor stimulates adenyl cyclase increasing cAMP production from ATP
What drugs affect noradrenaline and how?
Reserpine- depletes NA stores by inhibiting vesicular uptake
Amphetamine (indirect sympathomimetic)- enters vesicles displacing NA into cytoplasm, increases AN leakage out of neuron
Cocaine blocks NA re-uptake
Low levels of NA are associated with depression, so how would you make a drug to counter this:
- You can block the NA transporter
- You can inhibit MAO
- A a2 antagonist would also work
What does dopamine do and where is it released from?
Monoamines: Dopamine (DA)
Involved in:
- Movement
- Reward
- Inhibition of prolactin release
- Memory consolidation
- Parkinson’s disease
- Schizophrenia
- Addiction
- Emesis
- ADHD
Dopamine released from:
Substantia nigra- projects to the striatum important for control/initiation of voluntary movement
This is known as the nigrostriatal pathway
VTA- mesocorticolimbic dopamine system – DA projection from midbrain project to nucleus accumbens, amygdala and the hippocampus
Important in addiction and schizophrenia / psychoses
This is known as the mesolimbic pathway- this is important in the rewards system
Tuberohyphyseal pathway – prolactin secretion
Mesocortical pathway- dopaminergic neurons which project from the NTA directly to the frontal cortex
Dopamine is released from the hypothalamus, transported to the pituitary, inhibits prolactin
Dopamine receptor also located in the CTZ so involved in emesis and memory consolidation
How are dopamine levels regulated?
L-dopa enters the neuron and gets metabolised to dopamine via dopa decarboxylase
Dopamine gets inside dopamine vesicles and upon stimulation gets released via exocytosis where they can activate dopamine receptors
Dopamine receptors comprise two types:
D1
D2- found post and pre-synaptically, act like auto-receptors (so inhibit further release of dopamine)
DA excess leads to DA being taken into neuron by DA transporter where it is metabolised by MAOB (a subtype of MAO)
What is the difference between D-1 and D-2 receptor families?
D1-like receptor family are Gs/olf coupled receptors whereas D2-like are Gi/o
So activation of D1 receptors stimulate adenylyl cyclase which increases production of cAMP which will increase PKA
PKA will phosphorylate various proteins including DARPP-32, important in dopamine signalling
Activation of D2-like receptors will inhibit adenylyl cyclase which will reduce cAMP and PKA
It will also increase opening of potassium ion channels and inhibit calcium ion channels
What is serotonin?
Distribution of 5-HT neurons resembles that of NA.
Cell bodies grouped around the midline (ridge/ raphe).
9 raphe nuclei and each nucleus projects to different regions of the brain including the cortex, the thalamus, the hypothalamus, the hippocampus, the amygdala, the cerebellum and spinal cord
The more caudal (near medulla, rear) innervate the spinal cord and modulate pain-related sensory signals
The more rostral (front / pons) innervate most of the brain
Where does serotonin come from?
Serotonin comes from tryptophan
Tryptophan gets metabolised to 5-hydroxytryptophan by tryptophan hydroxylase
5-hydroxytryptophan gets metabolised to 5hydroxytryptamine (serotonin) via an enzyme called dopa decarboxylase
How is serotonin regulated?
Serotonin gets inside vesicles and release via exocytosis to stimulate 5-HT receptors
There are about 14 different subtypes of the 5HT receptor, all G protein-coupled except for 5-HT3 which is an ion channel receptor
Predominantly found post-synaptically except for 5HT1D which is an autoreceptor
Serotonin is also transported back into neuron by 5HT transporter and metabolised by MAO
What are auto-receptors?
Auto-receptors; inhibit cell firing and transmitter release at the terminal regions
Note that these receptors can also be found post-synaptically
