W9 -Neurotransmitters Systems III: Monoamines Flashcards
Why is it important?
It is involved in behavioural effects, eg. motivation, rewards, pleasure, movement, learning and cognition, arousal and moods.
They are identified to lead to mental health issues - like depression, schizophrenia, psychosis, Parkingson’s disease, drugs abuse, dementia, Alzheimer’s.
Important to know to develop drugs.
What do Venalfaxine, Citalopram and Prozac, Olanzapine, Levodopa and Aricept do?
Drugs:
Venlafaxine = Antidepressants - increases serotonin and noradrenaline.
Citalopram and Prozac = antidepressants that target the serotonin transporter. Increases serotonin.
Olanzapine = Antipsychotic by blocking dopamine D2 receptor.
Levodopa = Precursor of dopamine - manage symptoms of Parkingsonism like rigidity.
Aricept = Management of dementia and alzheimers - inhibits anti cholinesterase.
Recreational drugs also affects the monoamine system.
What are CNS systems that control behaviour?
- Autonomic nervous system
- Hypothalamic-pituitary neurohormones
- Diffuse monoamine system
What is the sympathetic nervous system?
Increases, fear, fights, flight, sexual stimulation.
Autonomic nervous system.
What is the parasympathetic nervous system?
Relaxation, recovery, growth, digestion takes place.
What is The Diffuse Modulatory Systems of
the Brain (monoamines)?
The modulatory system is the system that releases 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 - Noradrenaline
– Serotonergic Raphe Nuclei - Serotonin
– Dopaminergic Substantia Nigra and Ventral tegmental Area - Dopamine
– Cholinergic Basal Forebrain and Brain Stem Complexes - Acetylcholine
What are the behavioural effect: The Diffuse Modulatory Systems of the Brain
A: Point to point communication
-Fast, restricted
B: Diffuse modulatory systems
-slower, widespread
Behavioural effects: Mood, memory, reward, movement, motivation
These don’t inhibit or excite, they modulate the excitation. This is why they are attractive pharmacologically. They don’t completely change, they modulate.
What are some examples of metabotropic receptors?
5-HT1
Inhibits AC
5-HT2
Stimulates PLC
Dopamine D1
Stimulates AC
Dopamine D2
Inhibits AC
Noradrenaline
Stimulates AC
Noradrenaline
1 Stimulates PLC
Noradrenaline
2 Inhibits AC
What is the monoamine: Noradrenaline (NA)?
Noradrenergic Locus Coeruleus (LC)- Noradrenaline
Arousal
Wakefullness
Exploration and mood (low NA in depressed)
Blood pressure
Addiction/gambling
These neurones project in certain areas such as the cortical region, amygdala (involved in emotions), hypothalamus (thermogenesis, appetite regulation, endocrine centre etc), cerebellum (motor coordination) and down to the spinal cord.
What is the synthesis of catecholamines?
The precursor of Dopamine is the amino acid Tyrosine.
Tyrosine + Tyrosine hydrolase = DOPA
DOPA + DOPA decarboxylase = Dopamine
Dopamine + Dopamine B-hydroxylase = Noradrenaline
Noradrenaline + Phenylethanolamine N-methyltransferase = adrenaline
How is NA regulated?
- Post-synaptic
– Carry on the message - Pre-synaptic (autoreceptors)
– Usually inhibitory
– Negative feedback mechanism - Reserpine-depletes NA stores by inhibiting vesicular uptake - basically, blocks NA getting inside vesicles. This means NA gets depleted in the synaptic cleft. This drug is associated with negative moods. Also used as an antihypertensive.
- Amphetamine (indirect sympathomimetic)-enters
vesicles displacing NA. Into cytoplasm, increase NA leakage out of neuron. This is a psychostimulant. The NA leaks out and accumulates in the synaptic cleft. Results in a big surge of NA. This is the excitement people feel.
In a neurone, the NA gets inside a NA vesicle. Once they are inside, they release the content in the synaptic vesicle. It activated NA receptors.
NA is regulated by the reuptake via NA transporter. Its function is to take up excess NA in the synaptic cleft and break it down and metabolised by the enzynme Monoamine (MAO), which destroys NA.
Where do the various pathways of adrenaline/noradrenaline do?
There are a and B adrenaline/noradrenaline receptors.
a subdivides to a1 and a2.
a1 = Phosphlipase C = PIP, IP3 DAG
IP3 = Ca2+ = smooth muscle contraction glycogenolysis.
a2= inhibits adenyl cyclase. This decreases cAMP = smooth muscle contraction.
a2 = Also inhibits release of noradrenaline due to Ca+ decrease
B = stimulation of Adenyl cyclase = cAMP = Contraction of cardiac muscle, smooth muscle relaxation glycogenolysis.
What is noradrenaline?
- Reserpine-depletes NA stores by inhibiting
vesicular uptake - Amphetamine (indirect sympathomimetic)-enters
vesicles displacing NA into cytoplasm, increase NA leakage out of neuron - Cocaine-blocks NA re-uptake
- Noradrenaline (NA)
– Main action inhibitory (β) - Also excitatory (⍺ / β)
– Termination: neuronal uptake and MAO
– Main cell body in locus coeruleus - NAergic neurons active when ‘awake’
- Amphetamine - alertness and exploratory behaviour
– High density in brainstem, hypothalamus & medial temporal lobe
– Functions: - Arousal, wakefullness, exploration and mood (low NA in depressed patients)
- Blood pressure regulation, (antihypertensive e.g. clonidine 2)
- (Addiction/gambling)
What is the monoamine: Dopamine (DA)?
Dopaminergic Substantia Nigra (SN) and Ventral tegmental Area (VTA) - Dopamine is released in the striatum.
Involved in: Movement, Reward, Inhibition of prolactin release, Memory consolidation
Parkinson’s Disease - result of Nigrostriatal neurone degradation- characterised by difficulty in movement.
Schizophrenia - overstimulation of the mesolimbic dopaminergic areas lead to positive reactions such as hallucinations.
Addiction, Emesis, ADHD
The mesolimbic pathway consisting of Dopaminergic neurones with cell bodies located in that area of the brain (VTA). These project to various ridges of brain including the nucleus accumbens (Ac) - rewards and pleasure. Also extends to Am - emotions and also the hyppocampus- memory and learning.
Mesocortical pathway leads from directly the SN to the frontal cortex. The Tubero-hypophyseal pathways stem from the hyppocampus releasing dopamine.This is closely related to portal system, where it is transferred via circulation to pituitary. Here it will act on the D2 receptor to inhibit release of prolactin.
Dopamine is also present in the chemoreceptor trigger zone (CTZ) - induce vomiting.
How is dopamine regulated?
L-dopa get metabolised by Dopa decarbohydroxylase to Dopamine.
Dopa gets inside synaptic vesicles, the content gets released and they activate D1 and D2 receptors.
D2 are found pre and post synaptically.
Too high = psychosis, addiction etc
Too low = impairment in movement etc
Excess dopamine in the synaptic cleft = Dopamine transporters collect it and pushes it back to the presynaptic neurone. Once inside, it would get metabolised and broken down by an isoenzyme of monoamine oxydase B (MAOB) - completely destroying Dopamine.
One way to increase dopamine is to administer L-dopa. Can also block dopamine transporters. Inhibiting MAOB.
