NEURO: Neurotransmitter Systems III: Monoamines Flashcards
(39 cards)
What is a monoamine?
A monoamine is a compound having a single amine group in its molecule. Monoamines refer to the particular neurotransmitters; noradrenaline, serotonin and dopamine. These neurotransmitters are involved in mediating a wide range of physiological and homeostatic functions, which vary with the part of the brain being examined.
What are the 3 CNS systems that control behaviour?
- The autonomic nervous system
- Hypothalamic-pituitary neurohormones
- Diffuse monoamine system
What are the 4 main systems of the diffuse monoamine system?
The 4 main systems:
- Noradrenergic Locus Coeruleus
- Serotonergic Raphe Nuclei
- Dopaminergic Substantia Nigra and Ventral tegmental Area
- Cholinergic Basal Forebrain and Brain Stem Complexes.
What 4 principles do the 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, restricted point-to-point signalling:
- neurotransmitters producing excitatory or inhibitory potentials
- glutamate, GABA, ACh
SLOW transmission: Diffuse Modulatory system
- neurotransmitters and neuromodulators
- 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
- Noradrenaline α1: stimulates PLC
- Noradrenaline α2: inhibits AC
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 (via the LC) enabling us to think and take action fast.
- Important in wakefullness
- inhibiting sleep.
- Exploration and mood (low NA in depression)
- It also affects our cardiovascular system by increasing our heart rate, increasing our 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.
How is Noradrenaline synthesised?
Tyrosine –> DOPA (catalysed by enzyme Tyrosine hydroxylase)
DOPA –> Dopamine (catalysed enzyme by DOPA decarboxylase)
Dopamine —> Noradrenaline (catalysed enzyme by Dopamine-β-hydroxylase)
Nordrenaline can be converted to adrenaline by Phenylethanolamine N-methyltransferase, but this is irrelevant here.
How is Noradrenaline (NA) regulated?
NA is packed into vesicles in the pre-synaptic neuron. Upon noradrenergic neuron stimulation, NA is released into the synaptic cleft by exocytosis from the vesicles and pre-synaptic neuron. This activates the noradrenergic receptors on the post-synaptic neuron. There are also some noradrenergic neurones on the pre-synaptic neuron (e.g. α2), this is an autoreceptor and is usually inhibitory. It can regulate levels of NA via negative feedback mechanisms. Furthermore, an excess of NA can be regulated by being re-uptaken into the pre-synaptic neuron by the noradrenaline transporter. The NA will then be broken down and metabolised by an enzyme called monoamine oxidase (MAO).
What are the noradrenergic receptors?
There are α (α1 and α2) and β noradrenergic receptors. Both are GPCRs. Noradrenaline stimulates α1 and β receptors, and inhibits α2 receptors.
NA binds to α1 receptors (Gq):
activate Phospholipase C –> convert PIP2 to IP3 and DAG –> increase intracellular Ca2+ –> causing smooth muscle contraction, glycogenolysis and other various pharmacological effects.
NA binds to α2 receptors (Gi):
- this will inhibit adenyl cyclase –> thus decease the conversion of ATP to cAMP –> inhibit smooth muscle contraction
- it will also decrease intracellular ca2+ –> thus inhibit NA release
NA binds to the B receptor (Gs coupled):
activating adenyl cyclase –> increased ATP converted to cAMP –> increase contraction of cardiac muscle, smooth muscle relaxation, there will also be glycogenolysis.
List some drugs and their effect on noradrenaline levels.
- Reserpine: depleted NA stores by inhibiting vesicular uptake. Associated with depression and to treat hypertension.
- Amphetamine (indirect sympathomimetic): enters vesicles, displacing NA into the cytoplasm, increasing NA leakage out of the neuron. This causes a surge of NA and ‘excitement’.
- Cocaine-blocks NA re-uptake.
Low levels of NA associated with depression. Thus increasing NA in the synaptic media (cleft) can help counter that. Anti-depressants block NA transporters. Thus increase NA in the synaptic cleft. Some drugs block the monoamine oxidase enzyme and thus cause an NA surge.
Describe the dopaminergic (DA) monoamine pathways.
There are many dopaminergic pathways. These include the:
- NIGROSTRIATAL PATHWAY: the dopaminergic cell bodies are located in the substantia nigra. They project to the striatum where dopamine is released. This is important for the initiation/control of voluntary movement. Degeneration of these neurones are associated with movement impairment and diseases such as Parkinson’s Disease, dyskinesis and Dyskinesia (movement disorders). Parkinson’s disease is characterised by deficits of the dopamine receptors and degeneration of precursors (L-dopa).
- MESOLIMBIC PATHWAY: The dopaminergic cell bodies are located in the ventral tegmental area (area) and project DA to the various regions including: - the Nucleus Accumbens –> involved in reward and pleasure. - the Amygdala –> involved in emotionality - the Hypothalamus –> involved in memory and learning. Hyperactivity of the mesolimbic pathway is associated with positive symptoms of schizophrenia such as hallucinations.
- MESOCORTICAL PATHWAY: Dopaminergic neurons project from the ventral tegmental area directly to the frontal cortex - involved in higher cognitive functions.
- TUBERO-HYPOPHYSEAL PATHWAY: Dopaminergic neurones project DA from the hypothalamus to the pituitary via the hypophyseal circulation. In the pituitary it will bind to the dopamine D2 receptor and a inhibit prolactin release. Dopamine receptors are also located at the chemoreceptor trigger zone, dopamine is thus also involved in emesis (vomiting). DA is also involved in ADHD. prolactin secretion
How is dopamine synthesised?
Tyrosine –> DOPA (catalysed by enzyme Tyrosine hydroxylase)
DOPA –> Dopamine (catalysed enzyme by DOPA decarboxylase)
Describe dopamine regulation.
In the pre-synaptic neuron L-dopa (DA precursor) is converted to DA via dopa decarboxylase. DA gets into the DA vesicles and is released into the synaptic cleft following stimulation of the neuron. The DA can then activate the Dopamine receptors on the post synaptic neuron - D1 and D2. D2 is also found on pre-synaptic neurons and can act as an autoreceptor, thus inhibiting DA release from the pre-synaptic neuron.
It is very important to regulate levels of DA as high levels can cause psychosis and low levels can cause movement impairment.
An excess of DA in the synaptic cleft be re-uptaken into pre-synaptic neuron via DA transporters. This is then broken down into its metabolites by Monoamine Oxidase type B (MAOb). To increase dopamine levels (e.g. for Parkinson’s disease), more L-dopa (precursor) can be administered, the MAOb enzyme can be inhibited and the DA transporter can be inhibited.
Describe the dopamine receptors.
There are 2 kinds of dopamine receptors (and 5 receptor subtypes):
- D1-LIKE RECEPTORS: D1, D5
- D2-LIKE RECEPTORS: D2, D3, D4
Both types are GPCRs with 7 transmembrane domains, with N terminals found extracellular and C terminals found intracellularly. D1 receptors are linked to αGs subunits, and thus are excitatory. D2 receptors are linked to αGi subunits, and thus are inhibitory. The D1-like receptors stimulate adenyl cyclase thus increase cAMP activity thus increase PKA activity which phosphorylates various proteins including the DARPP-32 protein (important dopamine signaling molecule.) D2-like receptors inhibit adenyl cyclase thus decrease cAMP and PKA activity. D2-like receptors also increase opening of potassium channels and inhibit calcium channels leading to inhibition of neurotransmitter release.
Describe the serotonergic monoamine system.
Serotonin is released from serotonergic neurones which project from the raphe nucleus. This is where the serotonergic neuron cell bodies are found. They project to different areas of the brain, such as:
- the cortex
- the striatum (important for movement)
- the thalamus (important for relay of information in the brain)
- the hypothalamus (important for thermoregulation sleep regulation, endocrine control and appetite regulation)
- the hippocampus (important in learning and memory)
- the amygdala (important for emotionality)
- the cerebellum (important in motor coordination and to the spinal cord
- involved in pain modulation).
Briefly mention some actions of serotonin on the body.
- increased 5-HT in the cortex causes heightened perceptions
- increased 5-HT in the hypothalamus causes reduced appetite
- increased 5-HT in the amygdala causes elevated mood
- increased 5-HT in the spinal cord will suppress pain.
Ecstasy (mdma) is a drug that increases serotonin levels.
How is serotonin synthesised?
Tryptophan is the precursor of serotonin. It can only be obtained from food as the body cannot manufacture it.
Tryptophan is converted to 5-hydroxytryptophan, catalysed by enzyme tryptophan hydroxylase.
5-hydroxytryptophan is converted to 5-hydroxytryptamine, or serotonin, catalysed by enzyme dopa decarboxylase.
Serotonin can be metabolised by MAO.
Describe serotonin (5HT) regulation.
Serotonin is packaged into vesicles in the pre-synaptic neuron and can be released from the synaptic bouton via exocytosis into the synaptic cleft. Serotonin can then activate the post synaptic neuron serotonin receptors (there are 14 subtypes: 13 GPCRs and 1 LGICR - 5-HT3).
The 5HT1D receptor is an autoreceptor on the pre-synaptic neuron, this causes the inhibition of serotonin release from the pre-synaptic neuron.
Too high levels of 5HT are associated with serotonin syndrome which can induce seizures, and CVS collapse. Too low levels of 5HT is associated with depression.
Excess serotonin in the synaptic cleft is re-uptaken by the 5-HT transporter. It is is then broken down and metabolised by MAO.
How can serotonin drugs be used to treat depression?
Drugs that block serotonin reuptake transporters would be used. Drugs that inhibit monoaminoxidase could also be used. Both of these mechanisms ensure that there is more serotonin in the synaptic cleft.
Describe the monoamine serotonin receptors and some of their functions.
There are 14 5-HT receptors consisting of 14 subtypes (all of which are GPCRs except for the LGICR 5-HT3). The 5-HT receptors:
- 5-HT1 inhibitory, limbic system – involved mood, migraine
- 5-HT2 (5-HT2A), excitatory, involved in hallucinogenic, limbic system & cortex
- 5-HT3 excitatory, medulla – involved in vomiting
- 5-HT4 presynaptic facilitation (ACh) – involved in cognitive enhancement
- 5-HT6 and 5-HT7 – involved in cognition and sleep
Termination: MAO, neuronal uptake
Function / disorders:
- Mood (anxiety/depression)
- Psychosis (5-HT antagonism antipsychotic)
- Sleep/wake (5-HT linked to sleep, 5-HT2 antagonists inhibit REM sleep)
- Feeding behaviour (5HT2A antagonist increase appetite, weight gain; antidepressants decrease appetite
- Pain, migraine (5-HT inhibits pain pathway, synergistic with opioids)
- Vomiting
Define autoreceptors. List the transmitter and the corresponding autoreceptor.
Autoreceptors: inhibit cell firing and transmitter release at the terminal regions.
5-HT: 5-HT1A (cell body) and 5-HT1D (post-synaptically)
Dopamine: D2 or D3
Noradrenaline: α2
Define reuptake transporters. List some transporters and their reuptake sites.
Transporters usually take the neurotransmitter back up into the pre-synaptic terminal. The transporters and their reuptake sites:
Dopamine - DAT (on dopamine neuron)
5-HT - SERT (on H-HT neurons)
NA - NET (on noradrenaline neurons)
Glutamate - EAAT1 (mostly on astrocytes)
Dopamine - vMAT2 (into vesicles)
