Neurotransmitter systems III: Monoamines Flashcards
What are the central nervous systems which controls behaviour?
Autonomic Nervous System
Hypothalamic-Pituitary Neurohormones
Diffuse Monoamine Modulatory System
What are the Diffuse monoamine modulatory systems?
4 monoamine modulatory systems:
- Noradrenaline: Noradrenergic Locus Coeruleus
- Serotonin (5-HT): Serotonergic Raphe Nuclei
- Dopamine: Dopaminergic Substantia Nigra and Ventral Tegmental Area
- Acetylcholine: Cholinergic Basal Forebrain and Brain Stem Complexes
What do the 4 diffuse modulatory systems have in common?
Ø Released from neurones which arise from brain stem
Ø Neurones project from central core where cell bodies are located to many different regions of the brain where the neurotransmitter gets released
Ø One neurone influences many others
Ø Synapses release transmitter molecules into extracellular fluid
What type of receptors are monoamine receptors?
G-protein coupled receptors
Describe the Noradrenergic modulatory pathway.
noradrenergic neurones project from central core called Locus Coerulus to different brain regions (e.g. cortex, amygdala, hypothalamus, cerebellum, spinal cord)
Describe the Action of noradrenaline at synaptic bouton.
1) Noradrenaline gets into synaptic vesicles
2) Noradrenaline released upon stimulation by action potential
3) Noradrenaline binds to post-synaptic noradrenergic receptors (G-coupled) to carry on the message
4) Noradrenaline also activates pre-synaptic auto-receptors (a2 receptors) which act via a negative feedback mechanism and inhibit the release of noradrenaline
What are the Effects of increased noradrenaline?
- Cardiovascular effects (tachycardia, high blood pressure)
- Addictive-like behaviour (gambling)
- Hyperarousal
What are the Effects of decreased noradrenaline?
- Depression
- Parkinson’s disease
Describe process of Noradrenaline Regulation: Reuptake mechanism.
noradrenaline transporters on pre-synaptic membrane reuptake excess noradrenaline from synapse
once inside the synapse, noradrenaline is metabolised and broken down by monoamine oxidase (MAO), terminating its action
Describe the structure of Noradrenaline receptors.
G-protein coupled receptors:
- Alpha 1 (Gq)
- Alpha 2 (Gi)- autoreceptors
- Beta (Gs)
What are the Drugs that increase noradrenaline levels?
· Reserpine: depletes noradrenaline stores by inhibiting vesicular uptake
· Amphetamine (indirect sympathomimetic): enters vesicles displacing NA into cytoplasm, increasing NA leakage out of neurone into synapse
· Cocaine: blocks NA reuptake
Describe the Action of drugs in depression treatment.
Drugs to increase noradrenaline:
- block monoamine oxidase (MOA)
- block noradrenaline transporters
- block serotonin transporters
What are the Dopaminergic Modulatory Pathways?
Nigrostriatal Pathway
Mesolimbic Pathway
Mesocortical Pathway
Tubero-hypophyseal Pathway
Describe the Nigrostriatal pathway.
dopaminergic neurones project from substantia nigra (SN), where cell bodies are found, to the striatum where dopamine is released to induce MOVEMENT
*degeneration of these neurones decreasing dopmaine levels in the striatum, causing Parkinson’s disease (suppressed movement)
Describe the Mesolimbic pathway.
dopaminergic neurones project from ventral tegmental area (VTA) to amygdala, hippocampus and nuclear accumbens, where dopamine is released to induce REWARD (e.g. food, sex)
- Abused drugs over-stimulate this pathway, increasing pleasure/reward, leading to addiction
- Hyperactivity of this system causes psychotic episodes in schizophrenics
Describe the Mesocortical pathway.
dopaminergic neurones project from ventral tegmental area (VTA) to the cortex, where dopamine is released
Describe the Tubero-hypophyseal pathway..
dopaminergic neurones project from hyopthalamus to the portal capillary system in the median eminence where dopamine is released, acting as a neurohormone by binding to its receptors in the anterior pituitary and inhibiting release of prolactin
*prolactin responsible for mammary gland enlargement and milk production
Dopamine is involved in…
addiction (gambling) emesis ADHD Schizophrenia (hyperactivity of mesolimbic pathway) Parkinson's disease (lack of dopamine)
Describe the porcess of Synthesis of Catecholamines.
1) Tyrosine is converted to DOPA by tyrosine hydroxylase
2) DOPA is converted to dopamine via DOPA decarboxylase
3) Dopamine is then metabolised to noradrenaline via Dopamine-β hydroxylase
4) Noradrenaline can then further be metabolised to adrenaline
What determines whether a neurone is dopaminergic or noradrenergic?
The presence of Dopamine-β hydroxylase in excess makes neurones dopaminergic
Neurones without this enzyme are noradrenergic
What are the Effects of increased dopamine?
addiction
psychosis
What are the Effects of decreased dopamine?
Parkinson’s disease
Describe the process of Dopamine Regulation: Reuptake Mechanism.
dopamine transporters on pre-synaptic membrane reuptake excess dopamine from synapse
once inside the neurone, dopamine is metabolised and broken down by monoamine oxidase b (MOAb), terminating its action
Describe the Actions of drugs in Parkinson’s treatment.
Drugs to increase dopamine:
- block monoamine oxidase b (MOAb)
- block dopamine reuptake transporters
Describe the structure of Dopamine Receptors.
D1-like (Gs coupled)
>D1 & D5
D2-like (Gi coupled)
>D2, D3, D4
Where are dopamine receptors are found?
- Post-synaptic D1 and D2 receptors
- Pre-synaptic D2 or D3 auto-receptors
· D1 and D2 receptors are found in the striatum, limbic system, thalamus and hypothalamus
· D3 receptors are found in the limbic system
· D4 receptors are found in the cortex and limbic system
Dopamine is associated with…
movement addiction stereotypy hormone release vomiting
Describe the Serotonergic pathway.
serotonergic neurones project from central core called Raphe nucleus to regions such as cerebellum, cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, spinal cord, where serotonin is released
What is the Effect of serotonin?
Different effects in different brain regions:
· Binds to receptors in cortex and causes heightened perceptions
· Binds to receptors in hypothalamus and reduces appetite
· Binds to receptors in amygdala and causes elevated mood
Other effects:
- sleep/wake cycle
- vomiting
- psychosis
- reducing pain, migraine
Describe the Synthesis of Serotonin.
Precursor of serotonin is the amino acid tryptophan:
1) Tryptophan is metabolised by tryptophan hydroxylase to 5-hydroxytryptophan
2) 5-hydroxytryptophan is metabolised by L-Aromatic acid decarboxylase to serotonin (5-HT)
3) 5-HT can be metabolised further by monoamine oxidase to 5-hydroxyindoleacetylaldehyde
4) This metabolite can be further metabolised to 5-HIAA (5-hydroxyindoleacetic acid) by aldehyde dehydrogenase
What are the Effects of low serotonin?
depression
Describe the process of Serotonin Regulation: Reuptake Mechanism.
Serotonin transporters on pre-synaptic membranes reuptake excess serotonin from the synapse
once inside the neurone, the serotonin is metabolised and broken down by monoamine oxidase (MOA), terminating its action
Describe the structure of Serotonin receptors.
Post-synaptic and pre-synaptic 5-HT receptors (14 subtypes):
-all G-protein coupled receptors apart from one (5-HT3) which is an ion channel
Describe the structure of Monoamine Transporters.
These take the neurotransmitter back up into the pre-synaptic terminal.
- 12 transmembrane domains
- both ends intracellular
- pump monoamines (NA, DA, 5HT) in neurone
Describe the Cholinergic Modulatory Pathways.
Septohippocampal Pathway
-cholinergic neurones project from the septum to the hippocampus, where acetylcholine is released
Nucleus Basalis
-cholinergic neurones project from the nucleus basalis to the cortex where acetylcholine is released
Striatal Interneurons
-small cholinergic neurones called striatal interneurons found within the striatum release acetylcholine.
Substantia Nigra
-cholinergic neurones project from the substantia nigra to the thalamus, where acetylcholine is released.
What are cholinergic neurones involved in?
cognition
learning
memory
What does the degeneration of cholinergic neurones cause?
dementia and Alzheimer’s, causing for cognitive symptoms such as memory loss
Describe the structure of Acetylcholine receptors.
Muscarinic (G-protein)
- M1,3,5 excitatory
- M2&4 inhibitory
Nicotinic (ligand-gated ion channels)
Describe the process of Acetylcholine Regulation.
Acetylcholinesterase breaks down acetylcholine to choline and acetate, terminating its activity
Choline then is re-uptaken into pre-synaptic neurone to be recycled
Describe the Action of drugs to treat dementia/Alzheimer’s.
Drugs increase acetylcholine levels:
-inhibit acetylcholinesterase enzyme
Acetylcholine is involved in…
arousal epilepsy (mutations of nAChR genes) learning and memory motor control, pain, addiction schizophrenia ADHD depression anxiety Alzheimer's
Give some Other transmitters/modulator substances.
Histamine Purines Neuropeptides Lipid Mediators Melatonin
What are opioid peptides (neuropeptides) derived from?
a bigger protein e.g. β endorphin is derived from pro-opiomelanocortin (POMC)
once the peptide is released from the neurone it acts on receptors
How are neuropeptides synthesized?
- Encoded by DNA
- Gene modified in rER and Golgi
- Proteolytic cleavage in Golgi breaks down big proteins into many different peptides e.g. β endorphin, which are stored in synaptic vesicles for release upon stimulation
Which drugs interact with the diffuse system?
Amphetamine (psychostimulant)
Cocaine (central stimulant)
What are Amphetamine-like drugs?
methylphenidate & MDMA:
- release cytosolic monoamines
- prolonged use causes degeneration of nerves and death (neurotoxic)
Pharmacological effects:
- increased alertness and locomotor stimulation (increased aggression)
- stereotyped behaviour
- anorexia
- less physical and mental fatigue
- increased blood pressure
- decrease gastric motility
- improved confidence/lack of tiredness
Give some Therapeutic uses of amphetamine-like drugs.
Therapeutic uses:
- ADHD (methylphenidate)
- Appetite suppressants
- Narcolepsy
What is the effect of Cocaine?
blocks catecholamine reuptake, increasing dopamine at synapse
Pharmacological effects:
- euphoria
- locomotor stimulation
- fewer stereotyped behaviour than amphetamine
- heightened pleasure
- lower tendency for delusions, hallucinations and paranoia
