Neurotransmitters Systems III: Monoamines Flashcards
What CNS Systems are in place to control behaviour?
- Autonomic nervous system
- Hypothalamic-pituitary neurohormones
- Diffuse monoamine system
What are the roles of the CNS?
> the sympathetic nervous system is body activation
parasympathetic nervous system is relaxation and
recovery
What is the significance of monoamines?
The diffuse modulatory systems of the brain
What are the four main monoamine systems?
- Noradrenergic Locus Coeruleus
- Serotonergic Raphe Nuclei
- Dopaminergic Substantia Nigra and Ventral tegmental
Area - Cholinergic Basal Forebrain and Brain Stem Complexes
Describe the fast point-to-point signalling neurotransmission across the CNS
- Neurotransmitters producing excitatory or inhibitory
potentials - Ligand-gated ion channels
- Glutamate, GABA, ACh
Describe the slow transmission that occurs in the CNS
- Neurotransmitters and neuromodulators
- G-protein coupled receptors
- Monoamines, peptides, ACh
Name the metabotropic receptors of the CNS
5-HT1 Inhibits AC 5-HT2 Stimulates PLC Dopamine D1 Stimulates AC Dopamine D2 Inhibits AC Noradrenaline β Stimulates AC Noradrenaline α1 Stimulates PLC Noradrenaline α2 Inhibits AC
- AC = adenylyl cyclase
- *PLC = phospholipase C
What are the functions of noradrenaline?
- Arousal, wakefullness, exploration and mood (low NA in
depressed patients) - Blood pressure regulation, (antihypertensive e.g.
clonidine α2) - (Addiction/gambling)
Describe the effects of the drug reserpine on the noradrenergic receptors
Reserpine depletes NA stores by inhibiting vesicular uptake
Describe the effects of amphetamine on noradrenergic receptors
Amphetamine (indirect sympathomimetic)-enters vesicles displacing NA into cytoplasm, increases NA leakage out of neuron
Describe how cocaine effects noradrenaline receptors
Cocaine-blocks NA re-uptake
What are the main actions of noradrenaline receptors?
Main action inhibitory (β) Also excitatory (⍺ / β)
How are noradrenergic synaptic transmission terminated?
Termination of noradrenaline occurs via neuronal uptake and monoamine oxidase
Where are noradrenergic receptors mainly located?
Main cell body in locus coeruleus
- NAergic neurons active when ‘awake’
- Amphetamine - ↑ alertness and exploratory behaviour
High density in brainstem, hypothalamus & medial temporal lobe
What are the 2 receptor locations and their functions?
Post-synaptic
- Carry on the message
Pre-synaptic (autoreceptors)
- Usually inhibitory
- Negative feedback mechanism
What is the function of autoreceptors?
Inhibit cell firing and transmitter release at the terminal region
Where are autoreceptors found?
Presynaptically
Note that these receptors can also be found post-synaptically
– but they are not autoreceptors if they are post-synaptic
What is the role of neurotransmitter transporters?
Usually take the neurotransmitter back up into the presynaptic terminal
Describe the structure of monoamine transporters
12 Transmembrane Domains
Both ends intracellular
Pump monoamines in neuron
Function: DA, NA, 5HT transporters back into neurones
What is the role of dopamine?
Inhibits central neurons (K+ channels)
Binds to D1 (D1 & D5) and D2 (D2, D3, D4) receptors
How is dopamine acitvity regulated?
Termination by Monoamine Oxidase B, neuronal uptake
What are the physiological functions of dopamine?
Functions / disorders
- Movement
- addiction
- stereotypy
- hormone release
- vomiting
What are the main brain pathways dopamine works across?
Tubero-hypophyseal pathway
Main pathways: Substantia nigra to basal ganglia (Parkinson’s disease)
Midbrain to limbic cortex (schizophrenia)
Explain how dopamine exerts its effects?
Dopamine released in the hypothalamus in the portal capillary system connecting the hypothalamus to the pituitary gland.
When bound to dopamine receptors in the pituitary, dopamine inhibits the release of Prolactin (PL)
Which pathologies is dopamine involved in?
Involved in:
PD, Schizophrenia, Addiction, Emesis and ADHD
Too much dopamine in the synaptic cleft leads to addiction
Outline the synthesis of catecholamines
Tyrosine produced in the neuron and converted to DOPA by tyrosine hydroxylase and then to dopamine by DOPA decarboxylase
Dopamine gets metabolised to noradrenaline by Dopamine-𝜷-hydroxylase
Noradrenaline can get metabolised further to Adrenaline
How do neurons decide to release (nor)adrenaline or dopamine?
Neurons with Dopamine-𝜷-hydroxylase in excess release noradrenaline, those without are dopaminergic
Where is dopamine produced?
Produced from precursor L-DOPA at the dopaminergic end terminus
How is dopamine transported ready for release?
When the neurone is activated dopamine is released in the synaptic milia
What are the 2 types of dopamine receptors and their location?
D1 are postsynaptic receptors
D2 autoreceptors are pre and postsynaptic
Explain the effects of dopamine binding to its D2 receptors
Dopamine binds to its receptors
When bound to its autoreceptor (D2) it inhibits the release of dopamine → regulatory control
How is dopamine release mediated?
Control of dopamine levels in the synaptic cleft are vital for normal physiological functions of the brain
This is done in the same way noradrenaline is mediated
Excess dopamine is taken into the neuron via dopamine transporter and broken down into metabolites by monoamine oxidase B
How do Parkinson’s disease targeting drugs alter dopamine effects?
Drugs targeting Parkinson’s disease inhibit monoamine oxidase B to increase dopamine
What are the 2 types of dopamine receptors?
There are 2 types of dopamine receptors:
D1-like receptors (D1 & D5)
D2-like receptors (D2,3 & 4)
Where are the different dopamine receptors found?
D1 and D2 receptors in striatum, limbic system, thalamus & hypothalamus
D3 receptors in limbic system NOT striatum
D4 receptors in cortex & limbic system
Describe the structure of dopamine receptors
These are GPCRS with 7 transmembrane domains. Each is coupled to different G proteins
Which G protein are D1 receptors coupled to?
D1 receptors activate the Gs pathway stimulating AC → cAMP increasing PKA and induces phosphorylation for secondary messenger signalling
Outline the D2 receptors G protein coupled signalling
D2 are coupled to the Gi protein. This causes the inhibition of AC → cAMP (inhibitory)
What is serotonin?
A monoamine released from serotonergic neurons projecting from the Raphe nucleus
What is the role of serotonergic neurons?
Serotonergic neurons project to various brain regions including the cerebellum, cortex, striatum, hippocampus and spinal cord
What effect does serotonin have in the brain cortex?
When serotonin is released into the brain cortex (top) it binds to its receptors to induce heightened perceptions - cognitive effect
What effect does serotonin produce in the hypothalamus?
In the hypothalamus serotonin reduces appetite when bound to its receptors
Describe the effects of serotonin in the amygdala
When released and bound to its receptors in the amygdala, serotonin elevates the mood - antidepressants commonly increase serotonin levels
What other physiological functions is serotonin heavily involved in?
Serotonin is also involved in sleep, vomiting (antiemetic effect)
Outline the synthesis of serotonin
Tryptophan (a.a) is the precursor molecule of serotonin
It is metabolised by tryptophan hydroxylase into 5-hydroxytryptophan which is metabolised further by L-aromatic acid decarboxylase into serotonin 5-HT
5-HT can be further metabolised by monoamine oxidase into 5-hydroxy acetaldehyde and then aldehyde dehydrogenase converts it into 5-hydroxyindoleacetic acid (5-HIAA)
How is serotonin transported to the synaptic cleft?
Serotonin carried in vesicles and released across synaptic cleft when the neurone is activated
There are ~10 subtypes of 5-HT receptors
Which serotonin receptor mediates the release of serotonin release?
5HT₁D is an autoreceptor (presynaptic) inhibiting serotonin release
How do 5HT₁D receptors regulate serotonin release?
Excess serotonin is transported back into the neuron via serotonin transporter where it is metabolised and broken down via monoamine oxidase
As depression is associated with decreased serotonin levels, what is the required mechanism of antidepressants?
Drug needs to increase serotonin levels -
block transporter or inhibit monoamine oxidase
Describe the serotonin receptors
5-HT receptors (14 subtypes) all G-protein coupled except 5-HT3
Outline the role and location of the different serotonin receptors
5-HT1 inhibitory, limbic system – mood, migraine
5-HT2 (5-HT2A), excitatory, limbic system & cortex
5-HT3 excitatory, medulla – vomiting
5-HT4 presynaptic facilitation (ACh) – cognitive
enhancement
5-HT6 and 5-HT7 – novel targets, cognition, sleep
How is serotonin release stopped?
Termination – MAO, neuronal uptake
What are the functions/disorders associated with serotonin?
Mood (anxiety/depression)
Psychosis (5HT antagonism antipsychotic)
Sleep / wake (5-HT linked to sleep, 5-HT2 antagonists
inhibit REM sleep)
Feeding behaviour (5HT2A antagonist increase apetite, weight gain; antidepressants decrease appetite
Pain, migraine (5-HT inhibits pain pathway, synergistic with opioids)
Vomiting
How does LSD effect serotonin levels?
LSD: Hallucinogenic drug - 5HT antagonism
Heightened perception, Stimulation, Reduced appetite, Elevated mood
Where is Ach most commonly found?
Abundant in basal forebrain, hippocampus and striatum regions of the brain.
Cholinergic neurons specifically release Ach
What is the major cholinergic pathway in the brain?
There are various cholinergic pathways in the brain
One of the main ones project from the nucleus basalis onto the cortex where ACh is released
What are the other brain pathways involved in cholinergic signalling?
Smaller interneurons found in the striatum also release Ach
Other cholinergic neurones release Ach projecting from the septum (emotional behaviour and stress regulation) to the hippocampus (learning & memory)
Cholinergic neurons also project from the substantia nigra to the thalamus
These neurons play a vital cognitive role and are significant in memory and learning
How is ACh signalling terminated?
Termination via acetylcholinesterase (AChE) hydrolyses Ach
How is Ach produced?
ACh excitatory neurotransmitter formed from a choline and an acetyl group
It is transported in cholinergic vesicles and released into the synaptic cleft
What are the 2 types of receptors Ach binds to?
Nicotinic (ionotropic / fast)
Muscarinic (G-protein coupled / slow)
Outline the 4 muscarinic Ach receptors and their roles
M1 excitatory (↓ M1 receptors in dementia)
M2 presynaptic inhibition (inhibit Ach release)
M3 excitatory glandular/smooth muscle effects (side
effects)
M4 and M5 function not well known
What are the functions of Ach?
Arousal
Epilepsy (mutations of nAChR genes)
Learning and memory (KO mice)
Motor control (M receptors inhibit DA), pain, addiction
Involved in schizophrenia, ADHD, depression, anxiety, Alzheimers
What is the role and action of histamine?
Histamine
- H1 (arousal) and H3 (presynaptic / constitutively active)
Functions: sleep / wake, vomiting
What are the effects of Purine modulatory substances?
Purines
- Adenosine (A1, A2A/2B) and ATP (P2X)
Functions: sleep, pain, neuroprotection, addiction, seizures, ischaemia, anticonvulsant
What are the effects of neuropeptides?
Neuropeptides:
- Opioid peptides
μ, δ, κ
- Tachykinins (Substance P, neurokinin A & neurokinin B)
NK1 (Substance P), NK2 (neurokinin A), NK3 (neurokinin
B)
Functions: pain
Why are opioid peptides associated with addiction?
Fast synaptic transmission – neurotransmitters producing rapid excitatory or inhibitory potentials
Where are opioid peptides released from?
Neuromodulators released from glial cells (particularly astrocytes).
Glial cells known as inexcitable neurons.
Glutamate acts via ligand gated receptors and also through G protein receptors
How does opioid neurotransmission differ from the CNS?
Although transmission principles are the same as in the periphery CNS is made more complex because of the interconnections between neurons and also the fact that other cells e.g. glial cells also release mediators.
Also longer term changes affect the balance between these systems
Many subtypes: improves selectivity CNS complex, connectivity
Describe the synthesis and release of neuropeptides
Genes give rise to POMC (opioids) mRNA which is packaged to undergo modifications via the golgi apparatus.
POMC undergoes proteolytic cleavage into smaller / modified proteins e.g. beta-endorphins etc. which are transported into vesicles to be released across the synaptic cleft
Describe the effects of lipid mediators in the body
Lipid mediators
-Products of conversion of eicosanoids to
endocannabinoids
-act on CB1 (inhibit GABA, glutamate release)
-involved in vomiting (CB1 agonist block it, MS, pain,
anxiety, weight loss/rimonabant CB1 antagonist)
Describe the effects of melatonin
Melatonin
-MT1, MT2 receptors
- involved in sleep regulation, circadian rhythmicity,
agonists for jet lag and insomnia
What are the pharamacological effects of psychostimulants like amphetamine?
↑ alertness and locomotor stimulation (↑ aggression)
Euphoria / excitement
Stereotyped behaviour
Anorexia
↓ physical and mental fatigue (improves monotonous tasks)
Peripheral sympathomimetic actions (↑ blood pressure & ↓ gastric motility)
Confidence improves/lack of tiredness
What are the therapeutic uses of psychostimulants?
ADHD (methylphenidate), appetite suppressants, narcolepsy
Why are psychostimulants involved in addictive disroders?
Amphetamine-like drugs (methylphenidate & MDMA) release cytosolic monoamines (DA)
Prolonged use neurotoxic
Degeneration of amine-containing nerve terminals, cell death
Explain the effects of central stimulants like cocaine
Blocks catecholamine reuptake
↑ DA, stimulant effect
What are the pharmacological effects of cocaine?
Euphoria
Locomotor stimulation
Fewer stereotyped behaviours than amphetamine
Heightened pleasure
Lower tendency for delusions, hallucinations and paranoia
Explain the pharmacokinetics of cocaine use
HCl salt, inhaled and i.v. administration
- Nasal inhalation less intense, leads to necrosis of nasal
mucosa
Freebase form (‘crack’), smoked, as intense as i.v route
