Neurotransmitters lll: Monoamines (neuro) Flashcards
The diffuse modulatory systems 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
- serotonergic raphe nuclei
- dopaminergic substantia nigra and ventral tegmental area
- cholinergic basal forebrain and brain stem complexes
- can be point to point communication (fast, restricted) or diffuse modulatory systems (slower, widespread)
- behavioural effects: mood, memory, reward, movement, motivation
Examples of metabotropic receptors
Stimulates AC - Dopamine D1, noradrenaline beta,
Stimulates PLC - 5-HT2, noradrenaline alpha1,
Inhibits AC - 5-HT1, Dopamine D2, noradrenaline alpha2,
(AC=adenylyl cyclase, PLC=phosplipase C)
Effects of Noradrenaline
- arousal
- wakefullness
- exploration and mood (low NA in depressed)
- blood pressure regulation (antihypertensive eg clonidine alpha2)
- addiction/gambling
Synthesis of catecholamines
- tyrosine -> DOPA, using tyrosine hydroxylase
- DOPA -> dopamine, using DOPA decarboxylase
- dopamine -> noradrenaline, using dopamine beta-hydroxylase
- noradrenaline -> adrenaline, using phenylethanolamine N-methyltransferase
Regulation of NA
- post-synaptic - carry on the message
- pre-synaptic (autoreceptors) - usually inhibitory, negative feedback mechanism
- reserpine - depletes NA stores by inhibiting vesicular uptake
- amphetamine (indirect symphathomimetic) - enters vesicles displacing NA into cytoplasm, increased NA leakage out of neuron
- cocaine - blocks NA reuptake
Function of noradrenaline
- NA alpha 1 -> phospholipase C -> PIP, IP3, DAG, Ca2+ -> smooth muscle contraction, glycogenolysis
- NA alpha 2 -> adenyl cyclase -> Ca2+ -> inhibition of NA release
- NA alpha 2 -> adenyl cyclase -> ATP, cAMP -> smooth muscle contraction
- NA beta -> ATP, cAMP -> contraction of cardiac muscle, smooth muscle relaxation, glycogenolysis
Noradrenaline (NA)
- main action inhibitory (beta), also excitatory (alpha/beta)
- termination: neuronal uptake and MAO
- main cell body in locus coeruleus (NAergic neurons active when awake, amphetamine increases alertness and exploratory behaviour)
- high density in brainstem, hypothalamus and medial temporal lobe
Dopamine (DA)
- involved in: movement, reward, inhibition of prolactin release, memory consolidation
- parkinsons disease, schizophrenia, addiction, emesis, ADHD
- inhibits central neurons (K+ channels)
- D1 (D1, D5) and D2 (D2, D3, D4) receptors
- D1 and D2 receptors in striatum, limbic system, thalamus and hypothalamus
- D3 receptors in limbic system, not striatum
- D4 receptors in cortex and limbic system
- termination: MAO, neuronal uptake
- main pathways: substantia nigra to basal ganglia (parkinsons disease), midbrain to limbic cortex (schizophrenia)
- functions/disorders: movement, addiction, stereotypy, hormone release and vomiting
Seratonin (5-HT)
- 5-HT receptors (14 subtypes) all G-protein coupled except 5-HT3:
• 5-HT1 inhibitory, limbic system – mood, migraine
• 5-HT2 (5-HT2A), excitatory, hallucinogenic, limbic system & cortex
• 5-HT3 excitatory, medulla – vomiting
• 5-HT4 presynaptic facilitation (ACh) – cognitive enhancement
• 5-HT6 and 5-HT7 – novel targets, cognition, sleep
– Termination – MAO, neuronal uptake
– Function / disorders
• 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 apetite
• Pain, migraine (5-HT inhibits pain pathway, synergistic with opioids)
• Vomiting
Seratonin (5-HT) receptor subtypes
subtype -> signal transduction -> localisation -> function
- 5-HT(1A) -> inhibition of AC -> hippocampus -> autoreceptor
- 5-HT(1B) -> inhibition of AC -> substantia nigra -> auto receptor
- 5-HT(1D) -> inhibition of AC -> cranial blood vessels -> vasoconstriction
- 5-HT(1E) -> inhibition of AC -> cortex
- 5-HT(1F) -> inhibition of AC -> brain, periphery
- 5-HT(2A) -> activation of PLC -> platelet, smooth muscle, cerebral cortex -> platelet aggregation, contraction, neuronal excitation
- 5-HT(2B) -> activation of PLC -> stomach fundus -> contraction
- 5-HT(2C) -> activation of PLC -> choroid plexus
- 5-HT(3) -> ion channel -> PNS -> neuronal excitation
- 5-HT(4) -> activation of AC -> GI tract, hippocampus, neuronal excitation
- 5-HT(5A) -> inhibition of AC -> hippocampus -> unknown
- 5-HT(5B) -> unknown
- 5-HT(6) -> activation of AC -> striatum -> unknown
- 5-HT(7) -> activation of AC -> hypothalamus, intestine -> unknown
Autoreceptors
- inhibit cell firing and transmitter release at the terminal regions
- transmitter -> cell body -> terminal
- 5-HT -> 5-HT(1A) -> 5-HT(1D) (5-HT(1B))
- dopamine -> D2 or D3 -> D2 or D3
- noradrenaline -> alpha2 -> alpha2
- receptors can only be found post-synaptically
Transporters
- transmitter - reuptake site
- dopamine - DAT (on dopamine neurons)
- 5-HT - SERT (on 5-HT neurons)
- NA - NET (on NA neurons)
- glutamate - EAAT1 (mostly on astrocytes)
- dopamine - vMAT2 (into vesicles)
Monoamine transporters
- 12 TMDs
- both ends intracellular
- pump monamines in neuron
- DA, NA, 5HT transporters
Acetylcholine (ACh)
– Abundant in basal forebrain, hippocampus
and striatum
– Termination – acetylcholinesterase (AChE)
– ACh excitatory neurotransmitter
• Nicotinic (ionotropic / fast)
• Muscarinic (G-protein coupled / slow)
– M1 excitatory (decreased 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
– Functions:
• 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
Other transmitter/ modulator substances
• Histamine
– H1 (arousal) and H3 (presynaptic / constitutively active)
– Functions: sleep / wake, vomiting
• Purines
– Adenosine (A1, A2A/2B) and ATP (P2X)
– Functions: sleep, pain, neuroprotection, addiction, seizures, ischaemia, anticonvulsant
• Neuropeptides
– Opioid peptides (mu, delta, kappa)
– Tachykinins (Substance P, neurokinin A & neurokinin B)
• NK1 (Substance P), NK2 (neurokinin A), NK3 (neurokinin B)
– Functions: pain
• Lipid mediators
-Products of conversion of eicosanoids to
endocanabinoids
-act on CB1 (inhibit GABA, glutamate release)
- involved in vomiting (CB1 agonist block it, MS, pain,
anxiety, weight loss/rimonabant CB1 antogonist)
• Melatonin
-MT1, MT2 receptors
- involved in sleep regulation, circadian rhythmicity,
agonists for jet lag and insomnia
