Neurotramission in the CNS

  • Hierarchical systems
    • clear anatomic distribution
    • large myelinated rapidly conducting fibres
    • control major sensory & motor functions
    • Major excitatory neurotransmitter
      • aspartate
      • glutamate
    • inhibitory neurotransmitters
      • GABA
      • Glycine
  • Diffuses systems
    • broadly distributed
    • divergent
      • axons branched and synapses with many cells
    • act diffusely far away from site of release
    • produce slow and long lasting & diverse effects on NT synthesis, effect on receptors & ionic conductance
    • Examples
      • NA
      • Adrenaline
      • Dopamine
      • serotonin
      • peptides

Synaptic transmission

  • Chemical mediators involved in synaptic transmission in CNS
    • Neurotransmitter
      • substance contained in a neuron, released by presynaptic terminals to produce excitatory/inhibitory responses in postsynaptic neurons
      • eg
        • acetylcholine
        • serotonin
        • noradrenaline
        • adrenaline
        • dopamine
        • GABA
        • glutamate
    • Neuromodulator
      • substance that is released by neurons & astrocytes – produces slower pre/postsynaptic responses
      • eg
        • CO2
        • ammonia
        • nitric oxide
    • Neurotropic factor
      • substance released by non-neuronal cells
        • act on tyrosine-kinase-linked receptors
        • regulate gene expression, control neuronal growth, & phenotypic characteristics
      • eg
        • growth factors
        • cytokines
        • chemokines

Neurotransmitter classification

  • Classical, non-peptide NT
    • Monoamines
      • NA. A
      • Dopamine
      • 5-HT
      • Histamine
    • Acetylcholine
    • Amino acids
      • Inhibitory amino acids (IAA)
        • GABA
        • Glycine
      • Excitatory amino acids (EAA)
        • glutamate
        • aspartate
  • Peptide NT
    • Substance P
    • Opioid peptides
    • Others
      • Vasopressin
      • Oxytocin
      • Tachykinins
      • CCK
      • NPY
      • VIP
  • Others
    • Nitric oxide
    • Adenosine
    • Cannabinoid
    • Purines
    • Arachidonic acid

Synthesis, storage, release & fate of neurotransmitters

image

*Revise from Dr Achike’s foundation 2 notes

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Neurotransmitter – Criteria for acceptance

  1. Present in presynaptic terminal
  2. Synthesised in the neuron
    • Precursors
      • Tryptophan (for 5-HT)
      • Choline (for ACh)
    • Presence of rate-limiting enzymatic step
      • Enzymes usually in soma and nerve terminals
  3. Stored in synaptic vesicles in nerve terminals
  4. Released from nerve terminal
    • following an action potential which causes calcium influx
  5. Same substance applied exogenously in small concentrations produce same action
    • same receptors
  6. Specific mechanism exists terminating its action
    • enzymatic breakdown
      • ACh
    • Specific uptake using transporter protein
      • NA
      • dopamine
      • 5-HT
    • Once in axoplasm, NT is subjected to enzymatic metabolism

Signalling mechanism for drug effects

image

  1. Intracellular receptor
  2. Transmembrane Enzyme Receptor
    • Receptor & Effector on same molecule
  3. Transmembrane Enzyme Receptor
    • Effector on separate molecule from Receptor
  4. Transmembrane ion channels
    • Ionotropic
  5. G-protein-coupled receptors
    • Act on separate effector molecule
    • Metabotropic

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NEUROTRANSMITTERS

Noradrenaline

image

  • Clusters of cell bodies
    • in the locus coeruleus (LC) in the brain stem
    • Axons project to cortex, hippocampus, cerebellum
      • via the medial forebrain bundle
    • Other NA neurons lying close to the LC in the pons & medulla
    • Nerve terminals release NA diffusely
  • Actions
    • reward system
    • mood
    • arousal, attention, learning, memory
    • neuroendocrine regulation
    • blood pressure regulation
  • Actions in CNS
    • Generally inhibitory
      • Sometimes excitatory
    • In LC
      • Silent during sleep, increase in activity during arousal/unfamiliar wake-up stimuli
        • depending on modd, depressed patients are unresponsive
  • Effect of CNS drugs on NA
    • CNS stimulants increase wakefulness and alertness
      • amphetamine releases catecholamines in brain
    • NA Involved in BP regulation
      • Clonidine (in the nucleus tractus solitarus) reduce sympathetic outflow from the vasomotor center in the medulla oblongata leading to fall in BP
  • Psychotropic drugs
    • Excitation (related to biogenic amines)
      • Tricyclic antidepressants, coccaine
        • block reuptake
      • amphetamines
        • block uptake, increase release
      • monoamine oxid
        ase inhibitors
        • block metabolism
    • Sedation/depression
      • reserpine
        • depletes stores
      • clonidine, alpha-methyldopa
        • reduce sympathetic outflow

Adrenaline

  • Small group of adrenergic neurons with cells bodies
    • lying more ventrally to the NA neurons in the brain stem
    • their axons run in the pons, medulla and hypothalamus
    • important in control of CVS
  • Descending fibres which run to the lateral horn of the spinal cord
    • increase sympathetic discharge in the periphery

Dopamine

  • Cell bodies at all levels.
    • Short, median and long axons
  • Pathways
    • Mesolimbic mesocortical pathway
      • reward, motivation, hyperactivity
      • increase – schizophrenia
      • actions of antipsychotic drugs
    • Nigrostriatal pathway
      • motor control
      • decrease – Parkinson’s
      • actions of drugs for Parkinson’s disease
    • Tuberoinfundibular/Tuberohypophyseal pathway
      • endocrine control
      • side effects of antipsychotic drugs
  • Receptor families (G-protein coupled receptors)
    • D1 family
      • subtypes D1, D5
    • D2 family
      • subtypes D2, D3, D4
        • Antipsychotic drugs block D2 receptors
        • Clozapine act on D4 receptors
  • Important in
    • Schizophrenia
    • Parkinson’s disease
    • ADHD
    • Drug dependence & certain endocrine disorders
  • Inhibit
    • release of prolactin – enchance release of growth hormone
  • High concentration of dopamine found in
    • basal ganglia
    • limbic system
    • hypothalamus
  • Metabolised by
    • MAO –> DOPAC
    • COMT and MAO –> HVA
  • Reuptake of Dopamine blocked by (block amine transporter)
    • cocaine
    • amphetamine
      • block NA at presynaptic terminal of neuron
  • Also stimulates
    • chemoreceptor trigger zone (CTZ)
      • -> nausea, vomiting

5-HT Systems/Serotonin

  • Cell bodies in
    • raphe/midline region of the pons & upper brain stem
    • axons project diffusely via midbrain bundle to the cortex, limbic system, hypothalamus
    • cells at the caudal part of the brain stem project to the cerebellum, medulla and spinal cord
  • Functions
    • feeding behaviour
      • body weight regulation
    • hallucinations
    • sleep, wakefullness
    • mood
    • sensory impulse transmission (nociception)
    • body temperature, blood pressure, sexual functions
    • vomiting
  • All receptor subtypes: metabotropic
    • except 5HT3-R: ionotropic
  • Receptors in CNS
    • 5HT1A-R
      • limit the firing of cells in raphe & limbic system
      • anxiolytics
      • antidepressants
    • 5HT1B-R and 5HT1D-R
      • presynaptic inhibitory receptors in basal ganglia
      • 5HT1B-R and 5HT2C-R agonists
        • decrease appetite
      • 5HT-1D-R agonists (sumatriptan)
        • treat migraine
    • 5HT2-R
      • excitatory postsynaptic effect
        • abundant in cortex & limbic system
      • target at various hallucinogenic drugs
    • 5HT3-R (in area postrema)
      • involved in vomiting
      • in cortex and brain stem extending to the dorsal horn of the spinal cord
        • excitatory in function
      • 5HT3-R antagonist
        • ondansetron
          • used for nause, vomiting
            • chemotherapy
          • anxiolytic effect
    • 5HT4-R (in striatum)
      • has presynaptic effect to increase ACh release
        • enhance cognition

Summary:

5HT 1 raphe & limbic system
5HT 2 cortex & limbic system
5HT 3 cortex & brain stem
5HT 4 striatum

Clinical uses:

5HT 1A-R Antidepressants
5HT 1B & 2C-R agonists Decrease appetite
5HT 1D-R agonists Treat migraine (sumatriptan)
5HT 3-R antagonist treat nausea & vomiting – chemotherapy (ondansetron)

Acetylcholine

  • Cell bodies at all levels with short & long axons
    • basal forebrain –> cortex, interneurons in basal ganglia
    • brainstem –> thalamus
    • septum –> hippocampus
  • Action
    • arousal, learning, motor control, memory
      • Physostigmine (anti AChE)
        • arousal (+ ACh)
      • Atropine (muscarinic receptor antagonist)
        • sedation (-ACh)
      • Hyoscine (muscarinic receptor antagonist)
        • amnesia
  • Receptors
    • Muscarinic-R (G-protein coupled)
      • many subtypes
      • Agonists
        • inhibit ACh release
      • Antagonists
        • increase ACh release
    • Nicotinic-R (ionotropic)
      • widespread
      • many subtypes
      • located presynaptically
        • facilitate release of other neurotransmitters (glotamate, dopamine)
  • Abnormalities of cholinergic pathways (decrease cognition)
    • dementia
    • parkinson’s & huntington’s
      • dysfunction of many local interneurons in corpus striatum
      • associated with motor coordination loss
    • alzheimer’s
      • degene
        ration of neurons in the magnocellular forebrain nuclei
      • associated with memory loss

Histamine

  • Neurons originate in
    • magnocellular nuclei in posterior hypothalamus (called tuberomamillary nucleus)
  • Widespread distribution
  • Action
    • arousal
    • neuroendocrine regulation
    • strongly anti-emetic
      • treat nausea, vomiting
  • Receptors
    • H1
      • excitatory
      • antagonist: strongly sedative
    • H2
      • inhibitory
    • H3
      • excitatory

Amino acid neurotramitters – Glutamic acid (eaa)

  • Found in relay neurons at all levels
  • 4 receptor subtypes
    • NMDA receptor
      • excitatory
      • blocked by PCP and ketamine
      • involved in synaptic plasticity related to learning & memory
      • excessive activation following a neuronal injury may cause cell death
    • AMPA receptor
      • fast EPSP
      • wide distribution
    • Kainate-receptor
      • fast EPSP
      • limited distribution
      • presynaptc inhibiton
    • Metabotropic subtype
      • G-protein coupled
      • found in pre & post synaptic
        • presynaptic: inhibitory
        • postsynaptic: excitatory
      • involved in synaptic plasticity and excitotoxicity

Amino acid neurotransmitters – GABA

  • Main NT mediating IPSP in brain and spinal cord
  • 2 receptor subtypes
    • GABA-a
      • open Cl- channels
      • activated by:
        • benzodiazepines
          • sedative-hypnotic
          • anxiolytic
        • barbiturates
        • gabapentin
          • anticonvulsant
    • GABA-b
      • metabotropic
      • coupled to G-protein that either open K+ channels / close Ca2+ channels
      • activated by baclofen

Neuropeptides

  • Most coexist with classical NT and act together with other NT
  • Substance P & glutamate
    • used in control of pain
  • Examples of neuropeptides
    • Opioid peptides
      • distributed all over brain & spinal cord
      • Presynaptic: inhibitory
        • decrease Ca2+ conductance
        • decrease cAMP
      • Postsynaptic: inhibitory
        • increase K+ conductance
        • decrease cAMP
    • Substance P
      • found in type C neurons
      • involved in pain/nociceptive sensory pathways in spinal cord
  • Comparison between neuropeptides with classical neurotransmitter
    • Difference
      • synthesis of pro-peptides occur in rough endoplasmic reticulum of the soma
      • the processed and secreted in vesicles which are transported via the axon to nerve endings
      • during transport, active peptides are generated within the vesicles
      • No reuptake /specific enzymes exist for terminating their action
      • once empty, vesicles cannot be refilled, but must be replaced with preloaded vesicles
    • Similarity
      • at nerve terminals, peptides are released via exocytosis in response to increased intracellular Ca2+ / other signals
      • effects can be
        • excitatory
        • inhibtory
        • pre/post synaptic
        • exerted over short/long distances
      • peptides serve mainly as neuromodulators by activating G-protein coupled receptors
      • Longer onset of action

Other neurotransmitters & neuromodulators

  • Nitric Oxide (NO)
  • Purines (ATP, Adenosine)
  • Adenosine
    • not stored in vesicles
      • released by carrier
  • Methylxanthines (caffeine, theophylline)
    • antogonists of A2 receptors
    • cause wakefullness
  • Melatonin
    • synthesised from 5HT in pineal gland
    • Depends on light intensity
      • low in the day
      • high at night
    • Causes sedation and resets biological clock
      • medicine for jet lag

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Drugs acting on CNS

  • General
    • General anaesthetics
  • Selective
    • Analgesics, Antypyretics, antiemetics
    • Stimulants
    • Appetite suppressants
    • Antidepressant, antipsychotic
    • Drugs for
      • epilepsy
      • Parkinson’s
      • Alzheimer’s
      • Migraine

Site & Mechanism of drug actions

  • Direct interactions with molecular components of ion channels on axons
    • eg. carbamazepine, phenytoin, local anaesthetics, general anaesthetics
  • Interaction at synapses (most drugs)
    • Presynaptic
      • alter synthesis, storage, release, reuptake or metabolism of the neurotransmitter
    • Activate/inhibit both pre/post synaptic receptors for specific transmitters
    • Interfere with actions of 2nd messengers

CNS drugs are selective, because different groups of neurons use different neurotransmitters. These are grouped into networks with different functions.

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Terri is obsessed with making medical school as painless as possible. She studies and compiles medical school notes in a concise, easy-to-understand format. She also enjoys reading contributions by others. She is an investor in sustainability projects. Her ideal weekend is wine tasting and experimenting on bread-making. She has yet to master the art of Sourdough baking.

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