Neurotransmitters & Nervous System Pathways

• “Classical” neurotransmitters:

  •Released from presynaptic terminal

  •Synthesised in presynaptic cell

  •Stored in presynaptic vesicles

  •Vesicle exocytosis from presynaptic cell (action potential)

  •Activates postsynaptic receptors
• Non-classical or unconventional neurotransmitters:

  •Not necessarily stored or released by vesicles

  •Not necessarily released presynaptically & active postsynaptically

  but are produced and released in a regulated manner
• Major neurotransmitters

  Glutamate

    Gamma-aminobutyric acid (GABA)

    Glycine

    Noradrenaline

    5-hydroxytryptamine (5-HT, serotonin)

    Dopamine

    Histamine

    Acetylcholine

  •These are released by classical neurotransmission (presynaptic exocytotic vesicle release)
• Amino acid NTs

  Glutamate

    Gamma-aminobutyric acid (GABA)

    Glycine
• Monoamine NTs

  Noradrenaline

    5-hydroxytryptamine (5-HT, serotonin)

    Dopamine

    Histamine
• GABA is technically an amino acid by chemical structure as it has functional carboxylic acid and amine groups, and is included in the amino acid group of neurotransmitters. However, it is not a proteinogenic alpha amino acid like Glu and Gly.
• Other neurotransmitters

  •Neurones may release some of these as well as their primary neurotransmitter

  •Some are released as classical neurotransmitters, others unconventional, and some (e.g. adenosine) may be either

  •Purines:  adenosine, ATP, ADP, AMP

  •Gases:  e.g. nitric oxide (NO), carbon monoxide (CO)

  •Neuropeptides:  many, e.g. enkephalin, orexin

  •Lipids:  e.g. endocannabinoids
• Some neuropeptides are better known as hormones (e.g. oxytocin). However, they are also in some areas of the brain released as neurotransmitters rather than hormones.
• CNS signal integration

  Glu and GABA are the main drivers of neuronal activity via ionotropic receptors: depolarising (Glu), hyperpolarising (GABA)

  Other neurotransmitters modulate cell activity via receptors or altering ion channel activity. ACh main excitatory NT in PNS (e.g. autonomic ganglia, NMJ)

  
• Glutamate (Glu)

  •Primary excitatory NT in CNS

  •Heavily associated with central cell metabolism – Kreb’s cycle & nitrogen metabolism

  Synthesised from and broken down into glutamine

  •Removed by reuptake into cells and astrocytes

  
• Glutamate is heavily linked into central cell metabolic pathway: the Krebs cycle via alpha-ketoglutarate and as a key molecule in cellular nitrogen metabolism (glutamine synthetase pathway). In practice, most of it comes from astrocytic release of glutamine, which is taken up and metabolised to glutamate in the presynaptic terminal.
• Hepatic encephalopathy

  •Glutamine key metabolite in regulation of nitrogen

  •Liver failure leads to hyperammonaemia – ↑ ammonium (NH4+)

  •NH4+ absorption by astrocytes and excessive glutamine production

    Swelling and dysfunction of astrocytes

    Increased extracellular glutamate & neuronal dysfunction

  
• Glutamate receptors

  •Ionotropic receptors(“Non-NMDA”):

    AMPA receptors

    NMDA receptors

  •Metabotropic receptors mGluR1-8
• mGluR receptors, whilst vital for brain signalling, have little recognised medical relevance: few clearly associated pathologies, no current therapeutic drugs established
• Non-NMDA glutamate receptors

  •AMPARs are the main glutamate receptor for membrane depolarisation

  •Permeable mostly to Na+ (also K+)

  •Few therapeutically relevant drugs

  
• NMDA glutamate receptors

  •Requires co-agonist (glycine or d-serine)

  •Ligand & voltage gated: 

  Mg2+ ion blocks pore at rest, removed by cell depolarisation

  •Permeable to Na+, K+, Ca2+

  Key role in some Ca2+-dependent intracellular signalling, neurotoxicity risk

  •Several relevant drugs (e.g. anaesthetics, drugs of abuse)

  
• Gamma-aminobutyric acid (GABA)

  •GABA is the primary inhibitory neurotransmitter in the brain

  •Synthesised from glutamate by glutamate decarboxylase (GAD)

  •Removed from synapse by reuptake transporters

  •Broken down to glutamate by GABA transaminase (GABA-T)

  
• GABAA receptor:

  Inhibitory anion channel

  Cl- influx → hyperpolarisation

  •Major relevance as drug target:

  anxiolytics, hypnotics, anticonvulsants, general anaesthetics, sedatives, muscle relaxants (central), alcohol

  
• GABAB receptor:

  •Gi/o-linked GPCR expressed throughout CNS

  •Pharmacological target for muscle relaxation

  
• Glycine

  •Easily obtained from main cell metabolism

  •Main inhibitory neurotransmitter in spine (replacing GABA)

  •Main functions in motor control and pain sensitivity – loss of co-ordination and hyperalgesia if blocked

  •Glycine receptors very similar to GABAARs in structure & function:

    Ionotropic Cl- channel, hyperpolarising

  •Low drug relevance, some toxins: strychnine, tetanus toxin
• Monoamine NTs -

  Catecholamines : Dopamine , Noradrenaline

  Indoles: 5-hydroxytryptamine

  Imidazoles: Histamine
• Melatonin is a hormone released by the pineal gland, thus like adrenaline is not a neurotransmitter, although has significant effects on the CNS. It is involved in sleep regulation, especially circadian rhythm.
• dopamine can also be transported by the noradrenaline transporter, and is catabolised by both MAO-A and MAO-B.
• Dopamine (DA)

  •Synthesised from tyrosine

  Key step L-DOPA to dopamine by DOPA decarboxylase (DOPA-D)

  •Mostly removed by dopamine reuptake transporter (DAT) then catabolism by:

  Monoamine oxidase A (MAO-A)

  Monoamine oxidase B (MAO-B)

  Catechol-O-methyltransferase (COMT)

  •Some extracellular catabolism by MAO-B

  
• Dopaminergic nuclei

  Main dopaminergic nuclei:

  •Substantia nigra pars compacta (SNc)

  •Ventral tegmental area (VTA)

  •Arcuate nucleus of hypothalamus (ARC / ARH) or infundibular nucleus

  
• Dopaminergic nuclei

  A) Substantia nigra

  B) putamen

  C) Thalamus

  D) dorsal striatum

  E) Ventral tegmental area (VTa)

  F) frontal lobe

  G) parietal lobe

  H) occipital lobe

  I) Arcuate nucleus of hypothalamus

  J) Pituitary Gland

  K) nucleus accumbens

  
• Key dopaminergic functions

  •Motor control (e.g. Parkinson’s disease, Huntington’s disease)

    Via nigrostriatal pathway (SNc to striatum)

  •Reward / pleasure / addiction

    Mesolimbic pathway (VTA to nucleus accumbens, amygdala &   hippocampus)

  •Cognition, attention, memory, reward

    Mesocortical pathway (VTA to prefrontal cortex)

  •Hormonal – prolactin release from pituitary

    Tuberoinfundibular pathway (ARH to hypothalamus)
• Dopamine receptors

  •All dopamine receptors are GPCRs

  D1-like family: D1 & D5, Gs-linked

  D2-like family: D2-4, Gi/o linked

  •High relevance to medical conditions / drugs (generally D2 > D1 > D3-5)

  Dopaminergic pharmacology key to emesis, motor disorders (e.g. Parkinson’s disease), psychosis, drug addiction

  
• Noradrenaline (NA/NE)= ‘norepinephrine’ (INN)

  •Synthesised from dopamine by dopamine beta-hydroxylase (DβH)

  •Removed by noradrenaline reuptake transporter (NET)

  •Catabolised by enzymes MAO-A and COMT

  
• Noradrenergic pathways

  NA neurones in locus cœruleus:

  •Widespread innervation of brain

  •Generally stimulant in CNS:

  ↑ arousal, ↑ alertness, ↑ reward

  ↑ excitement

  •Enhances release of 5-HT, DA

  •Major drug target in periphery & CNS:

  CNS: antidepressants, anxiolytics, stimulants (inc. drugs of abuse)

  
• Adrenoceptors

  •Metabotropic:

    α1 – Gq linked

    α2 – Gi/o linked

    β1-3 – Gs linked

  •In CNS, α2 and β1 are most common receptors

  •α2 activation often ↓ NT release (NA,others) CNS depressants

    α2 agonists as sedatives, muscle relaxants 

    α2 antagonism may contribute to treating depression
• 5-HT (serotonin)

  •Metabolised from tryptophan

  •Removed by serotonin reuptake transporter (SERT)

  •Catabolism by MAO-A

  Note that aromatic L-amino acid decarboxylase (AADC) is a different name for DOPA-decarboxylase - same enzyme, different name

  
• Serotonergic pathways

  Dorsal raphe nuclei in brainstem:

  Widespread innervation of brain with complex, wide-ranging effects, e.g.

  •Mood (↑)

  •Anxiety (↑ / ↓)

  •Body temperature (↑)

  •Appetite (↑)

  •Cognitive e.g. memory (mixed)

  •Arousal (mostly ↑)

  •Sexual function (↓)

  Cerebral vasoconstriction (↑)

  
• 5-HT receptors – ionotropic

  •One ionotropic cation channel – 5-HT3 receptor

  •Similar structure to nAChR & GABAA receptors

   

  •Permeable to Na + & K+ 

  •Mostly associated with vomiting & memory pathways

  
• 5-HT receptors – metabotropic

  •Numerous metabotropic GPCRs, 5-HT1-2,4-7:

    5-HT1,5:  Gi/o-linked 

    5-HT2,4,6-7:  Gs-linked

   

  •5-HT1-2 very common and well-studied, involved in most serotonergic pathways; 5-HT4-7 are rarer and less understood

  •CNS 5-HT signalling mainly medically relevant to:

    Mood (depression, anxiety), hallucinogens, pain modulation,   migraine, vomiting

   

  •Heavily involved in enteric nervous system (e.g. GI motility)
• Histamine (HA)

  •Synthesised from histidine

  
  

  •Receptors:  H1 – Gq-linked

    H2 – Gs-linked

  
  

  •Modest drug relevance in CNS: 

    drowsiness (1st gen antihistamines)

    antiemetics

  Major non-neurotransmission signalling role in periphery (e.g. inflammation, GI acid, vasodilation, etc.)
• Histaminergic pathways

  •HA released from cells in tuberomammillary nucleus (TMN)

  •Widespread innervation of brain

  •Sleep regulation (↑ wakefulness)

  •Also ↑ endocrine activity, ↓ appetite

  Ascending reticular activating system also called ascending arousal system: the main set of brain nuclei in subcortical areas that promote wakefulness

  
• Acetylcholine

  •Main excitatory (depolarising) neurotransmitter in periphery

  •Synthesised from choline and acetyl Co-A by choline acetyltransferase

  •Catabolised extracellularly by acetylcholinesterase

  
• Cholinergic nuclei

  Numerous subcortical and brainstem nuclei

   

  •Widespread innervation of brain

  •Complex, wide-ranging effects, generally stimulant:

    ↑ arousal

    ↑ memory

    cognitive function

  
• Main CNS cholinergic areas

  •Basal forebrain nuclei:

  efferents to cortex and other regions e.g. hippocampus & amygdala;

  ↑ arousal, ↑ attention, ↑ memory, cognitive functions

  •Mesopontine nuclei:

  diffuse efferents across brain, esp. subcortical areas, cerebellum sleep/wake regulation (↑ arousal); motor & cognitive connections

  •Striatum:

  cholinergic interneurones modulate dopaminergic signalling

  relevance in motor disorders