Neurotransmitters: Release & Action

• Neurotransmitters facilitate communication between neurons and their target tissues.
• Neurotransmitters are synthesized and released from nerve endings into the synaptic cleft.
• They bind to receptor proteins on the target tissue's cellular membrane.
• This binding excites, inhibits, or modifies the target tissue's function.

Neurotransmitter Release

• Neurotransmitters are stored in vesicles within the presynaptic nerve's terminal bouton.
• An action potential triggers neurotransmitter release by causing calcium influx through voltage-dependent calcium channels.
• Calcium facilitates the fusion of neurotransmitter-filled vesicles with the synaptic membrane.
• Neurotransmitters are then released into the synaptic cleft.

Neurotransmitter Action

• Neurotransmitters bind to receptors on the postsynaptic membrane after crossing the synaptic cleft.
• Binding opens or closes ligand-gated channels, altering the membrane's permeability to ions like calcium, sodium, potassium, and chloride.
• This permeability change leads to a stimulatory (excitatory) or inhibitory response in the target cell.
• Neurotransmitters can either stimulate (excitatory) or inhibit (inhibitory) the target cell.
• Excitatory neurotransmitters depolarize postsynaptic cells, generating an action potential.
• Inhibitory neurotransmitters hyperpolarize target cells, moving them away from the action potential threshold.
• A neurotransmitter can have either an excitatory or inhibitory effect depending on the receptor it acts on.

Classification of Neurotransmitters

• Can be classified as small molecules or large molecules (neuropeptides)

Small Molecule Neurotransmitters

Class I

• Acetylcholine

Class II (Biogenic Amines)

• Dopamine
• Noradrenaline (Norepinephrine)
• Serotonin
• Histamine
• Adrenaline (Epinephrine)

Class III (Amino Acids)

• Gamma-aminobutyric acid (GABA)
• Glycine
• Glutamate
• Aspartate

Class IV (Soluble Gases)

• Nitric Oxide
• Carbon Monoxide

Large Molecule Neurotransmitters

• Neuropeptides (e.g., substance P, Somatostatin, Cholecystokinin)
• Endorphins (e.g., enkephalin)
• Oxytocin
• Cannabinoids

Excitatory Neurotransmitters

• Acetylcholine
• Epinephrine
• Norepinephrine
• Dopamine
• Serotonin
• Glutamate

Inhibitory Neurotransmitters

• Glycine (mainly)
• g-Aminobutiric acid (GABA)

Neurotransmitters vs. Hormones

• Neurotransmitters: released into synapses, rapid action on nearby cells, creates fast responses.
• Hormones: secreted into the bloodstream, travel throughout the body, longer-lasting effects, regulate growth, metabolism, and reproduction and act over a larger range.

Neuropeptides

• Function as both neurotransmitters and hormones.
• As neurotransmitters, they influence nearby neurons in synaptic spaces.
• As hormones, they affect distant organs via the bloodstream.
• Examples: oxytocin and substance P.

Small Molecule Neurotransmitters

• Includes biogenic amines (dopamine, serotonin, histamine), amino acids (GABA, glutamate), acetylcholine, and soluble gases (nitric oxide).
• Rapidly acting, synthesized and stored in small vesicles, involved in reflexes and acute responses.

Large Molecule Neurotransmitters (Neuropeptides)

• Larger, complex molecules like substance P, endorphins, and oxytocin.
• Synthesized in the cell body, transported to axon terminals in large vesicles.
• Influence behaviors, mood, and pain perception over a longer period.
• Affect broader neural circuits.

Receptor Types

• Metabotropic and ionotropic subtypes

Receptor Types and Neurotransmitters

Ionotropic Receptors

• Mediate effects by opening an ion channel on the cell surface.
• Generally very short lived effect.
• Instant effect.
• Quite specific effect.

Metabotropic (G-protein) Receptors

• Linked to G proteins, which initiate reactions within the cell when activated.
• Generally longer lasting effects.
• Slightly delayed effect.
• Often diffuse effects.

Speed of Transmission

• Fast transmission: less than 1/1000 of a second
  • Involves neurotransmitters binding directly to ligand-gated ion channels.
• Slow transmission: hundreds of milliseconds to minutes.
  • Involves neurotransmitters binding to G-protein coupled receptors.
• Glutamate is used by about half of the fast synapses in the brain that are excitatory.
• GABA is used by about half of the fast synapses that are inhibitory.

Terms Related to Drugs and Receptors

• Affinity: How avidly the drug binds to the receptor.
• Potency: The concentration or dose of a drug required to produce 50% of the drug's maximal effect and depends on a drug's affinity for its receptor.
• Efficacy: The ability of the drug to elicit a response when it binds to the receptor.

Key Aspects of Main Neurotransmitters

Acetylcholine

• Acts centrally and peripherally.
• One of the main neurotransmitters involved in the autonomic nervous system.

Synthesis

• Formed from choline within neurons.
• Choline acetyltransferase transfers an acetyl group from acetyl coenzyme-A to choline, resulting in acetylcholine.

Breakdown

• Inactivated and broken down to choline and acetate by acetylcholinesterase.

Receptors

• Two main types: nicotinic and muscarinic.
  • Nicotinic: ionotropic, stimulated by nicotine and acetylcholine.
  • Muscarinic: metabotropic, stimulated by muscarine and acetylcholine.

Dopamine

• Synthesized in 1910 by George Barger and James Ewens.
• Discovered as a neurotransmitter in 1958 by Arvid Carlsson (Nobel Prize).

Synthesis

• Tyrosine (from dietary proteins) is converted to L-DOPA by tyrosine hydroxylase.
• L-DOPA is then converted to dopamine by dopa decarboxylase.

Storage

• Dopaminergic neurons originate in substantia nigra pars compacta, ventral tegmental area (VTA), and hypothalamus.
• Projects axons through four major pathways:
  • The mesolimbic pathway
  • The mesocortical pathway
  • The nigrostriatal pathway
  • The tuberoinfundibular pathway

Pathways

• The mesolimbic pathway: transports dopamine from the VTA to the nucleus accumbens (reward pathway); blockage of D-2 receptors here accounts for the benefit of antipsychotics.
• The mesocortical pathway: goes from the VTA to the frontal cortex, involved with motivation and emotion; hypofunction here leads to negative symptoms of schizophrenia.
• The nigrostriatal pathway: connects the substantia nigra to the striatum; blockage here produces extrapyramidal side effects (EPSE's).
• The tuberoinfundibular pathway: goes from the hypothalamus to the pituitary gland; blockage of dopamine here causes the pituitary gland to secrete prolactin.

Breakdown

• Broken down in the presynaptic neuron by catechol-O-methyl transferase (COMT) into 3-Methoxytyramine and by monoamine oxidase (MAO) into 3,4-Dihydroxyphenyl-acetic acid
• Metabolised by both forms of MAO (MAO-A and MAO-B)

Receptors

• A class of metabotropic G protein-coupled receptors with five subtypes: D1, D2, D3, D4, and D5.
  • D1 and D5: D1-like receptors that activate adenylyl cyclase, increasing cAMP concentration.
  • D2, D3, and D4: D2-like receptors that inhibit cAMP formation by inhibiting adenylyl cyclase.

GABA (Gamma-aminobutyric Acid)

• Major inhibitory neurotransmitter of the brain.
• Binds to transmembrane receptors, triggering the opening of ion channels and causing hyperpolarization of the neuron (by letting chloride ions in or potassium ions out).
• Hyperpolarization means that the neurone is less likely to depolarise (hence inhibitory effect).

Receptors

• Two types of GABA receptor:
  • GABA-A: ligand gated ion channel complex
  • GABA-B: metabotropic receptors, G protein-coupled receptors that open or close ion channels via intermediaries (G proteins)
• Synthesized in the brain from glutamate
• Generally does not cross the blood–brain barrier.
• Degraded by GABA transaminase (valproate is a GABA-transaminase inhibitor).

Norepinephrine

Synthesis

• Synthesised from tyrosine in the following steps.
• Tyrosine is firstly converted to L-DOPA by tyrosine hydroxylase.
• L-DOPA is then converted to dopamine by DOPA decarboxylase.
• Dopamine is then converted to norepinephrine by dopamine beta-hydroxylase.
• Norepinephrine is then converted to epinephrine by phenylethanolamine-N-methyltransferase.

Release

• Main site of norepinephrine release is from the locus coeruleus (aka 'the blue spot) which is located in the pons.

Breakdown

• Broken down in the presynaptic neuron by both COMT (catechol-O-methyl transferase) and MAO (monoamine oxidase).

Serotonin

• Serotonin (5-Hydroxytryptamine, 5-HT) is made in the CNS in the raphe nuclei (in the brainstem) and in the GI tract (enterochromaffin cells).
• Synthesised from the amino acid L-tryptophan which is obtained from the diet.
• L-tryptophan can cross the blood brain barrier, whereas serotonin cannot.
• Transformation of L-tryptophan into serotonin involves two steps:
  • Hydroxylation to 5-hydroxytryptophan catalysed by tryptophan hydroxylase
  • Followed by decarboxylation of 5-hydroxytryptophan to serotonin (5-hydroxytryptamine) by L-aromatic amino acid decarboxylase

Breakdown

• Taken up from the synapse by a monoamine transporter (SERT).
• Substances that block this transporter include; MDMA, amphetamine, cocaine, TCA's, and SSRI's.
• Broken down by MAO and then by aldehyde dehydrogenase to 5-Hydroxyindoleacetic acid (5-HIAA).

Histamine

• Histamine is produced from the amino acid histidine by a histidine decarboxylase and is metabolised by the combined actions of histamine methyltransferase and MAO.

Glutamate

• Primary excitatory neurotransmitter in the central nervous system, involved in cognition, memory, learning, and pH regulation in the brain.

Synthesis

• Synthesized from glutamine, provided by glial cells (astrocytes).
• Astrocytes produce glutamine from glutamate via glutamine synthetase.
• Glutamine is transported to neurons, where it is converted back to glutamate by glutaminase.

Storage

• Stored in vesicles within presynaptic neurons and released into the synaptic cleft in response to an action potential.

Receptors

• Three types of glutamate receptors:
  • Ionotropic receptors: NMDA, AMPA, and kainate receptors, directly mediate synaptic excitation.
  • Metabotropic receptors (mGluRs): G protein-coupled, modulate neuronal excitability and synaptic plasticity.

Role in pH Regulation

• Contributes to pH regulation through metabolic cycling.
• After release, it is taken up by astrocytes, converted to glutamine, and transported back to neurons.
• This process consumes hydrogen ions, helping buffer against pH fluctuations.

Breakdown

• Primarily removed from the synapse by reuptake into neurons and glial cells.
• Can be converted back to glutamine.

Glycine

• Inhibitory neurotransmitter in the spinal cord, brainstem, and retina, reducing neuronal excitability.

Synthesis

• Synthesized from the amino acid serine by the enzyme serine hydroxymethyltransferase.
• Serine can be obtained from dietary sources or synthesized in the body from the glycolytic intermediate 3-phosphoglycerate, particularly in the liver.

Storage

• Stored in synaptic vesicles within neurons and released upon stimulation.

Receptors

• Glycine receptors are ionotropic and mediate inhibitory neurotransmission:
  • GlyR (Glycine receptor): Ligand-gated chloride channels that hyperpolarize neurons by allowing chloride ions into the cell, making them less likely to depolarize.

Breakdown

• Reabsorbed from the synaptic cleft by glycine transporters on neurons and glial cells, which helps terminate its action.