Neurons and Neurotransmitters

• Neurotransmitters are released from a neuron's axon terminal into the synapse.
• Neurons send electrical signals down the axon, which triggers the release of neurotransmitters.
• Neurotransmitters carry signals across the synapse to the dendrites of the next neuron, where the chemical signal is converted back to an electrical signal.
• Neurons are the fundamental units of the brain and nervous system, and they transmit electrical signals/information.
• A neuron consists of the cell body, dendrites, and axon.
• Neurotransmitters are molecules acting as chemical messengers, carrying signals from one nerve cell to the next target cell (nerve, gland, or muscle cell).
• Neurotransmitters are contained in vesicles at the axon terminals and released into the synapse.
• The neurotransmitters diffuse across the synaptic space from the presynaptic membrane and bind to receptors on the postsynaptic membrane.
• Multiple neurotransmitters can be found in one nerve cell.

Criteria for Labeling a Molecule as a Neurotransmitter

• Synthesis of the molecule occurs within the neuron (de novo synthesis).
• The molecule is stored within the nerve ending prior to release in synaptic vesicles.
• Release of the molecule from the presynaptic endings occurs in response to an appropriate stimulus, like an action potential.
• There is binding and recognition of the released molecule by the postsynaptic target cell.
• A mechanism exists for the inactivation and termination of the biological activity of the neurotransmitter.

Neuromodulators

• These are molecules involved in cross-talk between neurons but do not meet all neurotransmitter criteria.
• Neuromodulators alter the effectiveness of synaptic transmission or cellular properties of neurons/glia.
• They are involved in pharmacological manipulation.
• Examples include Nitric oxide, Adenosine, Neurosteroids, and Polyamines.

How Neurotransmission Occurs:

• Neurotransmitters are released upon the generation of an action potential.
• When an action potential reaches the axon terminal, it opens calcium channels due to voltage change.
• Calcium entry leads to the mobilization of vesicles containing the transmitter, which then fuse with the synaptic membrane and release.

Types of Neurotransmitters

• Excitatory neurotransmitters cause a depolarizing change in voltage, making an action potential more likely.
• Inhibitory neurotransmitters hyperpolarize the membrane, reducing the likelihood of an action potential.
• Action potentials are propagated across neurons through the activation of postsynaptic receptors.
• There are two types of postsynaptic receptors: ionotropic and metabotropic.

Types of Postsynaptic Receptors

• Ionotropic receptors are transmembrane ion channels that open upon binding a chemical messenger like a neurotransmitter to an allosteric binding site.
• Ionotropic receptors open quickly but remain open for only a few milliseconds.
• An example is the Nicotinic acetylcholine receptor.
• Metabotropic receptors are membrane receptors coupled with G-proteins.
• Activation of metabotropic receptors induces intracellular events through a second messenger.
• Metabotropic receptors take longer to open, with a longer-lasting effect.
• An example is Muscarinic acetylcholine receptors.

Regulation of Neurotransmitters

• Neurotransmitters are regulated through removal from the synapse and by changing effective concentrations.

Mechanisms of Removal from Synaptic Space:

• Simple diffusion is a major mechanism for neuropeptide removal.
• Enzymatic degradation, exemplified by acetylcholinesterase cleaving ACh into acetate and choline.
• Re-uptake by presynaptic neurons enables reuse, a mechanism for catecholamine and amino acid removal.

Mechanisms to Alter Effective Concentration

• Changing the rate of synthesis
• Altering the rate of release at the synapse
• Blocking re-uptake
• Blocking degradation, which is a focus of therapeutic interventions

Classes of Neurotransmitters and Examples:

• Amines include Acetylcholine (ACh), Norepinephrine, Epinephrine, Dopamine, and Serotonin (5-HT).
• Amino acids include Glutamine and GABA (γ-amino butyric acid).
• Purines include ATP and Adenosine.
• Gases include Nitric oxide.
• Peptides include Endorphins and tachykinins.

Glutamate

• Glutamate is the most important excitatory neurotransmitter.
• Glutamate acts on both ionotropic and metabotropic receptors.
• It binds with the N-methyl-D-aspartate (NMDA) receptor.
• It is recycled by high-affinity transporters. Glial cells convert glutamate to glutamine, which diffuses back to neurons, where mitochondrial glutaminase regenerates glutamate for reuse.
• Chronic stimulation of NMDA receptors in the hippocampus is known as long-term potentiation, representing how memory is laid down.
• Increased extracellular Glutamate concentration can result from trauma, stroke, Huntington's chorea, AIDS-related dementia, and Parkinson's disease, leading to glutamate excitotoxicity.

Glutamate Excitotoxicity

• Excess glutamate is toxic to nerve cells.
• Activation of NMDA receptors induces apoptosis, aberrant calcium and sodium uptake, and nitric oxide production.
• Drugs that inhibit NMDA activation and suppress excitotoxicity in the hope of reversing stroke damage have unpleasant psychological side effects like paranoia and delusions.

γ-Amino Butyric Acid (GABA)

• Synthesized from glutamate by the enzyme glutamate decarboxylase.
• GABA is a major inhibitory transmitter in the brain.
• There are two types of GABA receptors: GABAA (ionotropic) and GABAB (metabotropic).
• Therapeutic drugs like benzodiazepines and barbiturates target the GABAA receptor (which has 5 subunits).
• Benzodiazepines potentiate the response to endogenous GABA and reduce anxiety, as well as cause muscle relaxation.
• Barbiturates stimulate the receptor directly in the absence of GABA, and can cause toxic side effects in overdose.

Glycine

• Acts as an inhibitory neurotransmitter in the spinal cord and brain stem, but has an excitatory effect in the cortex.
• Blocks impulses traveling down the cord to stimulate skeletal muscle.
• The Glycine receptor is an ionotropic receptor.
• Glycine is blocked by Strychnine.
• Modulation of Glycine receptors in the spinal column treats chronic pain.
• It is regulated by the glycine cleavage System (GCS), which breaks it down to ammonia and carbon dioxide.
• High GCS levels can be found in the liver, brain, and placenta.
• Defect in GCS results to Glycine encephalopathy.
• Glycine encephalopathy presents with hypotonia, seizures, mental retardation, and brain malformation.
• There is currently no effective medication for Glycine encephalopathy.
• Strychnine is an alkaloid pesticide from the seeds of Strychnos nux-vomica.
• It blocks glycine receptors by competitive inhibition, allowing motor impulses to pass without negative control.
• This leads to muscle rigidity, muscular convulsion, and death due to asphyxia.

Catecholamines

• Catecholamines include norepinephrine, epinephrine, and dopamine.
• They are biogenic amines.
• Catecholamines are synthesized in neurons using amino acid Tyrosine.
• They have a general modulatory effect on mood and arousal.
• Norepinephrine is a major transmitter in the sympathetic nervous system
• Norepinephrine is responsible for the "fight or flight response".
• Symptoms of the "fight or flight response" include tachycardia, vasoconstriction, sweating, and bronchodilatation.
• The effects of Norepinephrine "fight or flight response" are mimicked by amphetamines (used in ADHD treatment).
• Epinephrine is produced by the adrenal medulla under the influence of ACh containing nerves.
• Epinephrine is also linked to the "fight and flight response”.
• Epinephrine is more active than norepinephrine on the heart and lungs.
• Epinephrine has a stimulatory effect of glycogen metabolism, allowing adequate supply of glucose.

Adrenoceptors

• These are receptors for norepinephrine and epinephrine.
• There are two classes: Alpha and Beta.
• Epinephrine acts on both receptors, but norepinephrine is more specific for alpha-receptors.
• Alpha blockers (e.g., Clonidine) are used to treat hypertension.
• Beta blockers (e.g., Atenolol) antagonize stimulatory effects on the heart and treat hypertension and angina in ischemic heart disease.
• Beta agonists (e.g., Salbutamol) are used to treat bronchial asthma.

Catecholamines Regulation

• Catecholamines are degraded by:
  • Monoamine oxidase (MAO) which occurs by oxidation
  • Methyl Catecholamine-O-methyltransferase (COMT), by methylation
• This converts catecholamines to metanephrines and vanillylmandelic acid.

Pheochromocytoma

• Pheochromocytoma is a tumor of the adrenal medulla that presents with severe hypertension and headache. This can lead to stroke or heart failure due to an increase in catecholamines, causing vasoconstriction.
• Diagnosis involves measuring catecholamine in plasma/urine or metabolites such as metanephrines and vanillylmandelic acid in the urine.
• Pheochromocytoma is rare and dangerous, but is amenable to surgery.

MAO Inhibitors

• MAO Inhibitors are antidepressant drugs that inhibit Monoamine oxidase.
• MAO Inhibitors are used in the treatment of depressive disorders, panic disorders, and nervous system diseases like Parkinson's disease.
• Patients on MAO inhibitors may suffer from a hypertensive crisis if they consume foods containing high levels of tyramine (e.g., cheese, alcohol, fava beans).
• Tyramines are also degraded by MAO. In the presence of MAO inhibitors, high tyramine levels are taken up by adrenergic neurons.
• Dopamine acts both as a neurotransmitter and as an intermediate in the synthesis of norepinephrine.
• The major neurotransmitter in the nerves interconnects nuclei of basal ganglia and controls voluntary movements.
• Dopamine is also found in the limbic system and is involved in emotional responses and memories.
• Schizophrenia can result from a defect in dopaminergic pathway; antipsychotic drugs used to treat this disease bind to dopaminergic receptors.
• Dopamine causes vasodilatation in the periphery and is also used in the treatment of renal failure.
• Dopamine inhibits prolactin release. Dopamine agonists like Bromocryptin can treat breastmilk production or hyperprolactinemia.
• The major metabolite of dopamine is HVA (Homovanillic acid).
• Tyrosine hydroxylase deficiency is a hereditary disorder leading to brain dopamine deficiency. It leads to a progressive gait disorder and infantile parkinsonism.
• Treatment for Tyrosine hydroxylase deficiency includes administration of L-dopa, which is then converted to dopamine in the brain by the enzyme AADC (Aromatic AminoAcid Decarboxylase).
• AADC Deficiency catalyzes the conversion of L-dopa to dopamine and 5-hydroxytrptophan to serotonin.
• AADC deficiency results in brain deficiency of Dopamine and Serotonin.
• Clinical conditions for AADC deficiency include severe movement disorders, abnormal eye movements, and neurologic impairment.
• Treatment for AADC deficiency includes MAO inhibitors and Dopamine agonists (Bromocryptine).

Serotonin

• Serotonin (5-hydroxytryptamine or 5-HT) is derived from Tryptophan.
• 5-Hydroxytryptophan is converted to serotonin by dopa decarboxylase or AADC.
• There are biochemical similarities between serotonin synthesis and dopamine synthesis.
• Serotoninergic neurons are concentrated in the upper brain stem.
• Serotonin is more active during the awake period than during sleep.
• Serotonin controls degree of motor neuron responsiveness.
• Serotonin is implicated in vegetative behaviors like feeding and sexual behavior, as well as temperature control.
• Serotonin mediates satisfaction, happiness and optimism.

Acetylcholine

• Acetylcholine is the neurotransmitter of the parasympathetic nervous system
• Causes slowing of heart rate, bronchoconstriction and stimulation of the intestinal smooth muscle.
• It acts on neuromuscular junctions resulting to skeletal muscle contraction.
• Acetylcholine is also involved in learning and memory.
• Acetylcholine is synthesized from Choline and Acetyl CoA.
• Acetylcholine is degraded by the enzyme acetylcholinesterase.
• Choline is transported back to the axon for reuse.
• There are 2 types of receptors: Nicotinic (lonotropic) and Muscarinic (Metabotropic).

Nicotinic Receptor

• Binds Nicotine
• Is found on ganglia and at neuromuscular junction
• Allows Na+ and K+ to pass through
• Action of Nicotine is direct and rapid

Muscarinic Receptor

• Found widespread in the brain
• Are are major receptors on smooth muscle and glands innervated by parasympathetic nerves
• responds to fungal toxin Muscarine
• Is inhibited by Atropine

Acetylcholine Clinical Correlation:

• Acetylcholine agonists and Acetylcholinesterase inhibitors treat glaucoma by lowering intraocular pressure and increasing muscle tone of the eye for accommodation.
• It is also used to induce temporary miosis or pupillary constriction in eye surgery.
• Organophosphate insecticides or nerve gases inhibits acetylcholine esterase, increasing Ach concentration, which leads to diarrhea, bronchoconstriction and glandular secretions. This is antagonized by atropine and pralidoxime, which is a drug that removes the insecticide from the enzyme.
• Myasthenia gravis is a disease caused by autoantibodies against nicotinic acetylcholine receptors. This results in less transmission of impulses to ACh receptors.
• Myasthenia gravis manifests as weakness of voluntary muscles and ascending paralysis that may result to respiratory arrest.
• It is treated by acetylcholinesterase inhibitors such as pyridostigmine which increases the amount of Acetylcholine in the synapse.

Nitric oxide gas

• Produced from Arginine by Tetrahydrobiopterine dependent nitric oxide synthase
• Relaxation of vascular and intestinal smooth muscle
• It has a role in memory function
• Excessive nitric oxide has been implicated in neurodegenerative process associated with Parkinson's and Alzheimer's diseases probably due to an irreversible damage of the mitochondrial electron transport chain.
• NO is released directly in the synapse and isn't stored in vesicle, thus It isn't classified as a TRUE Neurotransmitter

Other Molecules with Transmitter Function

• ATP
• Histamine
• Peptides
  • Vasoactive intestinal peptides
  • Opioid peptides
  • Neuropeptides

Summary

• Neuronal signals are propagated from one neuron to the other and neurons communicate at synapses with neurotransmitters.
• Electrical signals travelling through the axons trigger the release of chemical signals or neurotransmitters.
• Neurotransmitters must possess 5 characteristics: synthesis, storage, specific stimulus, receptors, and a mechanism for degradation.
• Neurotransmitters can either be excitatory or inhibitory.
• Neurotransmitters include amines, amino acids, purines, gasses, and peptides; Nitric oxide cannot be classified as a true neurotransmitter, since it isn't stored in vesicles.
• The major neurotransmitters of the Nervous system are Glutamate, GABA, Glycine, Catecholamines, Serotonin, Acetylcholine.