Neurotransmitters

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Introduction

Neurotransmitters are chemical signals that neurons use to communicate with other neurons and different cells. Most have other uses in the body as well.

Unlike the neuromuscular junction, neuron synapses have more subtle and complex characteristics. Neurotransmitters can stimulate, inhibit, or modulate the postsynaptic neuron.

  • acetylcholine
  • dopamine
  • GABA
  • glutamate
  • histamine
  • norepinephrine
  • serotonin
  • others

Acetylcholine

Acetylcholine (ACh) is a common neurotransmitter secreted by a variety of neurons.

It binds to two different receptors - Ionotropic (fast) nicotinic receptors and metabotropic (slow) muscarinic receptors.

 

 

Role in Central Nervous System

Acetylcholine is restricted in the CNS, being limited to:

  • basal forebrain complex, innervating hippocampus and all of cortex
  • parts of the reticular formation
  • pontomesencephalotegmental cholinergic complex - innervates dorsal thalamus and parts of forebrain
  • likely involved in arousal, sleep-wake cycles, and perhaps learning and memory
  • Alzhemier's diease patients show a significant loss of acetylcholine in the cortex and hippocampus and corresponding loss of cells from the basal nucleus

 

 

Role in the Peripheral Nervous System

  • Preganglionic neurons of the autonomic nervous system, both the SNS and the PNS, secrete ACh, where its binds to ionotropic nicotinic receptors.
  • Postganglionic neurons of the vagus nerve act on metabotropic muscarinic receptors of cardiac cells to reduce heart rate
  • Postganglionic PNS neurons secrete ACh at synapses with cardiac and smooth muscle and glands, where it binds to .
  • Somatic neurons secrete ACh at the neuro-muscular junction, where it binds nicotinic receptors.
  • Some postganglionic SNS neurons express ACh at sweat glands, where it binds muscarinic receptors.

 

 

Receptors and Signaling

ACh is made in the pre-synaptic terminal by choline acetyltransferase and is stored and released from vesicles, each which contains 6000-10,000 ACh molecules.

  • ionotropic ACh receptors undergo conformational change upon ACh binding, inducing cation influx
  • metabotropic receptors activate a-GTP and βγ subunit, which activates K channels, inducing K influx and cell hyperpolarization

ACh is primaily removed form the synapse by the action of acetylcholineesterase (AChE)

 

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Agonists and Antagonists

 

Agonists

  • carbachol (muscarinic)
  • succinylcholine binds for prolonged time, leading to secondrary relaxation and flaccid paralysis
  • nicotine

AChE inhibitors (reversible)

  • donepezil (Aricept) (used in AD)
  • neostigmine (used in myesthenia gravis)

AChE inhibitors (irreversible)

  • malathion - insecticide
  • nerve gas - sarin

Antagonists

  • atropine (muscarinic)
  • curare (nicotinic)
  • benztropine
  • botulinum and tetanus toxins inhibit ACh vesicle release

 

Anticholinergic Effects

anticholinergic effects can cause dry mouth, constipation, blurry vision, delerium, cognitive impairment, etc

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Role in Disease

  • in myesthenia gravis, antibodies against the AChR form, usually following thymus hyperplasia.

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Dopamine

Dopamine is a neurotransmitter important for lots of things. It is also used as a drug.

 

 

Role in Central Nervous System

Dopamine is an important neurotransmitter in the CNS. It is involved in the following systems:

 

 

 

 

Role in the Peripheral Nervous System

  • Dopamine is an important postganglionic sympathetic neurotransmitter acting primarily in renal vascular beds.
  • It appears to induce vasodilation at lower doses but vasoconstriction at higher doses.
  • It is also likely involved in modulating signals in some ganglia and the ENS.
  • activates β1 receptors in the heart, increasing heart rate and contractility

 

 

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Dopamine Receptors and Signaling

  • All DA receptors in the brain are metabotropic, generally causing slow inhibitory action on CNS neurons.
  • The D1 receptor is typically associated with adenylate cyclase stimulation and cAMP production, thought to lead to smooth muscle relaxation and vasodilation
  • The D2 receptor is thought to inhibit adenylate cyclase, reducing calcium influx and opening potassium channels. It also also appears to inhibit NE release (after binding to pre-synaptic sites?)

 

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Role in Disease

  • Dopamine overactivity is associated with schizophrenia
  • Loss of dopamine signaling is involved with Parkinson's disease
  • Dopamine reward system is involved in most or all cases of drug addiction, with projections leaving the VTA and projecting to the nucleus accumbens.

 

D2 blockers can

 

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GABA

 

Role in Central Nervous System

  • 70-80% of CNS neurons use GABA as a neurotransmitter; as such, the brain is largely inhibitory

     

 

Role in the Peripheral Nervous System

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Receptors and Signaling

  • GABA and glycine bind to receptors gating Cl--selective channels, generating IPSPs

GABAA are ionotropic

GABAB are metabotropic, linked via G proteins to opening K channels or suppressing Ca channels

 

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Agonists and Antagonists

 

 

Agonists

  • benzodiazepines and barbiturates each bind to an allosteric site on GABAA channels, facilitating Cl- influx

 

Antagonists

 

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Role in Disease

 

 

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Glutamate

Glutamate, an amino acid, is the most common excitatory neurotransmitter in the nervous system.

 

Role in Central Nervous System

  • glutamate and aspartate primarily activate fast, ionotropic cation channels, generating small EPSPs. Many such EPSPs need to sum together to trigger an action potential. The threshold number varies but is roughly in the range of 10-100.
  • Glutamate signaling is thought to underly learning and memory
  • glutamate overexcitation is also thought to be involved in cell damage and death in Huntington's disease and following acute brain injury, as follows stroke or excessive seizures

Role in the Peripheral Nervous System

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Receptors and Signaling

Glutamine is converted to glutamate by glutaminase in the presynaptic cell, stored, and released.

 

Glutamate can act on four major classes of receptors.

AMPA receptors are ionotropic and are found in most excitatory synapses in the brain. They let Na+, K+, and very little Ca2+.

 

NMDA receptors, of which there are many, are also ionotropic. During hyperpolarization, NMDA receptors are blocked by magnesium, only opening above - 60 mV. This makes NMDA channels both ligand gated and voltage gated. They co-exist with AMPA-gated channels, opening more slowly once other channels have opened.

 

kainate receptor channels are a mystery.

 

mGlu Receptors are metabotropic.

 

 

Surrounding glial cells take up glutamate from the synapse, convert in back to glutamine, and return it to pre-synaptic cells.

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Agonists and Antagonists

 

 

Agonists

 

Antagonists

 

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Role in Disease

 

 

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Histamine

 

 

Role in Central Nervous System

 

Role in the Peripheral Nervous System

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Receptors and Signaling

 

 

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Agonists and Antagonists

 

 

Agonists

 

Antagonists

 

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Role in Disease

 

 

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Most common excitatory NT

amino acid

 

every neuron has glutamate receptors

 

Glutamine is converted to glutamate by glutaminase in the presynaptic cell, stored, and released.

Receptors include AMPA-R, NMDA-R, and MGluR.

 

NMDA receptors are blocked by magnesium during cell hyperpolarization, and allow Ca influx when the cell is depolarized.

these are thought to underly learning and memory and cell death during stroke.

 

 

Surrounding glial cells take up glutamate from the synapse, convert in back to glutamine, and return it to pre-synaptic cells.

Norepinephrine

Norepinephrine (NE) is the primary neurotransmitter of the sympathetic nervous system. Its effects are very similar to those of the hormone epinephrine, released by the adrenal medulla.

 

Role in the Central Nervous System

NE is used by modulatory system neurons in the locus coeruleus in the reticular activating system to affect arousal, anxiety, etc.

  • acts on β-adrenergic receptors on pyramidal cells, with little effect on its own; instead, primes cell for more powerful response to excitatory input such as glutamate
    • one way it does so by increasing phosphorylation of K channels, decreasing their opening and increasing the excitability of cells

 

Effects on the Body

 

Norepinephrine (NE) is released by most postganglionic cells of the SNS, where it binds to a variety of receptors.

 

Receptors

Adrenergic Receptors
  Receptor Locations Physiological Effects Intracellular effects Agonist Antagonist
α1 smooth muscle cells peripheral vasoconstriction increases IP3, DAG, and calcium phenylephrine prazosin
α2 presynaptic adrenergic nerve terminals, platelets, lipocytes, SMCs negative feedback on NE secretion; platelet aggregation inhibits adenylate cyclase, decreasing cAMP clonidine Yohimbine
β1 cardiomyocytes, kidney   stimulates adenylate cyclase, increasing cAMP levels isoproterenol, dobutamine atenolol, metoprolol
β2 lung, intestine bronciodilation
dec. intestinal motility
  albuterol, salbutamol  
β3          

 

Agonists

  • cocaine - inhibits reuptake
  • pseudoephedrine - causes NE release
  • phenylephrine - α1 agonist
  • salbutamol - β2 agonist
  • dobutamine - β1 agonist

Antagonists

  • pentolamine - α1 and α2 antagonist
  • prazosin - α1 antagonist
  • metoprolol - β1 antagonist

Serotonin

Serotonin (5-HT) is a vasoactive amine that acts both as a neurotransmitter and a local signal in inflammation. It has major effects on the brain, as well as the gastrointestinal system.

 

 

Role in Central Nervous System

Serotonin acts as both an excitatory or inhibitory neurotransmitter within the brain, with diffuse connections. Signaling appear to mediate sleep-wake cycles and different stages of sleep, as well as control of mood and emotional behaviour.

 

Cell bodies are located primarily in the raphe nuclei, found in the brainstem's midbrain and medulla (and pons?).

 

 

Role in the Peripheral Nervous System

Serotonin is produced, stored, and released by platelets following aggregation or stimulation by platelet activating factor. It has inflammatory effects similar to histamine, causing arteriole dilation and increasing venule permeability.

 

Serotonin is also produced by enterochromaffin cells in the pancreas.

 

 

Receptors and Signaling

Serotonin is produced from the amino acid tryptophan and released into the intrasynaptic space upon axonal stimulation. There are various receptor families.

 

Serotonin is taken back into the presynaptic cell, where it is metabolized by monoamine oxidase.

 

Different serotonin receptors are as follows:

Receptor

Action

5-HT 1A

neuronal inhibition; regulation of sleep, feeding, thermoregulation

increased stimulation: anxiety; decreased stimulation: depression

5-HT 1D

locomotion, muscle tone

5-HT 2A

neuronal excitation; learning, vasoconstriction, platelet aggregation

5-HT 2B

stomach contraction

5-HT 3

nausea, vomiting, anxiety

5-HT 4

gastrointestinal motility

 

Many hallucinogenic drugs, such as LSD, appear to interact with serotonergic systems.

 

 

 

 

Role in Disease

Disorders of serotonin appear to be involved in a number of psychiatric and other conditions, including:

 

 

Other Neurotransmitters

  • opiod peptides
  • tachykinins
  • endocannabinoids

 

The four main criteria used to define neurotransmitters are:

 

 

 

 

Trafficking Neurotransmitters

There are two main fashions of transporting neurotransmitters down the axon.

Slow axonal transport occurs via synthesis in the cell body, are packaged in the golgi, and are then transported down the axon.

Fast transport...

 

 

Neurotransmitter Production

In general, decarboxylation activates compunds, while deamination inactivates them.

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Resources and References

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