biol125-lectures/2016-10-16-lecture07.md

## Neurotransmitters

* Many different kinds, over 100
* There are two main types– small molecule neurotransmitters and neuropeptides
* Abnormalities of neurotransmitter function contributes to wide range of neurological diseases and psychiatric disorders

Note:

So we already defined what a neurotransmitter is. It is a substance that must be present inside a presynaptic neuron, it’s release must be dependent on calcium flux from an AP, and it must have specific receptors on the postsynaptic neuron.

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## Major categories of neurotransmitters

* Small molecule neurotransmitters– amino acids, purines, biogenic amines
* Peptide neurotransmitters– 3-36 amino acid polypeptides, often derived from longer polypeptides


Note:


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## Examples of small-molecule neurotransmitters

<div><img src="figs/Neuroscience5e-Fig-06.01-2R_8d4e8d9.jpg" height="100px"><figcaption></figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-06.01-1R_e607c99.jpg" height="100px"><figcaption></figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-06.01-3R_d60bc57.jpg" height="100px"><figcaption></figcaption></div>


Note:


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## Examples of small-molecule neurotransmitters

share hydroxylated benzene ring

<div><img src="figs/Neuroscience5e-Fig-06.01-4R_45b484a.jpg" height="100px"><figcaption></figcaption></div>

Note:

most of which share a hydroxylated benzene ring


* -Catechol, also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula C6H4(OH)2

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## Examples of peptide neurotransmitters

Endogenous opioid peptide.

<div><img src="figs/Neuroscience5e-Fig-06.01-5R_a49bcdd.jpg" height="100px"><figcaption></figcaption></div>

Note:



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## Neurotransmitter release can be regulated at many steps

* Synthesis– small molecules are generated from biosynthetic enzymes
* Neuropeptides are generated by translation followed by protein processing
* Packaging into vesicles– requires specific transporters on vesicle membrane, there are different types of vesicles, small clear-core (e.g. ACh and amino acids) and large dense core (neuropeptides), biogenic amines do both. Location in synapses is different
* Release– small vesicles release fast, large-dense take more effort

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## The synthesis, packaging, secretion, and removal of neurotransmitters

<div><img src="figs/PN06061_50a5195.jpg" height="100px"><figcaption></figcaption></div>

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## Small molecule neurotransmitters are synthesized at the presynaptic terminal

Raw materials are collected by active transport. Neurotransmitter is synthesized and packaged at terminus.

<div><img src="figs/PN06062_3641612.jpg" height="100px"><figcaption></figcaption></div>

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## Neuropeptides are synthesized in the cell body

Neuropeptides are synthesized in the nerve cell body, loaded into vesicles and transported down the axon via microtublules.

<div><img src="figs/PN06063_3a75543.jpg" height="100px"><figcaption></figcaption></div>

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## Small molecule neurotransmitters

* Acetylcholine
* Amino acids
* Glutamate
* Aspartate
* GABA
* Glycine
* Purines (ATP)
* Biogenic amines
    * Dopamine
    * Norepinephrine
    * Epinephrine
    * Serotonin
    * histamine

Note:


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## Acetylcholine

* The neurotransmitter used at the neuromuscular junction. Also used at synapses in visceral motor system and at some CNS synapses– called cholinergic neurons
* Synthesized from acetyl CoA and choline by choline acetyl transferase (ChAT)– its presence is a good indication that the neuron is cholinergic
* Removed from synapse by acetylcholine esterase (AChE) has high activity can cleave 5000 molecules per second
* Sarin “nerve gas” is a AChE inhibitor

Note:

ACh: skeletal muscle excitation vs release from vagus nerve that slows down heart beat (cardiac muscle)—

* -Ligand gated channel that depolarizes skeletal muscle fibers vs g-protein coupled receptor that results in hyperpolarization of cardiomyocytes.

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## Acetylcholine

acetylcholineesterase (degradation)

choline acetyltransferase (synthesis)

<div><img src="figs/Neuroscience5e-Fig-06.02-0_dd0e243.jpg" height="100px"><figcaption></figcaption></div>

Note:

from krebs cycle you get Acetyl CoA. Na-Choline cotransporter exchanges Na ions for choline.

choline acetyltransferase…

VAChT packs ACh into vesicles. 

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## AChE Inhibition

* Sarin and Soman: toxic irreversible AChE inhibitors. Also known as “nerve gases” for use in chemical warfare.
* Designed to dispersed as a vapor cloud or spray, which allows their entry into the body through skin contact or inhalation. Drug quickly penetrates into bloodstream and is distributed to all organs, including the brain.
* Symptoms: profuse sweating and salivating, uncontrollable vomiting, gasping for breath, convulsing, and gruesome death . These are due to rapid accumulation of ACh and overstimulation of cholinergic synapses throughout the CNS and PNS. Death occurs through asphyxiation due to paralysis of the muscles of the diaphragm.

<div><img src="figs/MQ-ChOpener-6_72250dc.jpg" height="100px"><figcaption></figcaption></div>

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## Acetylcholine synthesis video summary

<div><video height=400px controls src="figs/Animation06-01NeurotransmitterPathwaysAcetylcholine.mp4"></video><figcaption>Neuroscience 5e Animation 6.1</figcaption></div>

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## Glutamate

* Most important transmitter for normal brain function.
* Nearly all excitatory neurons in the CNS are glutamatergic.
* Does not cross the blood brain barrier.
* Glutamine is most common precursor glutaminase converts it to glutamate. 
* Retrieved from synapse by glutamate transporters in glia and neurons. Glia (astrocytes) turn glutamate to glutamine and spit it back out
* Too much glutamate can kill the post-synaptic neuron (excitotoxicity). A major problem after damage due to stroke.

Note:

Most important neurotransmitter for normal brain function. Almost all excitatory neurons in CNS are glutamatergic. Half of all synapses estimated to use this transmitter. Glutamate is non-essential a.a. (by that I mean non-essential per dietary requirements) that does not cross the blood brain barrier. Synthesized inside neurons by local precursors.

histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.

Monosodium glutamate (MSG, also known as sodium glutamate) is the sodium salt of glutamic acid

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## Glutamate

<div><img src="figs/Neuroscience5e-Fig-06.05-0_0c18dfb.jpg" height="100px"><figcaption></figcaption></div>

Note:

system A transporter 2 (SAT2) transports glutamine into presynaptic terminal. Metabolized into glutamate by mitochondrial enzyme glutaminase. Also glucose metabolism from Krebs cycle can also produce glutamate. Packaged into vesicles by vesicular glutamate transporters (VGLUT). 3 different VGLUTs identified. 

Removed from cleft by excitatory a.a. transporters (EAATs). These are family of 5 Na⁺ dependent glutamate cotransporters. Some in glial cells, some in presynaptic terminals. Glutamate in glial cells by EAAT converted into glutamine by enzyme glutamine synthetase. Then transporter out by different transporter system N transporter 1 (SN1) then back into nerve cells by SAT2.

essential AA: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.

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## Glutamate

<div><img src="figs/Neuroscience5e-Box-05C-1R_bd8ae08.jpg" height="100px"><figcaption></figcaption></div>

Note:

histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.

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## Glutamate synthesis video summary

<div><video height=400px controls src="figs/Animation06-02NeurotransmitterPathwaysGlutamate.mp4"></video><figcaption>Neuroscience 5e Animation 6.2</figcaption></div> 

Note:

ACh role in Alzheimers: basal forebrain innervation to neocortex vs hippocampus. Cholinergic neuron degradation vs local postsynaptic neuron effects…

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## GABA and glycine

* Most inhibitory neurons use one or the other.
* Inhibits the ability to fire action potentials.
* GABA (gamma-aminobutyric acid) made from glutamate by glutamic acid decarboxylase (GAD), requires Vitamin B6 as cofactor. B6 deficiency can lead to loss of synaptic transmission.
* Glycine– about 1/2 of neurons in spinal cord use glycine.
* Both GABA and glycine are rapidly taken up by glia and neurons.
* Hyperglycinemia– defect in glycine uptake and removal leading to severe mental retardation.

Note:

As many as a third of synapses in the brain use GABA as an inhibitory transmitter. Most commonly found in local circuit neurons. 

glycine encephalopathy:  

[http://ghr.nlm.nih.gov/condition/glycine-encephalopathy](http://ghr.nlm.nih.gov/condition/glycine-encephalopathy)

>Glycine encephalopathy, which is also known as nonketotic hyperglycinemia or NKH, is a genetic disorder characterized by abnormally high levels of a molecule called glycine. This molecule is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Glycine encephalopathy is caused by the shortage of an enzyme that normally breaks down glycine in the body. A lack of this enzyme allows excess glycine to build up in tissues and organs, particularly the brain, leading to serious medical problems.

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## Glycine

* Inhibitory neurotransmitter
* Makes the post-synaptic membrane more permeable to Cl-. Can result in hyperpolarization of the post-synaptic cell
* Glycine receptor is primarily found in the ventral spinal cord
* Strychnine
* Glycine antagonist which can bind to the receptor without opening the Cl- channel
* (i.e. it inhibits inhibition)
* spinal hyperexcitability

<div><img src="figs/pt58a_e98273a.jpg" height="100px"><figcaption></figcaption></div>

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## Synthesis, release, and reuptake of the inhibitory neurotransmitters GABA and glycine

<div><img src="figs/Neuroscience5e-Fig-06.08-1R_025d494.jpg" height="100px"><figcaption></figcaption></div>

Note:

transported into vesicles by vesicular inhibitory amino acid transporter (VIAAT)

Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called GATs

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## Synthesis, release, and reuptake of the inhibitory neurotransmitters GABA and glycine

<div><img src="figs/Neuroscience5e-Fig-06.08-2R_cf6cdb2.jpg" height="100px"><figcaption></figcaption></div>

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## Biogenic amines

* Catecholamines– dopamine, norepinephrine, and epinephrine
* Histamine
* Serotonin
* All derived from tyrosine. Tyrosine hydroxylase is the rate limiting step and is a good histological marker for catecholaminergic neurons
* Are implicated in many complex behaviors

Note:

Biogenic amines regulate many functions in the CNS and PNS.  Ranging from homeostatic functions to cognition and attention.

* All come from same synthesis pathway
* defects in function implicated in many psychiatric disorders.
* targets of many drugs of abuse

*Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group.*

*reserpine used as antipsychotic, depletes Norep at synaptic terminals by blocking vesicle loading*

* organic structure template: R—NH2*

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## Catecholamine synthesis

Neuroscience 5e 6.10

<div><img src="figs/Neurscience5e-Fig-6_fc43ebb.jpg" height="100px"><figcaption></figcaption></div>

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## Dopamine

* Produced by the enzyme DOPA decarboxylase
* Made by substantia nigra pars compacta (which connects to corpus striatum for coordination of body movements).
* Does not cross the blood brain barrier, but levadopa (L-DOPA) does.
* Parkinson’s treatments include L-DOPA plus degradation enzyme inhibitors
* Cocaine inhibits uptake of dopamine (inhibits DAT)

<div><img src="figs/image_1d47b5b.png" height="100px"><figcaption></figcaption></div>

Note:

Synthesized in cytoplasm of presynaptic terminals.

Loaded into synaptic vesicles by vesicular monoamine transporter (VMAT). Dopamine in synaptic cleft is terminated by reuptake of dopamine into nerve terminals or glia cells by a Na-dependent dopamine cotransporter called DAT. Cocaine works by inhibiting DAT, increasing dopamine concentrations in synaptic cleft.  

Amphetamine also inhibits DAT as well as a transporter for norepinephrine

* Catabolized by monoamine oxidase and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT.  Inhibitors of these enzymes are targets of some kinds of antidepressants (phenelzine and tranylcypromine)
* Acts throught GPCRs. D3 parallels that of other metabotropic receptors like mAChR.  Subtypes act by activating or inhibiting adenylyl cyclase.
* Activation leads to complex behaviors. Antagonists can cause catalepsy (state where difficult to initiate voluntary movement). 
* L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines.
* it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase. 

*Encephalitis lethargica, sleeping sickness, 40 yrs later Oliver Sacks in NYC treats them with L-DOPA*

* neostriatum
* Part of
    * Basal ganglia[1]
    * Reward system[2][3]
* Components
    * Ventral striatum[2][3][4
    * Dorsal striatum[2][3][4]

The corpus striatum, a macrostructure which contains the striatum, is composed of the entire striatum and the globus pallidus. The lenticular nucleus refers to the putamen together with the globus pallidus.

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## PET scans before and after cocaine

Red means lots of unoccupied dopamine receptors

before

after

<div><img src="figs/image1_d2a2eb1.png" height="100px"><figcaption></figcaption></div>

<div><img src="figs/image2_0ee389f.png" height="100px"><figcaption></figcaption></div>

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striatum.

>Imaging studies in humans show that low striatal D2 receptor binding in cocaine abusers in the striatum correlates with decreases in glucose metabolism in the orbito-frontal cortex and cingulate gyrus, which process drive and affect, and may lead to continued drug-taking behavior (Volkow et al., 1993, 1999)

anterior cingulate cortex 

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## Projections from dopaminergic neurons in the human brainstem

<div><img src="figs/Neuroscience5e-Fig-06.11-1R_adab2f5.jpg" height="100px"><figcaption></figcaption></div>

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## Dopamine synthesis video summary

<div><video height=400px controls src="figs/Animation06-03NeurotransmitterPathwaysDopamine.mp4"></video><figcaption>Neuroscience 5e Animation 6.3</figcaption></div> 

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## Norepinephrine

* also called noradrenaline
* Comes from dopamine by way of dopamine-β-hydroxylase
* Sympathetic ganglion cells use it– project to visceral motor system (fight or flight response)
* Used as a transmitter from locus coeruleus in brainstem– projects to areas that are involved in sleep, attention, and feeding
* Its reuptake mechanism, the norepinephrine transporter (NET), is a target of amphetamines

Note:

VMAT for loading into vesicles

Norep transporter (NET) is a Na⁺ depedent cotranporter. NET is a target of amphetamines.

alpha and beta adrengergic receptors. GPCRs. Some alphas lead to slow depolarization. Some lead to slow hyperpolarization (acting on different K⁺ channels). 

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## Projections from noradrenergic neurons in the human brainstem

<div><img src="figs/Neuroscience5e-Fig-06.11-2R_fc0c7eb.jpg" height="100px"><figcaption></figcaption></div>

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## Norepinephrine synthesis video summary

<div><video height=400px controls src="figs/Animation06-04NeurotransmitterPathwaysNorepinephrine.mp4"></video><figcaption>Neuroscience 5e Animation 6.4</figcaption></div> 

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## Epinephrine

* Adrenaline– present at lower levels than the others
* Made by neurons in rostral medulla. Project to thalamus and hypothalamus

Note:

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## Projections from adrenergic neurons in the human brainstem

<div><img src="figs/Neuroscience5e-Fig-06.11-3R_c9ee16b.jpg" height="100px"><figcaption></figcaption></div>

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## Serotonin

* 5-hydroxytryptamine (5-HT)
* Made from tryptophan
* Reuptake by specific serotonin transporters
* Many antidepressants act by inhibiting serotonin reuptake (selective serotonin reuptake inhibitors-SSRIs). Prozac, Zoloft
* Found primarily in groups of neurons in the raphe region of the pons and upper brainstem
* The raphe nucleus projects widespread in forebrain areas that are implicated in sleep and wakefulness and mood

Note:

VMAT loads this (as well as other monoamines) into synaptic vesicles.

turkey/tryptophan—> sleep?   Yes— but not really, you’d have to eat a lot more (3x more according to tryptophan supplements) than typically at thanksgiving meal.

[http://www.snopes.com/food/ingredient/turkey.asp](http://www.snopes.com/food/ingredient/turkey.asp)

Chicken and ground beef contain almost the same amount of tryptophan as turkey — about 350 milligrams per 4-ounce serving.

Swiss cheese and pork actually contain more tryptophan per gram than turkey,

The amount of tryptophan in a single 4-ounce serving of turkey (350 milligrams) is also lower than the amount typically used to induce sleep. The recommendations for tryptophan supplements to help you sleep are 500 to 1,000 milligrams.

[http://www.webmd.com/food-recipes/the-truth-about-tryptophan?page=2](http://www.webmd.com/food-recipes/the-truth-about-tryptophan?page=2)

>The small, all-carbohydrate snack is tryptophan's ticket across the blood-brain barrier, where it can boost serotonin levels. So have your turkey, Somer says, because it will increase your store of tryptophan in the body, but count on the carbohydrates to help give you the mood boost or the restful sleep.

>"Research shows that a light, 30 gram carbohydrate snack just before bed will actually help you sleep better," Somer says.

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## Histamine

* Made from histidine, metabolized by monoamine oxidase
* Made by neurons in hypothalamus that send projections to all regions of the brain and spinal cord.
* Mediates arousal and attention.
* Histamine receptors are in the immune system and in the CNS.  The sedative side effects of Benadryl act through the CNS.

Note:

* H1 receptors (antagonists used for treating motion sickness because role in vestibular function)
* H2 receptors control secretion of gastrci acid in digestive system

*transported into vesicle by VMAT as catecholamines*

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## Synthesis of histamine and serotonin

<div><img src="figs/Neuroscience5e-Fig-06.14-0_8dfa976.jpg" height="100px"><figcaption></figcaption></div>

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## Widespread projections from histaminergic and serotonergic neurons in the human brain

<div><img src="figs/Neuroscience5e-Fig-06.13-0_4dffa68.jpg" height="100px"><figcaption></figcaption></div>

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## Serotonin synthesis video summary

<div><video height=400px controls src="figs/Animation06-05NeurotransmitterPathwaysSerotonin.mp4"></video><figcaption>Neuroscience 5e Animation 6.5</figcaption></div> 

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## Peptide neurotransmitters

* 3-36 or so amino acids, cleaved from larger precursor proteins
* Catabolized by peptidases
* 5 general classes, brain/gut peptides, opioid peptides, pituitary peptides, hypothalamic releasing hormones, all others.
* Packaged into large dense core vesicles (amino acids are packaged into small clear core vesicles).
* Generally used as co-transmitters

Note:

* Many peptide known to be hormones also act as neurotransmitters
* melanocyte-stimulating hormone, adrenocorticotropin, Beta-endorphin regulate complex responses to stress
* substance P and opioid peptides involved in the perception of pain

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## Amino acid sequences of peptide neurotransmitters

<div><img src="figs/Neurscience5e-Fig-7_457014e.jpg" height="100px"><figcaption></figcaption></div>

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## Examples of peptide neurotransmitters

Endogenous opioid peptide.

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## Synthesis of neuropeptides

Neuropeptides are synthesized as pre-propeptides in the nerve cell bodies.

This includes a signal sequence that targets the peptides to the inside of the endoplasmic reticulum.

The signal sequence is cleaved to form the propeptide.

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## Synthesis of neuropeptides

ACTH– adrenocorticotripic hormone

modulation of pain

Note:

Proteolytic processing of the pre-propeptides, pre-proopiomelanocortin and pre-proenkaphalin

Processing the polypeptides that make the final neuropeptdies happens in an neurons cell body. Propeptide packaged into vesicles in golgi network. Final peptide processing occurs after packaging into vesicles.  Multiple neuroactive peptides can be released from a single vesicle. 

melanocyte-stimulating hormone, adrenocorticotropin, Beta-endorphin regulate complex responses to stress

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## Synthesis of neuropeptides

<div><img src="figs/Neuroscience5e-Fig-06.16-2R_2af6762.jpg" height="100px"><figcaption></figcaption></div>

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Proteolytic processing of the pre-propeptides, pre-proopiomelanocortin and pre-proenkaphalin

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## Peptide dense core vesicles

<div><img src="figs/05_003_816f885.jpeg" height="100px"><figcaption></figcaption></div>

Note:

Neurons very often make both a conventional neurotransmitter (such as glutamate, GABA or dopamine) and one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the co-existing neurotransmitters in small synaptic vesicles. 

The large dense-core vesicles are often found in all parts of a neuron, including the soma, dendrites, axonal swellings (varicosities) and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations.

This refers to the larger amount of material inside the dense-core vesicles, which contain not only neurotransmitters, but also proteases and other peptide chains that have been cleaved from the active neurotransmitter. 

Greater electron scattering in EM:  

Chemical fixation – for biological specimens aims to stabilize the specimen's mobile macromolecular structure by chemical crosslinking of proteins with aldehydes such as formaldehyde and glutaraldehyde, and lipids with osmium tetroxide.

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## Clear core vesicles release upon a single action potential

Neuroscience 5e 5.12

<div><img src="figs/PN06050_48d4116.jpg" height="100px"><figcaption></figcaption></div>

Note:

release of small molecule transmitters inside clear core vesicles 

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## Large core release after multiple action potentials

Neuroscience 5e 5.12

Note:

release of both types of neurotransmitter

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## Examples of peptide neurotransmitters

* Substance P– 16 amino acid peptide
* Present in human hippocampus, neocortex, and GI tract (hence a brain-gut peptide)
* Involved in the perception of pain
* Released from C-fibers which carry information about pain and temperature

Note:

accidental discovery of substance P.  ominous sounding compound from Area 51?  No.  It was an unidentified component of power extracts from brain and intestine.  High conc. in hippocampus, neocortex, and GI tract.  A brain/gut peptide.   Release of Subst P in cfibers can be inhibited by spinal interneurons releasing opioid peptides.

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## Opioids

* Bind to same post-synaptic receptors as opium
* Family with more than 20 members, three basic groups:  endorphins, enkephalins, and dynorphins
* Often co-localized with GABA and serotonin
* Tend to act as depressants, used for analgesics
* Repeated use often leads to tolerance and addiction

Note:

Opioids are named because they bind to same postsynaptic receptors as opium.

* -opium poppy cultivated for 5000 yrs
* -opium contains a variety of plant alkaloids, predominantly morphine. Morpheus, greek god of dreams. Very effective analgesic. Fentanyl, synthetic opiate with 80 times analgesic potency of morphine

Opioid peptides distributed throughout the brain. Colocalize with GABA and 5-HT. Tend to be depressants. They act like analgesics when injected intracerebrally. Initiate effects through GPCRs. Activate at low concentrations (nM to uM). mu, delta, kappa opioid receptor subtypes play role in reward and addiction. mu-receptor is primary site for opiate drugs.

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## Cannabinoids

* Cannabinoids
* Δ9-tetrahydrocannabinol (THC)
* Endocannabinoids
* anandamide
* 2-arachidonylglycerol (2-AG)
* Bind to G-protein coupled receptors (GPCRs): CB1 & CB2
* CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum

<div><img src="figs/Neuroscience5e-Box-06G-3R_0a7cb48.jpg" height="100px"><figcaption></figcaption></div>

<div><img src="figs/Neuroscience5e-Box-06G-4R_8fb7d74.jpg" height="100px"><figcaption></figcaption></div>

<div><img src="figs/Neuroscience5e-Box-06G-1R_7963b9b.jpg" height="100px"><figcaption></figcaption></div>

Note:

used for hemp (fiber, oil, seed)

cannabis sativa

cannabis indica

* -A hybrid Cannabis strain (White Widow) (which contains one of the highest amounts of Cannabidiol), flower coated with trichomes, which contain more THC than any other part of the plant

phytocannabinoids (85 active identified in cannabis)

THC: 

-agonist of both CB1 and CB2
-mild to moderate analgesic effects (dorsal root ganglion and PAG), antiemetic (anti-nausea)
-tolerance appears to be irregular throughout mouse brain areas
-possesses mild antioxidant activity

* Bioavailability10–35% (inhalation), 6–20% (oral)[3]
* Protein binding97–99%[3][4][5]
* MetabolismMostly hepatic by CYP2C[3]
* Biological half-life1.6–59 h,[3] 25–36 h (orally administered dronabinol)
* Excretion65–80% (feces), 20–35% (urine) as acid metabolites[3]

cannabidiol: a major phytocannabinoid, accounting for up to 40% of the plant's extract.  More complex effects than THC, may potentiate effects through CB1 density increases, inhibition of FAAH. Allosteric modulator of mu-opioid receptors. Less understood. 

cannabinol: higher affinity for CB2 (but weaker than THC)

Unconventional neurotransmitters. released from neurons, regulated by Ca²⁺, and have specific receptors, but not released from synapses by exocytotic vesicle mechanisms. Often unconventional NTs are associated with retrograde signaling from post to pre. 

[from https://en.wikipedia.org/wiki/Anandamide](https://en.wikipedia.org/wiki/Anandamide)

>Anandamide, also known as N-arachidonoylethanolamine or AEA, is an essential fatty acid neurotransmitter derived from the non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid) an essential ω-6 polyunsaturated fatty acid

>Anandamide's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[6] The latter are mainly involved in functions of the immune system.

These endocannabinoids are actually unsaturated fatty acids from enzymatic digestion of membrane lipids. Production stimulated by second messengers within postsynaptic neuron, typically a rise in postsynaptic Ca²⁺ concentration.

-anandamide

-2-arachidonylglycerol (2-AG)

Mechanism of release not clear, but likely that these hydrophobic signals diffuse through the postsynaptic membrane to reach cannabinoid receptors on nearby cells. Action terminated by carrier mediated transport into postsynaptic neuron and hydrolyzed by enzyme fatty acid hydrolase (FAAH).

-rimonabant, synthetic drug

GPCRs:

CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum

CB2 expressed in cells throughout the immune system. T cells, macrophages, B cells, peripheral nerve terminals (relief of pain), microglial cells

major CB2 targets are: >immune and immune-derived cells (e.g. leukocytes, various populations of T and B lymphocytes, monocytes/macrophages, dendritic cells, mast cells, microglia in the brain, Kupffer cells in the liver, etc.

>multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).[25] However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.[#Demuth:2006]

inhibits inhibition on presynaptic GABAergic neurons. Inhibits IPSCs. disinhibitory effect.

[#Demuth:2006]: Demuth DG, Molleman A (2006). "Cannabinoid signalling". Life Sci. 78 (6): 549–63. doi:10.1016/j.lfs.2005.05.055. PMID 16109430.


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## Summary

<div><img src="figs/Neuroscience5e-Tab-06.01_cec3255.jpg" height="100px"><figcaption></figcaption></div>

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