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@@ -12,92 +12,217 @@ So we already defined what a neurotransmitter is. It is a substance that must be
## Major categories of neurotransmitters
* Small molecule neurotransmitters– amino acids, purines, biogenic amines
* Small molecule neurotransmitters– acetylcholine, amino acids, biogenic amines, purines
* Peptide neurotransmitters– 3-36 amino acid polypeptides, often derived from longer polypeptides
Note:
---
## 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>
<div>
<figure><figcaption class="big">acetylcholine</figcaption><img src="figs/Neuroscience5e-Fig-06.01-1R_copy_6024655.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 6.1</figcaption></figure>
<figure style="margin:25px 0;"><figcaption class="big">purines</figcaption><img src="figs/Neuroscience5e-Fig-06.01-3R_copy_2d816ba.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 6.1</figcaption></figure>
</div>
<div><figcaption class="big">amino acids</figcaption><img src="figs/Neuroscience5e-Fig-06.01-2R_copy_55575eb.jpg" width="400px"><figcaption>Neuroscience 5e Fig. 6.1</figcaption></div>
Note:
Not expected to know chemical formulas for any neurotransmitters
---
## Examples of small-molecule neurotransmitters
share hydroxylated benzene ring
<figure><figcaption class="big">biogenic amines</figcaption><img src="figs/Neuroscience5e-Fig-06.01-4R_copy_6c270be.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 6.1</figcaption></figure>
<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
*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*
---
## Examples of peptide neurotransmitters
Endogenous opioid peptide.
<div><img src="figs/Neuroscience5e-Fig-06.01-5R_a49bcdd.jpg" height="100px"><figcaption></figcaption></div>
<figure><figcaption class="big">peptides</figcaption><img src="figs/Neuroscience5e-Fig-06.01-5R_copy_3c25836.jpg" height="300px"><figcaption>methionine enkephalin: an endogenous opioid peptide; Neuroscience 5e Fig. 6.1</figcaption></figure>
Note:
- usually 3-30 amino acids long
- more than 100 peptides
---
## 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
* Synthesis–
* Small molecules are generated from biosynthetic enzymes
* Neuropeptides are generated by translation followed by post-translational 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 can be in either vesicle type. Location in synapses is different
* Release– small clear-core vesicles release fast, large dense-core vesicles take more effort
Note:
<!-- *synthesis, packaging, secretion, and removal of neurotransmitters*
<figure><img src="figs/Neuroscience5e-Fig-05.03-0R_a8b0a13.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 5.3</figcaption></figure> -->
small clear-core vesicles
: clear centers in EM
: 40–60 nm diameter
large dense-core vesicles
: electron dense centers
: 90–250 nm diameter
---
## Small molecule transmitters are synthesized at the presynaptic terminal
Enzymes produced in nerve cell body are transported down axon. Neurotransmitter is synthesized and packaged at synaptic terminal.
<figure><img src="figs/Neuroscience5e-Fig-05.05-1R_copy_4507f9b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.5</figcaption></figure>
Note:
* synthesis of enzymes in cell body
* slow (0.5–5.0 mm/day) axonal transport of enzymes
* synthesis and packaging of transmitter in local synaptic terminal
* breakdown of transmitter by enzymes in extracellular space or nearby astrocytes, transport of precursors back into synaptic terminal
---
## Peptide transmitters are synthesized in the cell body
Neuropeptides are synthesized in the nerve cell body, loaded into vesicles, and transported down the axon via microtubules.
<figure><img src="figs/Neuroscience5e-Fig-05.05-3R_copy_e9ebd70.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.5</figcaption></figure>
Note:
* synthesis of propeptide precursors and enzymes in cell body
* fast axonal transport (400 mm/day) of enzymes and peptide precursors inside vesicles down microtubules (requires ATP motor proteins like kinesin)
* proteolytic processing of propeptides by enzymes to produce peptide neurotransmitter
* peptide neurotransmitter diffuses away, degraded by proteolytic enzymes (typically on extracellular surface)
---
## Synaptic vesicle types
<div><figcaption class="big">small clear-core vesicles</figcaption><img src="figs/Neuroscience5e-Fig-05.05-2R_copy_30d366b.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 5.5</figcaption></div>
<div><figcaption class="big">large dense-core vesicles</figcaption><img src="figs/Neuroscience5e-Fig-05.05-4R_copy_0b0e2ec.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 5.5</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.
---
## The synthesis, packaging, secretion, and removal of neurotransmitters
## Large dense-core vesicles release after high frequency AP stimulation
<div><img src="figs/PN06061_50a5195.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Fig-05.12-0R_5f31ced.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.12</figcaption></figure>
Note:
* release of small molecule transmitters inside clear core vesicles
* release of both types of neurotransmitter
---
## Small molecule neurotransmitters are synthesized at the presynaptic terminal
Raw materials are collected by active transport. Neurotransmitter is synthesized and packaged at terminus.
## Small molecule neurotransmitters
<div><img src="figs/PN06062_3641612.jpg" height="100px"><figcaption></figcaption></div>
<div style="font-size:0.8em;">
<div></div>
* Acetylcholine <!-- .element: class="fragment highlight-red" -->
* Amino acids
* glutamate
* aspartate
* GABA
* glycine
* Biogenic amines
* dopamine
* norepinephrine
* epinephrine
* serotonin
* histamine
* Purines (ATP)
</div>
Note:
---
## Neuropeptides are synthesized in the cell body
## Acetylcholine
Neuropeptides are synthesized in the nerve cell body, loaded into vesicles and transported down the axon via microtublules.
* 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) which has high activity– can cleave 5000 molecules per second
* Sarin "nerve gas" is a AChE inhibitor
<div><img src="figs/PN06063_3a75543.jpg" height="100px"><figcaption></figcaption></div>
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.
--
## Acetylcholine
<figure><figcaption class="big">
**choline acetyltransferase** (synthesis)
**acetylcholinesterase** (degradation)
</figcaption><img src="figs/Neuroscience5e-Fig-06.02-0_f4bacb8.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 6.2</figcaption></figure>
Note:
from krebs cycle you get Acetyl CoA. Na-Choline cotransporter exchanges Na ions for choline.
choline acetyltransferase...
VAChT packs ACh into vesicles
--
## AChE Inhibition
<div style="font-size:0.8em;">
<div></div>
* 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>
<div><img src="figs/MQ-ChOpener-6_copy_40a72ba.jpg" height="100px"><figcaption>Psychopharmacology Chp. 6, 2006 Sinauer</figcaption></div>
Note:
--
## Acetylcholine synthesis video summary
<div><video height=400px controls src="figs/Animation06-01NeurotransmitterPathwaysAcetylcholine.mp4"></video><figcaption>Neuroscience 5e Animation 6.1</figcaption></div>
Note:
@@ -106,100 +231,55 @@ Note:
## Small molecule neurotransmitters
<div style="font-size:0.8em;">
<div></div>
* Acetylcholine
* Amino acids
* Glutamate
* Aspartate
* GABA
* Glycine
* Purines (ATP)
* Amino acids <!-- .element: class="fragment highlight-red" -->
* glutamate
* aspartate
* GABA
* glycine
* Biogenic amines
* Dopamine
* Norepinephrine
* Epinephrine
* Serotonin
* dopamine
* norepinephrine
* epinephrine
* serotonin
* histamine
* Purines (ATP)
</div>
Note:
---
## 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.
---
## 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.
---
## 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>
Note:
---
## Acetylcholine synthesis video summary
<div><video height=400px controls src="figs/Animation06-01NeurotransmitterPathwaysAcetylcholine.mp4"></video><figcaption>Neuroscience 5e Animation 6.1</figcaption></div>
Note:
---
## 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.
* Most abundant neurotransmitter
* 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. 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.
Most common neurotransmitter for normal brain function. Almost all excitatory neurons in CNS are glutamatergic. Half of all synapses estimated to use this transmitter.
histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
Glutamate (glutamic acid) is non-essential a.a. (meaning non-essential per dietary requirements) that does not cross the blood brain barrier. Synthesized inside neurons by local precursors.
Monosodium glutamate (MSG, also known as sodium glutamate) is the sodium salt of glutamic acid
*Essential amino acids are: 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*
--
## Glutamate
<div><img src="figs/Neuroscience5e-Fig-06.05-0_0c18dfb.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Fig-06.05-0_9d0ed18.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 6.5</figcaption></figure>
Note:
@@ -209,17 +289,16 @@ Removed from cleft by excitatory a.a. transporters (EAATs). These are family of
essential AA: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
---
--
## Glutamate
<div><img src="figs/Neuroscience5e-Box-05C-1R_bd8ae08.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Box-05C-1R_copy_8635591.jpg" height="400px"><figcaption></figcaption></figure>
Note:
histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
---
--
## Glutamate synthesis video summary
@@ -233,12 +312,12 @@ ACh role in Alzheimers: basal forebrain innervation to neocortex vs hippocampus.
## 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.
* 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:
@@ -250,28 +329,31 @@ 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.
---
--
## Glycine
* Inhibitory neurotransmitter
* Makes the post-synaptic membrane more permeable to Cl-. Can result in hyperpolarization of the post-synaptic cell
* 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
* glycine receptor 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>
<div><img src="figs/pt58a_e98273a.jpg" height="100px"><figcaption>*Strychnos nux-vomica*</figcaption></div>
Note:
Strychnine
: highly toxic, colorless, bitter crystalline alkaloid
: from *Strychnos nux-vomica* native to India, Sri Lanka, and Indonesia
---
--
## 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>
<figure><img src="figs/Neuroscience5e-Fig-06.08-1R_ec0f42e.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.8</figcaption></figure>
Note:
@@ -279,11 +361,36 @@ transported into vesicles by vesicular inhibitory amino acid transporter (VIAAT)
Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called GATs
---
--
## 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>
<figure><img src="figs/Neuroscience5e-Fig-06.08-2R_4f2491c.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.8</figcaption></figure>
Note:
---
## Small molecule neurotransmitters
<div style="font-size:0.8em;">
<div></div>
* Acetylcholine
* Amino acids
* glutamate
* aspartate
* GABA
* glycine
* Biogenic amines <!-- .element: class="fragment highlight-red" -->
* dopamine
* norepinephrine
* epinephrine
* serotonin
* histamine
* Purines (ATP)
</div>
Note:
@@ -299,25 +406,23 @@ Note:
Note:
Biogenic amines regulate many functions in the CNS and PNS. Ranging from homeostatic functions to cognition and attention.
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.
* 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*
- *reserpine used as antipsychotic, depletes Norep at synaptic terminals by blocking vesicle loading*
- *organic structure template: R—NH2*
* organic structure template: R—NH2*
---
--
## Catecholamine synthesis
Neuroscience 5e 6.10
<figure><img src="figs/Neuroscience5e-Fig-06.10-0_d620c90.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 6.10</figcaption></figure>
<div><img src="figs/Neurscience5e-Fig-6_fc43ebb.jpg" height="100px"><figcaption></figcaption></div>
Note:
@@ -326,13 +431,11 @@ Note:
## 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.
* 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.
@@ -359,38 +462,32 @@ Amphetamine also inhibits DAT as well as a transporter for norepinephrine
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.
---
## PET scans before and after cocaine
<!-- 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>
Note:
before <div><img src="figs/image1_d2a2eb1.png" height="100px"><figcaption></figcaption></div>
after <div><img src="figs/image2_0ee389f.png" height="100px"><figcaption></figcaption></div>
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
-->
---
--
## Projections from dopaminergic neurons in the human brainstem
<div><img src="figs/Neuroscience5e-Fig-06.11-1R_adab2f5.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Fig-06.11-1R_a4286c3.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.11</figcaption></figure>
Note:
---
--
## Dopamine synthesis video summary
@@ -417,16 +514,17 @@ Norep transporter (NET) is a Na⁺ depedent cotranporter. NET is a target of amp
alpha and beta adrengergic receptors. GPCRs. Some alphas lead to slow depolarization. Some lead to slow hyperpolarization (acting on different K⁺ channels).
---
--
## Projections from noradrenergic neurons in the human brainstem
<div><img src="figs/Neuroscience5e-Fig-06.11-2R_fc0c7eb.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Fig-06.11-2R_7dc8aba.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.11</figcaption></figure>
Note:
---
--
## Norepinephrine synthesis video summary
@@ -444,11 +542,11 @@ Note:
Note:
---
--
## Projections from adrenergic neurons in the human brainstem
<div><img src="figs/Neuroscience5e-Fig-06.11-3R_c9ee16b.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Fig-06.11-3R_9d1377d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.11</figcaption></figure>
Note:
@@ -488,9 +586,9 @@ The amount of tryptophan in a single 4-ounce serving of turkey (350 milligrams)
## 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.
* 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:
@@ -503,20 +601,21 @@ Note:
## Synthesis of histamine and serotonin
<div><img src="figs/Neuroscience5e-Fig-06.14-0_8dfa976.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Fig-06.14-0_e342a8b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.14</figcaption></figure>
Note:
---
--
## 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>
<figure><img src="figs/Neuroscience5e-Fig-06.13-0_2e4abbc.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.13</figcaption></figure>
Note:
---
--
## Serotonin synthesis video summary
@@ -524,123 +623,81 @@ Note:
Note:
---
## 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).
* 5 general classes, brain/gut peptides, opioid peptides, pituitary peptides, hypothalamic releasing hormones, all others
* Packaged into large dense-core vesicles
* Generally used as co-transmitters
Note:
* Many peptide known to be hormones also act as neurotransmitters
* Many peptides 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
---
--
## Amino acid sequences of peptide neurotransmitters
<div><img src="figs/Neurscience5e-Fig-7_457014e.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Fig-06.17-0_8eb7593.jpg" height="400px"><figcaption> Neuroscience 5e fig. 6.17</figcaption></figure>
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## Examples of peptide neurotransmitters
Endogenous opioid peptide.
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---
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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.
* 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
<figure><img src="figs/Neuroscience5e-Fig-06.16-1R_1c3f58b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.16</figcaption></figure>
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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.
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
proopiomelanocortin
: precursor for melanocyte-stimulating hormone, adrenocorticotropin, beta-endorphin
: regulate complex responses to stress and modulation of pain
: beta-endorphin binds to mu-opioid receptors
---
ACTH
: adrenocorticotropic hormone
: corticotropin
: secreted by anterior pituitary gland
: produced in response to stress
: increases production of cortisol in adrenal glands
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## Synthesis of neuropeptides
<div><img src="figs/Neuroscience5e-Fig-06.16-2R_2af6762.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Fig-06.16-2R_11ddd71.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 6.16</figcaption></figure>
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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>
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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>
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release of small molecule transmitters inside clear core vesicles
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## Large core release after multiple action potentials
Neuroscience 5e 5.12
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release of both types of neurotransmitter
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## Examples of peptide neurotransmitters
## Examples of peptide transmitters– Substance P
* Substance P– 16 amino acid peptide
* Present in human hippocampus, neocortex, and GI tract (hence a brain-gut peptide)
@@ -649,14 +706,14 @@ release of both types of neurotransmitter
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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.
accidental discovery of substance P. Ominous sounding compound from Area 51? No. It was an unidentified component of powder 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.
---
## Opioids
## Examples of peptide transmitters– Opioids
* Bind to same post-synaptic receptors as opium
* Family with more than 20 members, three basic groups: endorphins, enkephalins, and dynorphins
* 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
@@ -665,73 +722,88 @@ 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
* 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.
---
## Cannabinoids
## Unconventional neurotransmitters– Cannabinoids
<div style="font-size:0.8em;">
<div></div>
* Cannabinoids
* Δ9-tetrahydrocannabinol (THC)
* Endocannabinoids
* anandamide
* 2-arachidonylglycerol (2-AG)
* Endocannabinoids
* anandamide <img style="display:inline;vertical-align:middle;margin:none;border:none;" src="figs/Anandamide_7fa01d6.svg" height="25px">
* 2-arachidonylglycerol (2-AG) <img style="display:inline;vertical-align:middle;margin:none;border:none;" src="figs/2-Ara-Gl_544fac0.svg" height="25px">
* Δ<sup>9</sup>-tetrahydrocannabinol (THC) <img style="display:inline;vertical-align:middle;margin:none;border:none;" src="figs/Tetrahydrocannabinol_b4f21b0.svg" height="25px">
* main psychoactive compound in *cannabis sativa*/*indica* <img style="display:inline-block;vertical-align:middle;margin:none;border:none;" src="figs/Neuroscience5e-Box-06G-1R_1bc059e.jpg" height="25px">
* 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>
<div><img src="figs/Neuroscience5e-Box-06G-4R_8fb7d74.jpg" height="100px"><figcaption></figcaption></div>
<div><figcaption class="big">CB1 expression in rodent</figcaption><img src="figs/Neuroscience5e-Box-06G-4R_ece2b22.jpg" height="150px"><figcaption>Neuroscience 5e Box 6</figcaption></div>
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<div><img src="figs/Neuroscience5e-Box-06G-1R_7963b9b.jpg" height="100px"><figcaption></figcaption></div>
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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.
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.
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).
[Anandamide](https://en.wikipedia.org/wiki/Anandamide)
: N-arachidonoylethanolamine
: essential fatty acid neurotransmitter
: derived from non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid, an essential ω-6 polyunsaturated fatty acid)
: effects can occur in either CNS or PNS
: effects by CB1 cannabinoid receptors in the CNS and CB2 cannabinoid receptors in the PNS [#Pacher:2006]
: CB2 receptors involved in regulating immune system function
: found in chocolate [#Tomaso:1996]
: endocannabinoids, long chain fatty acids like anandamide found in drosophila melanogaster [#Jeffries:2014] but cannabinoid receptors are not [#McPartland:2001]
[#Pacher:2006]: Pacher, P., Bátkai, S., and Kunos, G. (2006). The endocannabinoid system as an emerging target of pharmacotherapy, Pharmacol Rev, 58(3), 389-462
[#Tomaso:1996]: di Tomaso, E., Beltramo, M., and Piomelli, D. (1996). Brain cannabinoids in chocolate, Nature, 382(6593), 677-8
[#Jeffries:2014]: Jeffries, K. A., Dempsey, D. R., Behari, A. L., Anderson, R. L., and Merkler, D. J. (2014). Drosophila melanogaster as a model system to study long-chain fatty acid amide metabolism, FEBS Lett, 588(9), 1596-602
[#McPartland:2001]: McPartland, J., Di Marzo, V., De Petrocellis, L., Mercer, A., and Glass, M. (2001). Cannabinoid receptors are absent in insects, J Comp Neurol, 436(4), 423-9
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 amide hydrolase (FAAH).
Psychotropic
: psychoactive
: chemical substance that changes brain function resulting in altered perception, mood, or conciousness
* cannabis sativa
* cannabis indica
* phytocannabinoids (85 active identified in cannabis)
* used for hemp (fiber, oil, seed)
* 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
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
* Bioavailability 10–35% (inhalation), 6–20% (oral)[3]
* Protein binding 97–99%[3][4][5]
* Metabolism Mostly hepatic by CYP2C[3]
* Biological half-life 1.6–59 h,[3] 25–36 h (orally administered dronabinol)
* Excretion 65–80% (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). Breakdown product of THC
-rimonabant, synthetic drug
@@ -749,12 +821,24 @@ inhibits inhibition on presynaptic GABAergic neurons. Inhibits IPSCs. disinhibit
[#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.
Other cannabinoid-like compounds found in other plants (e.g. Echinacea). Some like b-caryophyllene (volatile plant terpene) are quite common among plants (incl cannabis sativa) and act as agonist (nM concentrations) of CB2 [#Gertsch:2010]. Most of these that have been found so far have affinities for CB2. Mostly just THC with non-selective affinity for CB1 (and CB2 modulation) at nM concentrations so far. But Falcarinol also has non-selective CB1 affinity (at µM concentrations) [#Gertsch:2010], and is widespread in Apiaceae (celery, carrot, parsley family) like *Daucus carota* also in red ginseng *Panax ginseng*) though it might work as an inverse agonist.
[#Gertsch:2010]: Gertsch, J., Pertwee, R. G., and Di Marzo, V. (2010). Phytocannabinoids beyond the Cannabis plant - do they exist?, Br J Pharmacol, 160(3), 523-9
*Apiaceae*
: angelica, anise, arracacha, asafoetida, caraway, carrot, celery, Centella asiatica, chervil, cicely, coriander (cilantro), culantro, cumin, dill, fennel, hemlock, lovage, cow parsley, parsley, parsnip, cow parsnip, sea holly, giant hogweed and silphium
*Daucus carota*
: wild carrot
: 'Queen Anne's lace'
: domesticated carrots are cultivars of a subspecies
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## Summary
<div><img src="figs/Neuroscience5e-Tab-06.01_cec3255.jpg" height="100px"><figcaption></figcaption></div>
<figure><img src="figs/Neuroscience5e-Tab-06.01_copy_98ede88.jpg" height="400px"><figcaption>Neuroscience 5e Table 6.1</figcaption></figure>
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