ANAT 322 Lecture Notes - Lecture 14: Fear Conditioning, Aldosterone, Nmda Receptor Antagonist
7 Jun 2018
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ANAT 322 Winter 2017
Lectures
Lecture 14:
→ Stress and Glucocorticoids in the Periphery and CNS
3. Glucocorticoids are hydrophobic molecules that do not circulate freely in the plasma and are bound
to proteins called albumin or corticosteroid binding globulin. These act as carriers and deliver the
steroids to the target cells. They do not enter the brain but they deliver the steroid to the brain once the
steroids reach the brain as they dissociate from the carrier protein and enter the tissue freely.
There are two mechanisms that will regulate the amount of steroids found in particular target sites.
One is called the multiple drug resistance protein which is a membrane protein that acts as a barrier. It
will prevent the entry into the brain of synthetic glucocorticoids like dexamethasone. Dexamethasone
will be excluded from the brain as well as high doses of cortisol so that corticosterone enters freely.
There is not a lot of cortisol in rodents but corticosterone does get into the brain.
In some regions of the brain you have an enzyme called 11 HSD that can convert metabolites of
active steroids back into the active steroid so the activity of the enzyme on different sites of the brain is
important because you can have an increase of active glucocorticoid through the activity of this enzyme.
4. Corticosterone is bound to CBG and also 11 dehydrocorticosterone binds to eat and they can freely
enter the brain. In some regions of the brain, the presence of this enzyme is important for transforming
11 dehydrocorticosterone into corticosterone.
The MDRpG will prevent corticosterone and dexamethasone from accessing the brain so it will be the
gate keeper.
5. 11-beta HSD is a very important enzyme regulating the in situ concentration of glucocorticoids.
The active steroid which is cortisol in humans and corticosterone in rats and prednisolone that can be
converted into the inert steroids cortisone, 11-dehydrocorticosterone and prednisone. This is achieved
through the opposite enzyme called 11β-HSD2 which is found in many different regions such as the
kidney, salivary gland and placenta.
We are talking about 11β-HSD1 which converts inert steroids into the active steroids and it can be
found in a number of different places such as the liver, adipose tissue, lungs and CNS. You can have
more steroids or local production in specific regions of the brain because of the presence of the enzyme
and its activity. This enzyme is also present in adipose tissue and participates in the metabolic syndrome
so when you have increased levels of glucocorticoids you can produce more locally because of the
increase of the activity of this enzyme.
6. Here we can see some of the studies that have put the importance of the two enzymes on the map in
pathology.
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ANAT 322 Winter 2017
Lectures
There has been a number of genetically modified animals and if we look at 11β-HSD1 transgenic
animals in which there is increase activity of the enzyme in adipose tissue results in increase in adipose
tissue, there is visceral obesity, type 2 diabetes, hypertension, insulin resistance (metabolic syndrome).
If you do a 11β-HSD1 knockout so there is no enzyme activity, you see the opposite phenotype as
there is resistance to diet induced obesity, there is redistribution of peripheral fat, increase in insulin
sensitivity that prevents the development of metabolic syndrome, among others.
If you overexpress 11β-HSD1 specifically in the liver, you start to see a fatty liver, dyslipidemia where
you deposit lipids in places where you are not supposed to such as the heart, muscle or skin.
If you do the reverse by increasing the 11β-HSD2, you see also resistance to diet induced obesity,
increase energy expenditure, and increase insulin sensitivity.
The enzymes can have very critical effects in pathology and the development of metabolic syndrome.
There is both 11β-HSD1 and D2 in the placenta which protects the fetus to elevated exposure to
glucocorticoids.
7. There are several time domains of glucocorticoid action, there are milliseconds time domains and
hours-days’ tie doais. Merae reeptors are i the illiseods tie frae whereas the hours-
days’ tie frae effets are aused y the geoi effets of gluoortioids. Gluoortioids id to
the receptor and there is activation of the receptor and dimerization so that it will then bind to
glucocorticoid responsive elements. Some activated receptors can bind to transcription factors and
either activate them or prevent them from affecting gene expression.
The RNA produced under the control of activated glucocorticoid receptors is transcribed into proteins
that can have different effects within the cell to change the membrane composition or activity of the
cell and itself. It can generate proteins that will bind to G coupled receptors, ion channels, other types of
ionotropic receptors and it can modify a number of parameters even within the cell.
9. Endocannabinoids are molecules that are analogous to THC which is the active component of
marijuana. These are produced in the post-synaptic cell upon stimulation so when a neuron is activated,
it will release glutamate which will stimulate the post-synaptic neuron that will in turn produce
endocannabinoids. These will then be released into the synaptic cleft and go back on the pre-synaptic
axon terminal to bind to CB1 receptors in the brain and the binding of endocannabinoids will reduce the
activity of the glutamate firing.
These are retrograde neurotransmitters because they are produced from lipids present in the
membrane of the post-synaptic cell and will go retrograde and turn off glutamate production in the pre-
synaptic cells.
These CB1 receptors are not only found in glutamate cells but they are also found on GABA cells so
either they turn off the activation or the inhibition of the post-synaptic neuron. Depending on which
type of neuron they are located, you will have the opposite effect.
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Stress and glucocorticoids in the periphery and cns: glucocorticoids are hydrophobic molecules that do not circulate freely in the plasma and are bound to proteins called albumin or corticosteroid binding globulin. These act as carriers and deliver the steroids to the target cells. They do not enter the brain but they deliver the steroid to the brain once the steroids reach the brain as they dissociate from the carrier protein and enter the tissue freely. There are two mechanisms that will regulate the amount of steroids found in particular target sites. One is called the multiple drug resistance protein which is a membrane protein that acts as a barrier. It will prevent the entry into the brain of synthetic glucocorticoids like dexamethasone. Dexamethasone will be excluded from the brain as well as high doses of cortisol so that corticosterone enters freely. There is not a lot of cortisol in rodents but corticosterone does get into the brain.
