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Neurophysiology and Signaling in CNS Diseases
1
...
Voltage-gated ion channels are not directly regulated by a ligand, but
act downstream of a GPCR
...
Electrical signal propagation is called conduction, while chemical signaling between neurons
is known as synaptic transmission
...
Electrical signals travel down the length of the neuron as action potentials, which are
unidirectional signals
...
When a
signal reaches a dead end, it must be converted from an electrical signal to a chemical signal
(i
...
action potential to neurotransmitter)
...

2
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Resting membrane potential is -70mV
...
The degree of
polarization controls conformation of integral membrane proteins and changes the driving force
for ions to go back and forth (open/close channels)
...
Depolarization is excitatory and occurs when positive ions flow into the cell
...

b
...
It opposes
an action potential and neurotransmitter release
...
Neuron Structure: Post-synaptic neurons receive input from multiple pre-synaptic neurons and
depolarization/hyperpolarization decides whether the signal continues
...

a
...

Depolarization results in an action potential
...
Motor neurons receive input from movement
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c
...


4
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a
...


i
...
Sodium
channels open with depolarization and allow sodium ions to flow in
...
Persistent
depolarization eventually blocks ion flow
...
N-type calcium channels at the synapse open with depolarization and
couple an action potential with neurotransmitter release
...

ii
...
By the time the
potassium channels open, depolarization has already occurred and the ion flow
contributes to hyperpolarization
...

b
...

GIRK channels hyperpolarize the neuron by allowing potassium ions to flow out of the cell
...
GIRKs are activated by Gβγ subunits and are inhibited by Gαq
...
Action potential conductance
a
...
These channels quickly close
...
Next, depolarization slowly opens potassium channels
...

c
...

6
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These receptors regulate neurotransmitter release from the pre-synaptic neuron and initiate an
action potential at the post-synaptic neuron
...
Ligand-gated ion channels (ionotropic) are excited by cations and inhibited by anions
...
Cationic (Na+, K+, Ca+) channels are not selective
...

1
...

a
...
Diversity is created when different cells mix-andmatch to make channels with distinct properties
...
Drugs typically activate the GABA receptors
...

2
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Nicotinic Acetylecholine receptor
ii
...
Basic residues allow anions to flow through
...
GABAA Receptors bind primary inhibitory neurotransmitter in brain
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Glycine receptors bind primary inhibitory neurotransmitter in spinal cord
...
GPCRS (metabotropic) inhibit calcium channels, activate potassium channels, and have
indirect second messenger effects
...
All major neurotransmitters bind GPCRS: Histamine, Acetylcholine, dopamine,
serotonin, opioids, noepinephrine, etc
...
Indirect effects on channels and gene expression mediated by second messengers
iii
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Calcium channels responsible for neurotransmitter release
2
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Gαi  βγ  inhibition of presynaptic voltage gates calcium channels  presynaptic inhibition

v
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Gαs  activation of presynaptic voltage-gated calcium channels  pre-synaptic
activation
vii
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Receptor regulation of membrane polarization
a
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Ligand-gated cation channel opening
ii
...
Post-Synaptic Inhibition: hyperpolarization (IPSP)
i
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GIRK potassium channel opening
c
...
Hyperpolarization
ii
...
Source of pre-synaptic inhibition mediators? Axoaxonic
...

8
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Sodium ions have come in and there is a traveling
depolarization
...
Calcium comes in to release vesicles
...
This is
very fast and calcium dependent
...

Presynaptic neuron releases glutamate and postsynaptic neuron is expressing a glutamate
channel
...

Postsynaptic neuron might be receiving a lot of signals
...
Here, the chemical signal is turned back into an
electrical signal
...
Can amplify or counteract
...
GPCRs can also be expressed postsynaptically
...
This opposes
depolarization of postsynaptic neuron
...
Multiple neurons are integrated intro circuits

a
...
Classes of Neurotransmitters
a
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Amino Acids: neutral amino acids (GABA, glycine), glutamate/glutamic acid
c
...
Drug targets in CNS disease: Presynaptic neuron, neurotransmitter synthesis, storage, metabolism,
release, uptake, and degradation, post-synaptic receptor, ionic conductance, etc
...
Drug Goals
a
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Pain: μOR agonists
c
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Pathogenesis of Depression
a
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Reserpine can chemically induce depression
...

b
...
Depressed
patients have a loss of volume in hippocampus and dendritic sprouting
...
Antidepressants and electroconvulsive treatment boost BDNF
...
Neuroendocrine regulation: Hypothalamic-pituitary-adrenal (HPA) axis of hormone
signaling impacts depression
...
Glucocorticoids, hypothyroidism, and estrogen
deficiency cause subtypes of depression
...

3
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These drugs can
block uptake, inhibit metabolism, or block receptor activation of serotonin and norepinephrine
...
SSRIs, SNRIs, TCAs, 5-HT2 antagonists, tetracyclics, MAOIs, ECT

b
...
Selective Serotonin Reuptake Inhibitors (SSRIs)
a
...
These make up the most commonly used anti-depressants and are also used to
treat anxiety, PTSD, OCD, panic disorder, PMDD, and bulimia
...
Examples: Fluoxetine, paroxetine, sertraline, fluvoxamine, (s)-citalopram

5
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SNRIs block both SERT and NET transporters, but lack the receptor blocking activity of TCAs
...
SNRIs are used to treat depression, neuropathic pain, fibromyalgia, anxiety, and stressincontinence
...
Examples: Venlafaxine, desvenlafaxine, duloxetine, milnacipran
6
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Tricyclic antidepressants are mixed serotonin and norepinephrine transporter inhibitors
...
There are major side-effects, so it is used as a
back-up for non-responsive patients
...
Examples: Imipramine, Desipramine, Clomipramine, Trimipramine, Amitriptyline,
Nortryptiline, Doxepin, Protryptyline
7
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5-HT1 causes neuronal inhibition
...
5-HT2 causes slow excitation, 5-HT2 inhibition may enhance 5-HT1 response
c
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Effectives for major depression and anxiety
e
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Other Drugs
a
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Maprotyline: Norepinephrine-selective transporter
ii
...
D2 receptor antagonist
b
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Mirtazapine: α-2 adrenergic antagonist, 5-HT2 antagonist, H1 antagonist
ii
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Some NET/DAT blocking activity
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No serotonin effects
...
Monoamine Oxidase Inhibitors
a
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Used to treat
depression, anxiety and panic
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MAO-A hydrolyzes norepinephrine, epinephrine, and serotonin
...

c
...

d
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Clinical Uses of Anti-Depressants: depression, anxiety disorders, pain disorders, PMDD, smoking
cessation, eating disorders
11
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Longer-lasting, diffuse effects, termination mechanisms unknown
b
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Opioids are diverse short peptides derived from long precursors and bind to Gi-coupled
metabotropic receptors (μ, δ, κ)
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Function to alleviate stress and pain
ii
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Endogenous opioids inhibit neurotransmitter release and inhibit activation of spinal
nociceptive neurons
...


i
...

1
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Opioid receptors (μ, δ, κ) are expressed on primary afferents (sensory neurons to spinal
cord) and nociceptive neurons (pain neurons in spinal cord)
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μ receptors are expressed on spinal
nociceptive neurons and peripheral terminals of sensory neurons
...
Sites of action include spinal cord, supraspinal, and peripheral terminals (postsynaptic mechanisms only)
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In general, the presynaptic neuron senses pain in the finger and dumps glutamate
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Opioids control strength of response
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iii
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iv
...

f
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Direct inhibition in ascending pathway

ii
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Indirect Inhibition in descending pathway

iv
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Receptors detect pain and causes depolarization of the primary afferent
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This releases the
breaks on the pain inhibitory neuron, which inhibits the GABAergic neuron
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Analgesic sites of action against μ opioid receptor agonists
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g
...
δ and κ receptors play lesser
role
...
Activation of μOR stimulates release of endogenous opioids that
activate all three opioid types
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Schizophrenia pathogenesis
a
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Antipsychotic drugs block dopamine receptors
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Patients have high DR-expression post-mortem
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Excessive serotonin signaling
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LSD/mescaline activate 5HTRs cause psychosis-like symptoms
...

c
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NMDA receptor antagonists induce ‘schizophrenia-like
symptoms
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13
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Dopamine receptor families: D1-like, Gs coupled (D1, D5)
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Antipsychotics and dopamine

a
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In the
1960s, antipsychotics were classified as dopamine antagonists
...

15
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Mesolimbic-mesocortical pathway (substantia nigra -> limbic system cortex)
b
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Tuberoinfundibular system (periventricular -> hypothalamus & pituitary
d
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Incertohypothalamic pathway
16
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Gaps in dopamine hypothesis: neural mechanisms not define, simple antagonist doesn’t
explain duration of effects, newer and more effective anti-psychotics are not potent D2R
antagonists, and there
b
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Pharmacologic effects of antipsychotics
a
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Neurophysiologic effects: slowing/synchronization of EEG
c
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Parkinsonism
e

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